tbuckley/cabot-search huggingface dataset:
High-Sensitivity Cardiac Troponin, Statin Therapy, and Risk of Coronary Heart Disease
Authors: Ian Ford, Anoop S.V. Shah, Ruiqi Zhang, David A. McAllister, Fiona E. Strachan, Muriel Caslake, David E. Newby, Chris J. Packard, Nicholas L. Mills
Journal: Journal of the American College of Cardiology (2016)

Cardiac troponin is an independent predictor of cardiovascular mortality in individuals without symptoms or signs of cardiovascular disease. The mechanisms for this association are uncertain, and a role for troponin testing in the prevention of coronary heart disease has yet to be established. This study sought to determine whether troponin concentration could predict coronary events, be modified by statins, and reflect response to therapy in a primary prevention population. WOSCOPS (West of Scotland Coronary Prevention Study) randomized men with raised low-density lipoprotein cholesterol and no history of myocardial infarction to pravastatin 40 mg once daily or placebo for 5 years. Plasma cardiac troponin I concentration was measured with a high-sensitivity assay at baseline and at 1 year in 3,318 participants. Baseline troponin was an independent predictor of myocardial infarction or death from coronary heart disease (hazard ratio [HR]: 2.3; 95% confidence interval [CI]: 1.4 to 3.7) for the highest (≥5.2 ng/l) versus lowest (≤3.1 ng/l) quarter of troponin (p < 0.001). There was a 5-fold greater reduction in coronary events when troponin concentrations decreased by more than a quarter, rather than increased by more than a quarter, for both placebo (HR: 0.29; 95% CI: 0.12 to 0.72 vs. HR: 1.95; 95% CI: 1.09 to 3.49; p < 0.001 for trend) and pravastatin (HR: 0.23; 95% CI: 0.10 to 0.53 vs. HR: 1.08; 95% CI: 0.53 to 2.21; p < 0.001 for trend). Pravastatin reduced troponin concentration by 13% (10% to 15%; placebo adjusted, p < 0.001) and doubled the number of men whose troponin fell more than a quarter (p < 0.001), which identified them as having the lowest risk for future coronary events (1.4% over 5 years). Troponin concentration predicts coronary events, is reduced by statin therapy, and change at 1 year is associated with future coronary risk independent of cholesterol lowering. Serial troponin measurements have major potential to assess cardiovascular risk and monitor the impact of therapeutic interventions.
An evaluation of bone marrow stromal-derived growth factor-1 and interleukin-8 levels in patients with stage I-III breast cancer with disseminated tumor cells.
Authors: C. Hall, S. Krishnamurthy, A. Lodhi, A. Bhattacharyya, A. Anderson, H. M. Kuerer, I. Bedrosian, A. Lucci
Journal: Journal of Clinical Oncology (2011)

10610 Background: Tumor cells that disseminate to the bone marrow (disseminated tumor cells, or DTCs), have been identified in 30% of stage I-III breast cancer (BC) patients and are known to predict outcome. However, the mechanisms involved in DTC metastasis to the bone marrow are unknown. We hypothesized that increases in bone turnover may result in the release of bone growth and “homing” factors into the bone marrow, facilitating BC metastasis to bone marrow and providing a “pre-metastatic niche” for BC cells. The purpose of this study was to determine if bone marrow plasma levels of two well characterized BC-bone “homing” chemokines, stromal-derived growth factor-1 (SDF-1) and interleukin-8 (IL-8), are increased in BC patients with DTCs. Methods: Sixty-five clinical stage I-III BC patients provided informed consent to participate in an IRB-approved study involving collection of bone marrow at the time of surgery for their primary BC. DTCs were assessed using an anti-cytokeratin antibody cocktail following ficoll enrichment and cytospin. Bone marrow plasma SDF-1 and IL -8 levels were quantified using enzyme-linked immunoassays. Results: Mean age was 54 years. Eighty-two percent of patients had T1/T2 tumors, and 38% had lymph node metastases. DTCs were identified in 12/65 (18.5%) of patients. No statistically significant correlations were observed between primary tumor characteristics (ER, PR, HER2, lymph node status, tumor grade) and presence of DTCs. Mean bone marrow plasma SDF-1 levels (1359 ± 379 pg/mL vs. 525 ± 312 pg/mL; p ≤0.001) and IL-8 levels (559 ± 108 pg/mL vs. 62 ± 45 pg/mL; p≤0.001) were significantly higher in DTC-positive vs. DTC-negative patients. Conclusions: Bone marrow plasma SDF-1 and IL-8 levels were significantly increased in patients with DTCs compared to DTC-negative patients. Further studies are needed to determine if patients harboring DTCs have unique microenvironmental factors within the bone marrow that predispose them to tumor cell dissemination.
505. VGX-3100 Drives Regression of HPV16/18 CIN2/3 and Robust Cellular Immune Responses in Blood and Cervical Tissue in a Blinded, Randomized, Placebo-Controlled Phase 2B Study
Authors: Matthew Morrow, Connie Trimble, Xuefei Shen, Michael Dallas, David Weiner, Jean Boyer, Jian Yan, Kimberly Kraynyak, Albert Sylester, Mary Giffear, Kathleen Marcozzi-Pierce, Divya Shah, Kate Broderick, Amir Khan, Jessica Lee, Laurent Humeau, Niranjan Sardesai, Mark Bagarazzi
Journal: Molecular Therapy (2016)

Objectives: Assessment of the safety and efficacy and immunogenicity of VGX-3100 in women with biopsy-proven CIN2/3 with concurrent HPV16 and/or HPV18 infection. Methods: The randomized, placebo-controlled, double-blind study, which was stratified by age and severity of CIN, evaluated cervical tissue changes after three 6 mg intramuscular doses of VGX-3100 followed by electroporation with Inovio's CELLECTRA(r)2000 device at weeks 0, 4, and 12. Results: Among 167 vaccinated women, the study met its primary efficacy endpoint; the percentage of patients who had regression of CIN2/3 to CIN1 or no disease at 6 months post third dose was significantly higher in the VGX-3100 group compared to placebo (p=0.034). In addition, the trial demonstrated the ability of VGX-3100 to clear HPV infection concurrent with regression of CIN2/3 (p=0.003). Post-hoc immune analysis also revealed significantly elevated immune responses in treated patients who had CIN2/3 regression concurrent with HPV clearance when compared to those who did not. This included the presence of CD8+ T cells in the blood exhibiting CD137 expression concurrent with perforin (p=0.032) as well as perforin in addition to granzyme A (p=0.036) as well as an influx of CD8+ T cells into cervical tissue (p=0.008). Conclusion: The successful phase 2b results represent a significant milestone in the development of active immunotherapies to treat HPV-related dysplasia and cancer. The data generated from the trial reveal a significant clinical benefit afforded by treatment with VGX-3100 and underscore the mechanism of action of HPV specific T cells. Thus VGX-3100 has the potential to provide an important alternative or adjunct to surgery in treating CIN 2/3.
Type 2B “Malmo/New York” Is Not So Rare among Italian Patients with von Willebrand Disease: The Role of P1266L/Q Mutations of the von Willebrand Factor Gene in Seven Cases.
Authors: Luciano Baronciani, Silvia La Marca, Giancarlo Castaman, Margherita Punzo, Rosanna Garavaglia, Valentina Rubini, Giovanna Cozzi, Maria T. Canciani, Augusto B. Federici
Journal: Blood (2007)
Abstract 4608: Racial differences in the distribution of prostate tumor biomarkers and treatment failure: The SCORE study
Authors: Priti Lal*, Kosj Yamoah*, Amy Ziober, Amy Walker, Wenting Zhou, Elaine Spangler, Charnita Zeigler-Johnson, Michael Feldman, Timothy R. Rebbeck
Journal: Cancer Research (2015)

Abstract Prostate cancer exhibits the greatest disparity in mortality between African American (AA) and European American (EA) men of any cancer in the US. The reasons for this disparity include access to care, screening patterns, and behavior. Biological differences may lead some AA men to have biologically aggressive tumors. Using the Study of Clinical Outcomes, Risk, and Ethnicity (SCORE) study, we identified prostate tumor tissues from men undergoing prostatectomy at the Hospital of the University of Pennsylvania between 1991-2008. Immunohistochemistry was undertaken on the FFPE tumors of 45 EA and 55 AA men (mean age: 59.1 years, range: 41-71). No statistically significant difference in marker phenotypes was observed for prevalence of TMPRSS2/ERG fusion proteins, or in staining intensity for PSMA or Rb. We observed statistically significant differences in marker phenotype for RACEMASE (EA Mean: 188.1 vs. AA Mean: 144.7, p = 0.004), c-myc (EA Mean: 54.7 vs. AA Mean: 21.6, p = 0.005), and AR (EA Mean: 192.1 vs. AA Mean: 136.5, p = 0.002). These data suggest that markers that have been reported to be associated with tumor aggressiveness differ between EA and AA men. We further evaluated whether these markers were associated with clinical outcome as measured by biochemical (PSA) failure (BF) after radical prostatectomy (RP). We observed 41 BF with a mean follow up of 32.6 months post-RP, compared with 68 non-BF with a mean follow up of 53.7 months post-RP. After adjusting for pathology tumor grade, only the presence of a TMPRSS2-ERG fusion protein was significantly associated with BF. We observed a significant interaction (p = 0.031) by race suggesting TMPRSS2-ERG fusions were less likely to be associated with BF in AA than in EA. These data suggest that TMPRSS2-ERG fusions may not be important predictors of prostate cancer outcomes in AA men as has been suggested in EA men. *These authors contributed equally to the work. Citation Format: Priti Lal*, Kosj Yamoah*, Amy Ziober, Amy Walker, Wenting Zhou, Elaine Spangler, Charnita Zeigler-Johnson, Michael Feldman, Timothy R. Rebbeck. Racial differences in the distribution of prostate tumor biomarkers and treatment failure: The SCORE study. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4608. doi:10.1158/1538-7445.AM2015-4608
Abstract 4881: Analysis of long-noncoding RNA interaction at chromatin by chromatin isolation by RNA purification (ChIRP)
Authors: Kan Saito, Konstantin Taganov, John M. Rosenfeld, Nick Asbrock, Vi Chu
Journal: Cancer Research (2015)

Abstract Gene regulation plays a critical role during development and progression of Cancer. While the regulation of gene expression by transcription factors and epigenetic influences has been well studied over time, pervasive genomic transcription and the role of non-coding RNAs in this process is a rapidly evolving field that remains to be thoroughly explored. Chromatin Isolation by RNA Purification (ChIRP) is one of the methods, which allows discovery of the sites of interaction of chromatin-associated RNAs (e.g. lncRNAs) with genomic DNA sequences by using probe-based hybridization to target RNA molecules in chromatin. To perform ChIRP multiple biotinylated oligonucleotide probes complementary to the RNA of interest are used. To help eliminate non-specific signals two different pools of probes are used (even and odd probe sets). These probe sets are combined with chromatin and hybridized to the chromatin-associated RNA. Complexes containing biotinylated-probes bound to the chromatin-associated RNA are then isolated using streptavidin magnetic beads. DNA can then be recovered and analyzed by quantitative PCR or next generation sequencing (ChIRP-seq). Alternatively, RNA may also be isolated from an aliquot of the recovered chromatin to detect other RNA molecules that may be associated with the RNA of interest. To enable the exploration of these RNA interactions in chromatin regulation, we have optimized the methods and developed ChIRP reagents. Using these reagents ChIRP experiments can be performed with reliable recovery of chromatin using lncRNA or other chromatin associated RNA as targets. Additionally, negative and positive control probe sets, and detection primers were developed to ensure first time success. We have performed ChIRP experiments with a HeLa cell lysate and capture oligos for the NEAT1 lncRNA. Isolated DNA was subjected to NGS library construction and sequenced on an Illumina HiSeq™ instrument. Sequences were aligned to the reference genome (hg19). The peaks were called separately for odd and even reactions, and only common peaks were selected. We successfully identified several NEAT1 binding sites in the genomic DNA sequence. In summary the methods developed allow unbiased discovery of RNA-associated genomic DNA sequences, RNA sequences, and potentially proteins. Citation Format: Kan Saito, Konstantin Taganov, John M. Rosenfeld, Nick Asbrock, Vi Chu. Analysis of long-noncoding RNA interaction at chromatin by chromatin isolation by RNA purification (ChIRP). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4881. doi:10.1158/1538-7445.AM2015-4881
CD11b+gr-1+ myeloid Derived Suppressor Cells (MDSC) In Normal Bone Marrow Suppress T Cell Proliferation and Enhance T-Regulatory Function Via a IL10-, IL4- and IDO-Independent Mechanism
Authors: Parvin Forghani, Wayne Harris, jian-Ming Li, M.R. Khorramizadeh, Edmund Waller
Journal: Blood (2010)
<i>NTRK1</i> gene fusions as a novel oncogene target in lung cancer.
Authors: Robert Charles Doebele, Aria Vaishnavi, Marzia Capelletti, Anh T. Le, Severine Kako, Mohit Butaney, Sakshi Mahale, Dara L. Aisner, Julia Haas, Steven W. Andrews, Doron Lipson, Philip J. Stephens, Marileila Varella-Garcia, Pasi Antero Janne, Vincent A. Miller
Journal: Journal of Clinical Oncology (2013)

8023 Background: The identification and therapeutic targeting of oncogenic drivers in lung adenocarcinoma has led to significant clinical improvements for patients with EGFR mutations or ALK fusions. However, many lung cancer patients do not yet have an identified oncogenic driver and the discovery of new actionable oncogenic drivers is thus an active area of investigation. Methods: Tumor samples from 36 ‘pan-negative’ (EGFR, KRAS, ALK, and ROS1) lung adenocarcinoma patients were analyzed using a next generation sequencing (NGS) test performed in a CLIA-certified lab (Foundation Medicine, Cambridge, MA). Fluorescence in situ hybridization (FISH) screening using a novel NTRK1 break-apart assay was performed on an additional 61 pan-negative samples. Cells expressing the novel NTRK1 fusions were assayed for transformation and pharmacologic inhibition. Results: Two tumor samples were identified with gene fusions containing the kinase domain of TrkA, encoded by NTRK1, including one each with an MPRIP-NTRK1 (M21;N14) and CD74-NTRK1 (C8;N12) fusion. RT-PCR confirmed mRNA expression and identity of the fusion partner and FISH analysis detected split 5’/3’ signals corresponding to the NTRK1 gene. A third sample was identified by FISH analysis. Cloning and expression of MPRIP- and CD74-NTRK1 into NIH3T3 and Ba/F3 cells show constitutive activation of the TrkA kinase domain and transformation. Treatment of cells expressing NTRK1 fusions with several candidate pan-Trk inhibitors (ARRY-772, -523, and -470) as well as CEP-701 and crizotinib demonstrate decreased phosphorylation of the fusion oncoprotein and inhibition of cell proliferation. Treatment of the index patient harboring the MPRIP-NTRK1fusion with crizotinib led to minor transient tumor shrinkage. Conclusions: We identified a novel class of oncogenes, NTRK1 fusions, in lung adenocarcinomas that can be detected by NGS or FISH. Additional studies to determine the frequency and characteristics of NTRK1 fusions in lung cancer are ongoing. Our findings suggest prospective clinical trials of Trk inhibitors in NTRK1 fusion positive patients may be warranted. Support: CO Bioscience Discovery and Evaluation Grant and CO Clinical and Translational Sciences Institute Grant.
Individual patient data meta-analysis of controlled attenuation parameter (CAP) technology for assessing steatosis
Authors: Thomas Karlas, David Petroff, Magali Sasso, Jian-Gao Fan, Yu-Qiang Mi, Victor de Lédinghen, Manoj Kumar, Monica Lupsor-Platon, Kwang-Hyub Han, Ana C. Cardoso, Giovanna Ferraioli, Wah-Kheong Chan, Vincent Wai-Sun Wong, Robert P. Myers, Kazuaki Chayama, Mireen Friedrich-Rust, Michel Beaugrand, Feng Shen, Jean-Baptiste Hiriart, Shiv K. Sarin, Radu Badea, Kyu Sik Jung, Patrick Marcellin, Carlo Filice, Sanjiv Mahadeva, Grace Lai-Hung Wong, Pam Crotty, Keiichi Masaki, Joerg Bojunga, Pierre Bedossa, Volker Keim, Johannes Wiegand
Journal: Journal of Hepatology (2016)
Abstract 3057: Potentiation of LPS-induced toxicity in human hepatoma HepG2 cells by aspirin and its protection by N-acetyl cysteine
Authors: Haider Raza, Annie John, Jasmin shafarin
Journal: Cancer Research (2015)

Abstract Bacterial lipopolysaccharides (LPS) induce cytotoxicity in vitro and inflammation-induced toxic responses in vivo. Use of nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin, has been reported to be beneficial in inflammation-associated diseases like cancer and diabetes. Their precise molecular mechanisms, however, are not clearly understood. Our previous studies on aspirin treated HepG2 cells strongly suggest cell cycle arrest and induction of apoptosis associated with mitochondrial dysfunction. In the present study, we have further demonstrated that HepG2 cells treated with LPS alone or in combination with aspirin induces subcellular toxic responses which are accompanied by increase in reactive oxygen species (ROS) production, oxidative stress, apoptosis and mitochondrial respiratory dysfunction. The LPS/Aspirin induced toxicity was attenuated by pretreatment of cells with N-acetyl cysteine (NAC). Oxidative stress and glutathione-dependent redox-homeostasis in the mitochondria were altered more severely compared to the extramitochondrial compartment of cells. Pre-treatment of HepG2 cells with NAC has demonstrated selective protection in redox homeostasis and mitochondrial dysfunction. Our results suggest that altered glutathione (GSH)-redox metabolism, oxidative stress and mitochondrial function in HepG2 cells play a critical role in LPS/aspirin-induced cytotoxicity. These results may help in better understanding the pharmacological and toxicological properties of NSAIDs in cancer cells exposed to bacterial endotoxins. (Supported by Sheikh Hamdan Medical Research Grant and Terry Fox Cancer Research Funds and a fund from CMHS Research Committee). Citation Format: Haider Raza, Annie John, Jasmin shafarin. Potentiation of LPS-induced toxicity in human hepatoma HepG2 cells by aspirin and its protection by N-acetyl cysteine. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3057. doi:10.1158/1538-7445.AM2015-3057
Phase I-II dose escalation study of celecoxib (C) in combination with paclitaxel (T) and carboplatinum (CP) in non small cell lung cancer (NSCLC)
Authors: V. Gupta, T. Weigand, R. Rangineni
Journal: Journal of Clinical Oncology (2004)

7310 Background: Preclinical data suggests COX-2 inhibitors prevent development of cancer,shrink established tumors,and inhibit angiogenesis in dose dependent manner with “optimal”blood levels of 1.8–5ug/ml of celecoxib(C). Clinical trials with C are limited to 800mg/d. We studied the effect of 800, 1200,and 1600mg/d in two divided doses of C with fixed doses of carboplatinum( CP) and paclitaxel(T) in NSCLC. Methods: 34 patients with inoperable stage I-III and IV, with evaluable disease and PS 1,2 received C and prophylaxis with H2 blockers or proton pump inhibitors for 7d prior to CP AUC- 6 q4wks and T60mg/m2 weekly for at least 4 mo.Dose escalation of C was after 4 patients at each dose level. GI and other side effects,heme,liver, kidney function were monitored weekly. Tumor response was q8wks. 2 patients had received prior non-taxane therapy. Blood levels of C were obtained by commercial HPLC assay in some patients after 4 hr dose of C. There were18 patients with 800mg/d C, 10 with 1200mg/d C and 6 with 1600mg/d C. Patients with StageI-III disease after 4mo induction chemotherapy received consolidation radiotherapy with or without chemotherapy. Results: The mean, range and n of blood levels( ng/ml ) of C were 1278,(600–2500),9;1866(1100–4200),6; and 2983,(1200–6100),7 respectively at 800,1200and 1600mg/d of C. There were 22 patients evaluable for response with 3CR,6PR,10SD, 3 progressive after 4mo of therapy. One stage IV patient with brain mets at 800mg of C died postop with GI bleed from incidental carcinoid of small bowel and one at 1600mg of C(blood level 1200ng/ml) after anticoagulation for DVT(INR 2.4), and one at 800mg mg of C from grade 4 neutropenia and pneumonia. Conclusions: 1. The MTD of celecoxib has not been reached. 2.There is significant variability of blood levels of celecoxib at all dose levels tested. 3. “Optimal” blood levels of celecoxib may not be easily achieved at 800mg/d of celecoxib and may require therapeutic monitoring to properly asses impact in clinical trials. 4. The therapeutic role of celecoxib in combination with chemotherapy or by itself requires ongoing investigation. No significant financial relationships to disclose.
Multiple Myeloma Cell-Osteoblast Interaction Results in Impaired Bone Formation.
Authors: Sonia Vallet, Teru Hideshima, Samantha Pozzi, Nileshwari Vaghela, Gaurav Gharti-Chhetri, Siddhartha Mukherjee, Iris Breitkreutz, Tanyel Kiziltepe, Yutaka Okawa, Hiroshi Ikeda, Loredana Santo, Diana Cirstea, Mario Boccadoro, Kenneth C. Anderson, Noopur Raje
Journal: Blood (2007)
Polymorphism in SFTPD gene affects assembly and constitutional serum levels of surfactant protein D in a Lebanese population
Authors: Dalia Fakih, Soulaima Chamat, Myrna Medlej-Hashim, Mirna Waked, Pascale Salameh, Grith Lykke Sørensen, Rania Jounblat
Journal: European Respiratory Journal (2014)

Surfactant protein D (SP-D), an oligomeric lung-derived lectin, has essential roles in innate immunity. It can be measured in serum. Previous studies have shown that constitutional SP-D serum levels and the protein degree of multimerization are genetically influenced. We aimed to establish the distribution profile of serum constitutional SP-D in the Lebanese population and to investigate the genetic influence of single nucleotide polymorphism (SNP) rs721917 within SP-D gene ( SFTPD)  on its multimerization and its serum basal level. The C/T alleles at this SNP level lead respectively either to a threonine or methionine at position 11 of the SP-D protein. SP-D was measured by ELISA in serum taken from 97 healthy subjects. The p.Met11Thr SNP was genotyped. Different forms of SP-D were separated by gel filtration chromatography. Basal serum SP-D levels varied extensively, over a range of 108.3 ng/ml to 2995 ng/ml. The p.Met11Thr SNP was significantly associated with the serum SP-D levels (p=0.01). Individuals homozygous for the T wild-type allele had the highest mean SP-D serum levels (1423 ng/ml) compared to heterozygous individuals (1139 ng/ml) and homozygous individuals for the C allele (671.4 ng/ml). Serum from heterozygous individuals showed two different molecular weight peaks corresponding to different forms of SP-D of ratio high/low 1:07. However, data showed a remarkable predominance of the low molecular weight form of SP-D (ratio high/low 1:4.65) in serum of individuals carrying the CC genotype. Our preliminary findings validate previous observations of the influence of the p.Met11Thr SNP on assembly and serum concentration of SP-D.
Growth Factor Receptor-Bound Protein 10 (Grb10) Regulates Hematopoietic Stem Cell (HSC) Self-Renewal Via Control of mTOR Signaling
Authors: Xiao Yan, Heather A Himburg, Phuong L Doan, Mamle Quarmyne, Evelyn Tran, Liman Zhao, Nelson J. Chao, John P Chute
Journal: Blood (2015)