tbuckley/cabot-search huggingface dataset:
Abstract LB-090: p53 binding sites in normal and cancer-derived cells are characterized by distinct chromatin context
Authors: Feng Cui
Journal: Cancer Research (2017)

Abstract The tumor suppressor protein p53 interacts with DNA in a sequence-dependent manner. Thousands of p53 binding sites have been mapped genome-wide in normal and cancer-derived cells. The way p53 selectively binds its cognate sites in different types of cells is not fully understood, however. We performed a comprehensive analysis of published p53 cistromes and identified 3,551 and 6,039 high-confidence normal and cancer binding sites that are enriched in genes involved in p53 signaling pathways. About 12% of these sites occur in the endogenous retrovirus 1 (ERV1) repeat family in the human genome. We further analyzed chromatin organization at the p53 binding sites in normal (GM12878) and cancer (K562) cells, and found that these sites are characterized by a high nucleosome occupancy and at the same time, by a high sensitivity to DNase I. Strikingly, compared to the sites derived from cancer cells, the p53 binding sites from normal cells are characterized by higher levels of transcriptionally active histone marks (H3K4me3 and H3K36me3) and DNA methylation. No difference was observed for the repressive histone marks (H3K27me3). These findings reveal two distinct epigenetic patterns associated with p53-DNA binding in normal and cancer-derived cells. Citation Format: Feng Cui. p53 binding sites in normal and cancer-derived cells are characterized by distinct chromatin context [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-090. doi:10.1158/1538-7445.AM2017-LB-090
Abstract 1478: Curcumin inhibits epithelial-mesenchymal transition and invasion in breast cancer cells by controlling miR-34a expression
Authors: Marcela Gallardo, Richard Ponce-Cusi, Gloria M. Calaf
Journal: Cancer Research (2017)

Abstract Breast cancer in advanced stages tends to develop metastases and / or chemoresistance, in both cases therapeutic options are limited and have low probability of success, which represents the biggest obstacle in reducing mortality from this disease. There is a close connection between the Epithelial-Mesenchymal Transition (EMT) process of cancer cells and the acquisition of invasive and metastatic ability. Numerous EMT mediators have been described in cancer and among them miRNAs play a fundamental role in regulating such process, suggesting that it could be a therapeutic target to address this phenotype. Curcumin (diferuloylmethane) is a derivative compound of Curcuma longa that has therapeutic properties in various cancers as blocking initiation and tumor progression through its anti-inflammatory, antioxidant, proapoptotic, antiangiogenic and antimetastatic effects. The role of curcumin on EMT in non-cancerous breast cells MCF-10F and in breast cancer cell lines MCF-7 and MDA-MB-231 was evaluated. This work shows that in all these cell lines curcumin induced the expression of tumor suppressor microRNA miR-34a and repressed the expression of several genes involved in EMT and metastasis as Axl, Slug, Twist, N-cadherin, vimentin, fibronectin, among others. Consequently, curcumin inhibited the migration and invasiveness in these cells, irrespective of the expression of estrogen and progesterone receptors and p53 mutational status. Blockade of miR-34a by transfection with antagomiR-34a inhibited the effect of curcumin on EMT genes and on the migratory/invasive potential of cells indicating that miR-34a plays a central role in the Curcumin-mediated suppression of EMT and invasion. Therefore, results confirm the suppressive effect of curcumin on EMT and invasion in breast cancer cells, showing that such substance exerts this effect by inducing expression of miRNA miR-34a and consequently the repression of several of its target genes. Supported by Tarapacá University, Arica, Chile (GMC). Citation Format: Marcela Gallardo, Richard Ponce-Cusi, Gloria M. Calaf. Curcumin inhibits epithelial-mesenchymal transition and invasion in breast cancer cells by controlling miR-34a expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1478. doi:10.1158/1538-7445.AM2017-1478
Are Genotoxic Carcinogens More Potent Than Nongenotoxic Carcinogens?
Authors: Silvio Parodi, Davide Malacarne, Paolo Romano, Maurizio Taningher
Journal: Environmental Health Perspectives (1991)

In this report we have raised the question whether genotoxic carcinogens are more potent than nongenotoxic carcinogens when studied in long-term carcinogenicity assays in rodents. To build a large database of compounds for which both carcinogenicity and genotoxicity had been investigated, we have used a database produced by Gold and co-workers for carcinogenic potency data (975 chemicals) and a database produced by Würgler for genotoxicity data (2834 chemicals). Considering compounds positive or negative in at least three short-term tests and in at least 75% of available tests, we could define 67 genotoxic carcinogens and 46 nongenotoxic carcinogens. Carcinogenic potency of genotoxic carcinogens was about 50 times higher than carcinogenic potency of nongenotoxic carcinogens. Our results are different from the results of Tennant et al.; their database (24 genotoxic carcinogens and 12 nongenotoxic carcinogens compatible with our definition) seems to suggest that there is practically no difference in potency between genotoxic and nongenotoxic carcinogens. The two databases have only four compounds in common and are also different in terms of number of elements for different chemical classes. Nitrosocompounds, nitrogen mustards, hydrazine derivatives, and polycyclic aromatic hydrocarbons are not represented in the database of Tennant. The overall impression from our analysis is that the usefulness of short-term tests of genotoxicity could be significantly better than what has been suggested by the previous work of Tennant et al. because these tests tend to detect, at least for many important chemical classes, the most potent carcinogens. This consideration may not be valid for certain classes of chemicals.
Abstract LB-045: Cogency of AR-V7 unexpected responders determined by using distinct detection technologies
Authors: Christof Bernemann, Verena Humberg, Martin Bögemann, Andres J. Schrader, Julie Steinestel, Jochen K. Lennerz
Journal: Cancer Research (2017)

Abstract Background: The validity of AR-V7 in CTC’s as a predictive marker for non-response to next generation ADT (abiraterone or enzalutamide) has recently been questioned. Specifically, a subset of AR-V7 positive patients showed responses to abiraterone or enzalutamide and assay performance differences could contribute to these unexpected findings. [[Unsupported Character - Codename &amp;shy;]]To our knowledge a direct performance comparison has not been performed. Here we present comparative head to head analysis of different AR-V7 detection technologies with respect to specificity, accuracy and clinical sensitivity. Methods: We performed comparison of two different AR-V7 detection technologies using either SYBR Green or TaqMan chemistry. Both assays were tested on identical in vitro samples consisting of genitourinary cancer cell lines as well as dilution series of AR-V7 positive cDNA samples. Finally, clinical samples with previously determined CTC and AR-V7 status using TaqMan chemistry were re-analyzed using SYBR Green chemistry. Results: Both assays performed identical in detection of AR-V7 in different genitourinary cancer cell lines. Additionally, by performing dilution series analyses we observed the same diagnostic threshold of both assays. When re-analysis of clinical samples was performed, both assays performed undistinguishable in determination of the AR-V7 status of mCRPC patients, including 3 patients exhibiting unexpected response to NHT despite AR-V7 positive CTCs. Finally, loss of AR-V7 positive CTCs in serial CTC analysis of one patient during abiraterone treatment was observed using both detection assays. Conclusion: By demonstrating nearly identical performance metrics, we excluded assay design differences as an underlying reason for the unexpected responses in a subset of AR-V7 patients. Interestingly, for the first time, we detected an AR-V7 positive mCRPC patient displaying a loss of AR-V7 positive CTCs during NHT therapy. These findings underscore that - irrespective of the method used - AR-V7 positive patients should not systematically be precluded from an otherwise safe treatment attempt. Citation Format: Christof Bernemann, Verena Humberg, Martin Bögemann, Andres J. Schrader, Julie Steinestel, Jochen K. Lennerz. Cogency of AR-V7 unexpected responders determined by using distinct detection technologies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-045. doi:10.1158/1538-7445.AM2017-LB-045
The Benefit of Early Preventive Dental Care for Children
Authors: Oscar Arevalo, Rosie Roldan
Journal: JAMA Pediatrics (2017)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Pediatrics HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Pediatrics journal
Abstract 590: A new standardized CD8 and PD-L1 dual assay
Authors: Florence Monville, Emmanuel Prestat, Nadia Yessaad, Marine Villard, Luciana Batista, Jerome Galon, Julien Adam, Jacques Fieschi
Journal: Cancer Research (2017)

Abstract PD1/PD-L1 pathway blockade results in a durable clinical response in a fraction of the non-small cell lung cancer (NSCLC) patients. Today, the expression of PD-L1, detected by immunohistochemistry (IHC) at the surface of tumor or tumor-infiltrating immune cells, is used to select patients that may respond to immune checkpoint inhibitors (ICI). However the predictive value of that biomarker alone is questioned. In order to better stratify NSCLC patients, we have developed a new dual-staining IHC assay of PD-L1+ and CD8+ cells (TILs) present in the tumor microenvironment on a single slide prepared from FFPE tissue. The assay was optimized and fully automated on the Benchmark XT platform (Roche Ventana) with anti-PD-L1 (HDX3) and anti-CD8 (HDX2) monoclonal primary antibodies, respectively revealed with DAB and fast red substrates. Stained slides are analyzed by a pathologist like any other existing IVD test together with the TILs information. In addition, after digitization, the samples are analyzed to quantify brown and red cells with a newly developed digital Pathology (DP) tool. The following parameters are reported by the DP tool: (1) CD8+ cell density (cells/mm²) ; (2) PD-L1+ cell density (cells/mm²) ; proximity between CD8+ and PD-L1+ cells, either centered on CD8+ or on PD-L1+ cells and finally cluster indexes for CD8+ cells and PD-L1+ cells. HalioDx DP analysis tool can calculate these parameters on any Regions Of Interest (ROI) defined by the user. Accuracy of the automated numeration of CD8+ and PD-L1+ cells was validated by an expert pathologist. Cell-to-cell distances were validated with an independent DP tool. Variability was assessed for all parameters using adjacent dual-stained slides on complete tissue sections. The concordance with main IVD approved PD-L1 methods was established on a representative set of 55 NSCLC tumours. HalioDx has developed an innovative assay based on the dual staining of CD8+ and PD-L1+ cells associated to a DP tool to standardize the evaluation of the tumor microenvironment. This assay could have higher predictive performance than existing IVD tests used to identify ICI resistant NSCLC patients. Citation Format: Florence Monville, Emmanuel Prestat, Nadia Yessaad, Marine Villard, Luciana Batista, Jerome Galon, Julien Adam, Jacques Fieschi. A new standardized CD8 and PD-L1 dual assay [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 590. doi:10.1158/1538-7445.AM2017-590
Safety and Efficacy of Remote Ischemic Preconditioning in Patients With Severe Carotid Artery Stenosis Before Carotid Artery Stenting
Authors: Wenbo Zhao, Ran Meng, Chun Ma, Baojun Hou, Liqun Jiao, Fengshui Zhu, Weijuan Wu, Jingfei Shi, Yunxia Duan, Renling Zhang, Jing Zhang, Yongxin Sun, Hongqi Zhang, Feng Ling, Yuping Wang, Wuwei Feng, Yuchuan Ding, Bruce Ovbiagele, Xunming Ji
Journal: Circulation (2017)

Remote ischemic preconditioning (RIPC) can inhibit recurrent ischemic events effectively in patients with acute or chronic cerebral ischemia. However, it is still unclear whether RIPC can impede ischemic injury after carotid artery stenting (CAS) in patients with severe carotid artery stenosis.Subjects with severe carotid artery stenosis were recruited in this randomized controlled study, and assigned to RIPC, sham, and no intervention (control) groups. All subjects received standard medical therapy. Subjects in the RIPC and sham groups underwent RIPC and sham RIPC twice daily, respectively, for 2 weeks before CAS. Plasma neuron-specific enolase and S-100B were used to evaluate safety, hypersensitive C-reactive protein, and new ischemic diffusion-weighted imaging lesions were used to determine treatment efficacy. The primary outcomes were the presence of ≥1 newly ischemic brain lesions on diffusion-weighted imaging within 48 hours after stenting and clinical events within 6 months after stenting.We randomly assigned 189 subjects in this study (63 subjects in each group). Both RIPC and sham RIPC procedures were well tolerated and completed with high compliance (98.41% and 95.24%, respectively). Neither plasma neuron-specific enolase levels nor S-100B levels changed significantly before and after treatment. No severe adverse event was attributed to RIPC and sham RIPC procedures. The incidence of new diffusion-weighted imaging lesions in the RIPC group (15.87%) was significantly lower than in the sham group (36.51%; relative risk, 0.44; 96% confidence interval, 0.20-0.91; P<0.01) and the control group (41.27%; relative risk, 0.39; 96% confidence interval, 0.21-0.82; P<0.01). The volumes of lesions were smaller in the RIPC group than in the control and sham groups (P<0.01 each). Ischemic events that occurred after CAS were 1 transient ischemic attack in the RIPC group, 2 strokes in the control group, and 2 strokes and 1 transient ischemic attack in the sham group, but these results were not significantly different among the 3 groups (P=0.597).RIPC is safe in patients undergoing CAS, which may be able to decrease ischemic brain injury secondary to CAS. However, the mechanisms and effects of RIPC on clinical outcomes in this cohort of patients need further investigation.URL: http://www.clinicaltrials.gov. Unique identifier: NCT01654666.
Abstract 1558: Data-driven approach to detecting novel gene interactions in cancer with applications to drug response prediction and cancer stratification
Authors: Assaf Magen, Avinash Das, Joo Lee, Sridhar Hannenhalli, Eytan Ruppin
Journal: Cancer Research (2017)

Abstract The effect of a gene’s activity on a phenotype depends on the context of a complex network of functionally interacting genes. Several genetic interactions (GIs), such as Synthetic lethality and Synthetic Rescues, have been reported to have a significant functional role in cancer progression and provide potential candidates for selective cancer treatments. However, numerous other types of GIs with potential clinical significance are yet to be explored. In this work we generalize the concept of GI and detect ~70,000 GIs of different types with both molecular and clinical signature. We demonstrate their clinical predictive value as well as their ability to stratify breast cancer patients into refined clinical subtypes that might allow for better diagnosis and modified course of treatment. These results compare favorably with previous sequence based approaches and provide evidence for the importance of context specific genomic events and their effect on tumor progression. Additionally, the GI network accurately predicts patients’ drug response, where difference GI types are found to be predictive of distinct drugs in a complementary manner. This work provides the basis for future exploration of novel GI types as well as individual interactions with major impact on cancer progression. Citation Format: Assaf Magen, Avinash Das, Joo Lee, Sridhar Hannenhalli, Eytan Ruppin. Data-driven approach to detecting novel gene interactions in cancer with applications to drug response prediction and cancer stratification [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1558. doi:10.1158/1538-7445.AM2017-1558
Abstract 1809: PKM2 promotes tumor angiogenesis by regulating HIF-1alpha through NF-kappaB activation
Authors: Ninel Azoitei, Alexander Becher, Konrad Steinestel, Arefeh Rouhi, Kristina Diepold, Susanne Bobrovich, Thomas Seufferlein
Journal: Cancer Research (2017)

Abstract Initially identified as a molecule that catalyzes the phosphorylation from phosphoenolpyruvate to pyruvate in the final step of glycolysis, the M2 isoform of pyruvate kinase (PKM2) was recently reported to have a central role in the metabolic reprogramming of cancer cells as well as participating in the regulation of apoptosis and proliferation. In this study, we have identified PKM2 as a crucial molecule for progression of pancreatic cancer in which tumor microenvironment has been reported to be highly hypoxic. Our data show moderate to strong PKM2 expression in all examined human pancreatic adenocarcinoma samples. Depletion of PKM2 was associated with impaired proliferation and augmented tumor cell death in vitro, while the in vivo tumor xenograft experiments revealed a close association between impaired tumor growth and decreased blood vessel formation. Furthermore, abrogation of PKM2 prevented hypoxia-mediated HIF-1alpha accumulation and HIF-1alpha promoter activity, which negatively impacted VEGF secretion by pancreatic cancer cells deprived of oxygen. Interestingly, PKM2 expression arrest was also mirrored by impaired hypoxia-driven promoter activity of NF-kappaB which also drives the transcription of VEGF. Ectopic expression of p65 restored VEGF transcription after PKM2 ablation inferring that the kinase regulates VEGF via NF-kappaB/p65 subunit. Altogether, our study suggests that in hypoxic pancreatic tumors PKM2 interferes both with NF-kappaB/p65 and HIF-1alpha activation that ultimately triggers VEGF-A secretion and subsequent blood vessel formation. Citation Format: Ninel Azoitei, Alexander Becher, Konrad Steinestel, Arefeh Rouhi, Kristina Diepold, Susanne Bobrovich, Thomas Seufferlein. PKM2 promotes tumor angiogenesis by regulating HIF-1alpha through NF-kappaB activation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1809. doi:10.1158/1538-7445.AM2017-1809
Nano-based delivery of RNAi in cancer therapy
Authors: Yong Xin, Min Huang, Wen Wen Guo, Qian Huang, Long zhen Zhang, Guan Jiang
Journal: Molecular Cancer (2017)

RNA interference (RNAi), a newly developed method in which RNA molecules inhibit gene expression, has recently received considerable research attention. In the development of RNAi-based therapies, nanoparticles, which have distinctive size effects along with facile modification strategies and are capable of mediating effective RNAi with targeting potential, are attracting extensive interest.This review presents an overview of the mechanisms of RNAi molecules in gene therapy and the different nanoparticles used to deliver RNAi molecules; briefly describes the current uses of RNAi in cancer therapy along with the nano-based delivery of RNA molecules in previous studies; and highlights some other carriers that have been applied in clinical settings. Finally, we discuss the nano-based delivery of RNAi therapeutics in preclinical development, including the current status and limitations of anti-cancer treatment.With the growing number of RNAi therapeutics entering the clinical phase, various nanocarriers are expected to play important roles in the delivery of RNAi molecules for cancer therapeutics.
Abstract P280: Deletion of Cardiac Ankyrin Repeat Kinase Reduces Ischemia/Reperfusion Injury in the Heart in Vivo
Authors: Ronald J Vagnozzi, Gregory Gatto, Lara Kallander, Victoria Ballard, Brian Lawhorn, Patrick Stoy, Erhe Gao, Thomas Force
Journal: Circulation Research (2011)

Ischemic heart disease impacts millions of Americans and can progress to heart failure. Current therapies do not address this progression and new therapeutic targets are needed. One novel potential target is cardiac ankyrin repeat kinase (CARK, also troponin I interacting kinase; TNNI3K). CARK is expressed only in the heart and is significantly up-regulated in failing human hearts. Beyond this, little is known about CARK’s biological roles. To determine CARK’s function in the injured heart we subjected transgenic (Tg) mice expressing wild-type or kinase-inactive (KI) CARK to 30 minutes of LV ischemia followed by 24 hours of reperfusion (I/R). CARK-Tg mice had significantly larger infarcts (32.2% AAR vs 16.1% in WT littermates, p&lt;0.05) following I/R. Cardiac troponin I (cTnI) serum levels were also significantly elevated in CARK-Tg mice after 24h, consistent with increased injury. Conversely, infarct size was decreased in mice expressing KI CARK and levels of cTnI were reduced, suggesting that blocking CARK activity may protect against acute injury. To test this, we employed an inducible, cardiac-specific knockout mouse (CARK-KO). CARK-KO mice showed a significant reduction in infarct size (20.52% vs 32.9%, p=0.01) as well as cTnI levels post-I/R. To confirm these findings, wild-type mice were treated with a small molecule CARK inhibitor and then were subjected to I/R. CARK inhibition significantly reduced infarct size (10.92% vs 21.74% p&lt;0.01) as well as serum levels of cTnI. These data indicate that loss of CARK reduces myocyte injury and death after I/R. To examine the mechanism of this effect, primary NRVM were either transduced with a CARK adenovirus or treated with one of two selective CARK inhibitors, and then subjected to oxidative stress using H2O2. CARK over-expression worsened, while CARK inhibition significantly blunted H2O2 - induced apoptosis. Taken together, these data suggest that CARK plays an adverse role in the heart’s response to ischemia, in part by increasing apoptosis. Furthermore, inhibition of CARK may protect the ischemic heart by limiting initial cell loss and thus reducing infarct size. These findings enhance understanding of CARK’s role in the heart and provide evidence for CARK as a novel therapeutic target for ischemic injury.