tbuckley/cabot-search huggingface dataset:
Abstract 2375: Multiclonal invasion in breast cancer identified by single cell DNA sequencing
Authors: Anna K. Casasent, Annalyssa N. Long, Aislyn Schalck, Emi Sei, Ruli Gao, Alexander Davis, Yong Wang, Mary E. Edgerton, Nicholas E. Navin
Journal: Cancer Research (2016)

Abstract Ductal carcinoma in situ (DCIS) is the most common form of early stage breast cancer and is frequently detected by mammography. Only 10% of low-grade and 30% of high-grade DCIS patients will later present with an invasive carcinoma, making it difficult to determine which patients to treat aggressively. Although DCIS is often considered a precursor to invasive breast carcinoma, a major question in the field is whether invasive subpopulations evolve directly from the in situ populations or independently. We hypothesize that early tumor cells evolve over an extended period of time in the ducts, generating multiple subpopulations that migrate out of the ducts together. To test this hypothesis, we developed an approach that combines laser-capture microdissection (LCM) with single cell sequencing to perform DNA copy number profiling while preserving the topographic location of cells. We applied this method to 10 high-grade breast cancer patients with defined in situ, invasive, and normal regions. Using these data, we delineated the clonal substructure and location of the in situ and invasive subpopulations. We found that most high-grade tumors are composed of 1-4 major clonal subpopulations that are intermixed in both the in situ and invasive regions. These subpopulations share a common evolutionary lineage or cell of origin. We also performed deep-exome sequencing (100X) of matched microdissected regions of in situ, invasive and adjacent normal tissue from these breast cancer patients. In each tumor we identified a large number of shared somatic mutations between the in situ and invasive regions, further supporting our direct genomic lineage hypothesis. We also identified a few mutations confined to the invasive tumor regions that may play an important role in the invasive phenotype. These data support a multiclonal invasion model in which distinct clones evolve in the ducts and subsequently migrate into the adjacent tissues to establish invasive tumors. This model has important implications for the diagnosis and therapeutic treatment of DCIS breast cancer patients since multiple clones may need to be targeted to inhibit invasion. Citation Format: Anna K. Casasent, Annalyssa N. Long, Aislyn Schalck, Emi Sei, Ruli Gao, Alexander Davis, Yong Wang, Mary E. Edgerton, Nicholas E. Navin. Multiclonal invasion in breast cancer identified by single cell DNA sequencing. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2375.
Abstract 3785: Targeting PDLIM5 for lung cancer
Authors: Deborah Park, Han Cheng, Tianji Chen, Merve Tor, Nour Khatib, Jason Huang, Qiyuan Zhou, Lijun Rong, Guofei Zhou
Journal: Cancer Research (2016)

Abstract Rationale: Lung cancer is the most common cause of cancer-related death in the United States and worldwide. Despite decades of efforts on research and smoking cessation, the 5-year survival rate of lung cancer patients remains poor at 15%, and the population of adenocarcinoma cases in nonsmokers is rising. PDLIM5, a member of the Enigma subfamily of PDZ and LIM domain protein family, contains an N-terminal PDZ domain and 3 LIM domains at its C-terminus. We have previously shown that PDLIM5 regulates TGF-β/Smad family, which are known to participate in the pathogenesis of lung cancer. In this study, we aim to investigate whether PDLIM5 plays a role in lung cancer and establish a high throughput screening (HTS) platform for PDLIM5-targeted drug discovery. Methods: We searched the Oncomine data base for PDLIM5 gene expression. We suppressed PDLIM5 in A549 cells and determined the expression levels of epithelial-mesenchymal transition markers. We exposed A549 cells to hypoxia or treated them with TGF-β1 and measured the expression levels of PDLIM5. We generated a stable mink lung epithelial cell line (MLEC) containing a TGFβ/Smad luciferase reporter with lentivirus-mediated suppression of PDLIM5 (MLEC-shPDLIM5) and measured levels of Smad2/3 and pSmad2/3. We used MLEC-shPDLIM5 and a control cell line (MLEC-shCTL) to screen the Prestwick library (1,200 compounds). We treated MLEC and A549 cells with paclitaxel and determined levels of Smad2/3 and pSmad2/3. Results: We found that PDLIM5 was overexpressed in non-small-cell lung carcinoma (NSCLC) patients and that the expression levels of PDLIM5 inversely correlated with the survival rate of lung cancer patients. Hypoxia but not TGF-β1 induced PDLIM5 expression levels. Suppression of PDLIM5 induced E-cadherin levels while decreased levels of vimentin and α-SMA. In MLEC, suppression of PDLIM5 decreased Smad-dependent luciferase activity, smad3, and pSmad2. More importantly, we identified and validated that paclitaxel as a PDLIM5 inhibitor in MLEC. Furthermore, we showed that paclitaxel inhibited Smad2 expression and Smad3 phosphorylation in A549 cells. Conclusions: We have shown that PDLIM5 is overexpressed in lung cancer cells and its upregulation is hypoxia-dependent but TGF-β independent. Loss of PDLIM5 inhibits EMT. We have identified paclitaxel as a PDLIM5 inhibitor. This system is robust and suitable for PDLIM5 targeted drug discovery. Support: a UIC UICentre Arm1 Inception Grant, a Gilead Sciences Research Scholars Program in Pulmonary Arterial Hypertension award and R01 HL123804 (G. Zhou). Citation Format: Deborah Park, Han Cheng, Tianji Chen, Merve Tor, Nour Khatib, Jason Huang, Qiyuan Zhou, Lijun Rong, Guofei Zhou. Targeting PDLIM5 for lung cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3785.
Uncontrolled Hypertension and Risk of Cardiovascular Mortality in China—Reply
Authors: Sarah Lewington, Ben Lacey, Robert Clarke
Journal: JAMA Internal Medicine (2016)

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Surveillance de la résistance aux antituberculeux en Europe, 1999
Authors: A Infuso, D Antoine, P Barboza, D Falzon
Journal: Eurosurveillance (2002)

A l'exception d'Israel, les donnees representatives sur l'Europe de l'Ouest et centrale indiquent de faibles taux de resistance a l'isoniazide (0-9%), a la rifampicine (0-2,1%) et`de de MDR (0-2,1%) parmi les nouveaux cas de tuberculos
Results of Phase I Study of Chimeric Fibril-Reactive Monoclonal Antibody 11-1F4 in Patients with AL Amyloidosis
Authors: Arielle L Langer, Susanna Miao, Markus Mapara, Jai Radhakrishnan, Mathew S. Maurer, Shahzad Raza, John G. Mears, Alan Solomon, Suzanne Lentzsch
Journal: Blood (2015)
A Phase 2 Study Of Single-Agent Brentuximab Vedotin For Front-Line Therapy Of Hodgkin Lymphoma In Patients Age 60 Years and Above: Interim Results
Authors: Christopher A. Yasenchak, Robert Chen, Jeff P. Sharman, Ralph V. Boccia, Beata Holkova, Peter J. Rosen, Jonathan W. Friedberg, Megan M. O'Meara, Andres Forero-Torres
Journal: Blood (2013)
Evidence for a shared genetic determination of Ischemic Stroke And Coronary Artery Disease - a genome-wide analysis
Authors: M Dichgans, R Malik, I R Koenig, J Rosand, R Clarke, S Gretarsdottir, B D Mitchell, J Erdmann, S Kathiresan, R McPherson, C Sudlow, M P Reilly, Thompson, P Sharma, J C Chambers, H Watkins, P M Rothwell, R Roberts, H S Markus, N J Samani, M Farrall, H Schunkert
Journal: Circulation Research (2013)
Endostar plus gemcitabine/cisplatin (GP) with maintenance endostar as first-line therapy for advanced non-small cell lung cancer (NSCLC): Preliminary results of a phase II study.
Authors: You Lu, Meijuan Huang, Qingxia Fan, Qi Wu, Jin Wang, Lu Li, Xi Zhang, Chengye Guo, Wenhui Li, Feng Peng, Xuenong Ouyang, Ding Yu, Xiaohong Cai, Yong Xu, Mei Hou, Rongcheng Luo, Tao Zhang
Journal: Journal of Clinical Oncology (2012)

e18033 Background: Endostar is a recombinant human endostatin. We conducted a multi-centre trial to investigate the efficacy and safety of Endostar plus GP with maintenance Endostar as first- line therapy for advanced NSCLC Methods: Chemotherapy-naïve patients with histologically or cytologically confirmed, measurable, stage ‡W NSCLC were enrolled from 11 centers in China. All patients received gemcitabine 1,000 mg/m2 (days 1 and 8) plus cisplatin 25 mg/m2 (days 1-3) every 21 days. Patients achieving objective response or disease stabilization following initial 2 cycles of GP were given Endostar (15 mg) on days 1–14 every 21 days in combination with another 2 cycles of GP. Then, patients who did not progress received maintenance endostar (15 mg) on days 1–14 every 21 days until disease progression or unacceptable toxicity. The primary was progression-free survival (PFS). Secondary endpoints were treatment-related toxicity and median overall survival (OS). Results: Between Oct.2008 and Sep. 2010, we enrolled 85 patients (median age: 52.2 years; median KPS score: 80; stage IV with M1b: 94.1%; adenocarcinoma: 64.6%). 48 (56.5%) patients complete 4 cycles of GP plus 2 cycles of Endostar and 33(38.8%) patients were treated with maintenance Endostar. For 38 patients receiving maintenance therapy, median PFS throughout the study period by independent review was 5.97 month and 1-year survival rate was 75.8%. Median PFS were 3.97 months for all 85 patients, while 1-year survival rate was 64.7%. No treatment related death occurred. 28(32.9%) patients had at least one grade 3/4 adverse events; the grade 3/4 hematologic toxicity included anemia in 32.9%, thrombocytopenia in 25.9%, neutropenia in 4.7% of patients. The grade 3/4 non-hematologic toxicities included nausea/vomiting in 18.8%, rash in 5.9%, hepatic impairment in 3.5%, diarrhea in 1.2%, hemorrhage in 1.2% of patients. Conclusions: This regimen, involving maintenance Endostar, didn’t significantly improve PFS in advanced NSCLC patients as compared to historic control although associated acceptable toxicity has been demonstrated
Abstract 2730: Association of <i>TERT</i> promoter mutations with telomerase expression in melanoma
Authors: Seungjae Lee, Patricia Opresko, Alberto Pappo, John Kirkwood, Armita Bahrami
Journal: Cancer Research (2016)

Abstract Telomerase reverse transcriptase (TERT) promoter mutations occur at a high frequency in melanoma, but the functional consequences of these mutations in melanoma remain to be clarified. In a large study of melanoma samples by The Cancer Genome Atlas network, mRNA expression analysis using RNA sequencing data showed that only TERT promoter mutations at C228T were associated with high TERT expression levels. The effect of hotspot C250 or C242T/C243T tandem mutations on telomerase expression has not yet been determined. To assess telomerase expression levels in melanomas harboring C250 or C242T/C243T mutations, we used real-time quantitative reverse transcriptase polymerase chain reaction (RT-qPCR) in a sample set of pediatric melanocytic tumors for which the methylation status and the mutational profile of the TERT promoter were known. We previously showed that in a subset of melanoma, TERT expression is mediated epigenetically by promoter hypermethylation rather than by promoter point mutations. Formalin-fixed paraffin-embedded (FFPE) tissues from 10 metastatic melanomas, of which 8 harbored a hotspot TERT promoter mutation (5 C250T; 2 C228; 1 C242T/C243T) and 2 carried a hypermethylated wild-type TERT promoter were examined. For controls, 9 atypical Spitz tumors with a wild-type unmethylated TERT promoter were also studied. Total RNA was isolated from FFPE tumor tissues and converted to cDNA. TERT expression levels were determined by RT-qPCR by using the TaqMan® Gene Expression Assay and normalized with GAPDH as the endogenous control. In the atypical Spitz tumor samples, TERT mRNA expression was undetectable or negligible. In contrast, TERT expression in all melanoma samples was elevated, ranging from 3- to 71-fold (median, 25-fold) when compared to an atypical Spitz tumor as a reference. Our data support that in melanoma, TERT promoter hotspot C250 and C242T/C243T mutations, similar to C228T mutations, correlate with TERT overexpression and that C250 and C242T/C243T mutations likely contribute biologically to tumorigenesis in melanoma. Citation Format: Seungjae Lee, Patricia Opresko, Alberto Pappo, John Kirkwood, Armita Bahrami. Association of TERT promoter mutations with telomerase expression in melanoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2730.
Phase II Study of Single Agent Clofarabine in Previously Untreated Older Adult Patients with Acute Myelogenous Leukemia (AML) Unlikely to Benefit from Standard Induction Chemotherapy
Authors: Harry Paul Erba, Hagop Kantarjian, David F. Claxton, M. Arellano, Roger M Lyons, Tibor J. Kovacsovics, Janice Gabrilove, Stephen Eckert, Rekha Abichandani, Stefan Faderl
Journal: Blood (2008)
Nicotinic acetylcholine receptor polymorphism, smoking history, and tobacco-related cancer in the general population.
Authors: D. Kaur-Knudsen, S. E. Bojesen, A. Tybjærg-Hansen, B. G. Nordestgaard
Journal: Journal of Clinical Oncology (2010)

1530 Background: Smokers often develop lung and bladder cancer; however, not all smokers develop these diseases. We examined whether the nicotinic acetylcholine receptor gene (CHRNA3) rs1051730 polymorphism can identify smokers in the general population at genetically high risk of tobacco-related cancer, that is, at higher risk than that explained by detailed smoking history alone. Methods: We genotyped 10,322 participants from the Danish general population, the Copenhagen City Heart Study. Detailed smoking history was obtained and validated at baseline. End-points during the following 18 years were lung and bladder cancer from the Danish cancer registry. Follow-up was 100% complete. Results: Among the 7831 ever smokers, CHRNA3 non-carriers (44%) and homozygotes (11%) had daily tobacco consumption of 16 and 18 g/day (Wilcoxon: p = 0.000004), cumulative tobacco consumption of 28 to 31 packyears (p = 0.001), and smoking inhalation of 72% and 78% (chi- square: p = 0.0002). As expected increasing baseline packyears smoked associated with increasing risk of lung and bladder cancer during the following 18 years (trend-tests: p = 4*10-47 and p = 0.0002); the hazard ratios for lung and bladder cancer in those with baseline > 40 packyears smoked vs. never-smokers were 44 (95% CI:14-105) and 2.9 (1.4-5.9) after multifactorial adjustment including genotype. In addition, CHRNA3 homozygotes vs. non-carriers had hazard ratios for lung and bladder cancer of 1.65 (1.18-2.30) and 1.79 (1.05-3.06) after multifactorial adjustment including detailed smoking history. The highest absolute 10-year risks were 11.4% for lung cancer and 4.4% for bladder cancer for homozygous smokers above 60 years who had smoked > 30 packyears at baseline. Conclusions: The nicotinic acetylcholine receptor rs1051730 polymorphism identifies 11% of smokers in the general population at excessive high risk of tobacco-related cancer, even after considering a full smoking history. No significant financial relationships to disclose.
Abstract 4186: Syngenomic fingerprint: the biomic characterization of the mouse syngeneic tumor models
Authors: John E. Prime, Suzanne Mosely, Jens-Oliver Koopmann, Dennis YQ Wang, Danielle Greenawalt, James Harper, Miika J. Ahdesmaki, Rebecca Leyland, Olivia Harris, Ross Stewart, Philip Brohawn, Brandon Higgs, Bryony Langford, Athula Herath, Robert Kozarski, Jane Coates-Ulrichsen, Judith Anderton, Michelle Morrow, Richard C. A Sainson, Robert W. Wilkinson
Journal: Cancer Research (2016)

Abstract The pre-clinical assessment of immuno-oncology (IO) therapies can be enabled by the use of murine syngeneic tumors established in immuno-competent mice. With the aims of selecting relevant models and of minimizing animal experimentation by reducing the number of models tested, the full characterisation of syngeneic models at the transcriptomic and genomic level is a key objective for pre-clinical scientists. Model characterisation includes global aCGH, exon array analysis and FACS profiling alongside exome sequencing. The model data is undergoing hypothesis free and driven analyses which are already generating valuable insights. Comparison of in vivo tumor samples with their in vitro equivalents has highlighted enrichment for a number of immune pathways; as has the comparison of different tumor lines. The genomic, transcriptomic and ‘proteomic’ model data are being integrated to give a functional output which will act as a ‘Syngenomic Fingerprint’ for each model. The resulting Syngenomic fingerprints will help pre-clinical scientists to refine their in vivo plans through an improved understanding of the limits and advantages as well as the clinical relevance of some of our preclinical models. It is also supporting the targeted modification of models to better match specific human cancer types. Citation Format: John E. Prime, Suzanne Mosely, Jens-Oliver Koopmann, Dennis YQ Wang, Danielle Greenawalt, James Harper, Miika J. Ahdesmaki, Rebecca Leyland, Olivia Harris, Ross Stewart, Philip Brohawn, Brandon Higgs, Bryony Langford, Athula Herath, Robert Kozarski, Jane Coates-Ulrichsen, Judith Anderton, Michelle Morrow, Richard C. A Sainson, Robert W. Wilkinson. Syngenomic fingerprint: the biomic characterization of the mouse syngeneic tumor models. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4186.
Abstract 460: Diagnostic and prognostic value of expression of CCND1 splice variant cyclin D1b in papillary thyroid carcinoma
Authors: Chan Kwon Jung, Sora Jeon, Yourha Kim, Ahwon Lee, Gyeong Sin Park
Journal: Cancer Research (2016)

Abstract Background: An active cyclin D1 isoform, cyclin D1b, arises as a result of a failure to splice the fourth intron of the CCND1 pre-mRNA transcript. The expression of cyclin D1b has been associated with tumorigenesis and tumor progression in many types of human cancer. However, no studies with cyclin D1b have yet been reported in the thyroid cancer. Methods: We investigated the CCND1 rs9344 (cDNA 870) polymorphism by TaqMan SNP genotyping assay and expression profiles of mRNA and protein of full-length cyclin D1 (cyclin D1a) and cyclin D1b by quantative real-time PCR and immunohistochemistry in 286 thyroid tumors including 16 nodular hyperplasias, 33 follicular adenomas (FA), 179 papillary thyroid carcinomas (PTC), 32 follicular thyroid carcinomas (FTC), 5 poorly differentiated carcinomas (PDC), 4 anaplastic thyroid carcinomas (ATC), and 17 medullary thyroid carcinomas (MTC). The relationships between cyclin D1 expression levels and clinicopathological features were analyzed. Results: The cyclinD1b mRNA expression level in all thyroid tumors was significantly higher in the AA and GA genotype groups compared with the GG genotype group (p&amp;lt;0.001 and p = 0.006, respectively). The mRNA expression levels of cyclin D1b was significantly higher in PTCs when compared to benign or other malignant tumors (p&amp;lt;0.001) while no significant difference in cyclin D1a mRNA expression was observed according to the genotypes or tumor types. PTCs showed similar expression levels of cyclin D1b mRNA regardless of histologic subtypes, even when compared with follicular variant. In immunohistochemistry analysis, cyclin D1b overexpression was observed in PTC, PDC, ATC, and MTC, but not in FA and FTC. Cytoplasmic overexpression of cyclin D1b was significantly associated with advanced tumor stage in all PTCs (p = 0.025). Nuclear overexpression of cyclin D1b was associated with an increased incidence of lymph node metastases (p = 0.014) in classic PTCs. Conclusion: The A allele of the rs9344 polymorphism predisposes for cyclin D1b production in thyroid cancer. Cyclin D1b overexpression has a diagnostic biomarker utility to differentiate PTC from benign follicular nodules and may be functionally involved in the progression of the disease. Citation Format: Chan Kwon Jung, Sora Jeon, Yourha Kim, Ahwon Lee, Gyeong Sin Park. Diagnostic and prognostic value of expression of CCND1 splice variant cyclin D1b in papillary thyroid carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 460.
Observational Study Of PNH Clone Size By High Sensitivity Flow Cytometry In High-Risk Patients InA Large Russian Population
Authors: Elena Babenko, Alexandra Sipol, Vyacheslav Borisov, Elena Naumova, Elena Boyakova, Dimitry Yakunin, Tatyana Glazanova, Zhanna Chubukina, Natalya Pronkina, Alexander Popov, Leonid Saveliev, Elena Partylova, Larisa Vlasova, Ilshat Mustafin, Bulat Ramazanov, Irina Galtseva, Zalina Fidarova, Svetlana Lugovskaya, Igor Lisukov, Alexander Kulagin
Journal: Blood (2013)