tbuckley/cabot-search huggingface dataset:
Abstract 485: Blood-based profiling of patients with NSCLC using CLIA certified cell-free DNA tests for EGFR, KRAS and BRAF point mutations and test use in clinical practice
Authors: Hestia Mellert, Scott Thurston, Trudi Foreman, Westen Hahn, Nicholas Dupuis, Gary Pestano
Journal: Cancer Research (2016)

Abstract Nearly 80% of patients will not have mutation results available at their initial oncology consult and as many as 1 in 4 patients will begin treatment in advance of receiving their tumor mutation results. These factors hinder diagnosis at the molecular level, which is an important component in the decision to commence treatment with specific targeted therapies. The goal of this study was to measure the utility of a CLIA-certified Laboratory Developed Test (LDT) in the absence of a tissue diagnosis. EGFR, KRAS and BRAF point mutations within the cell-free DNA (cfDNA) isolated from the plasma of patients with advanced stages of cancer were analyzed using Droplet Digital™ PCR (ddPCR) technology. The specific tests detected the EGFR sensitizing mutations L858R and exon 19 deletion (E746 - A750) and EGFR resistance mutation, T790M, the KRAS mutations G12C, G12V and G12D, as well as the BRAF V600E mutation. The tests were comprised of three components: (i) a whole-blood collection kit that ships at ambient temperature, (ii) cfDNA isolated from plasma for analysis using ddPCR, and (iii) a secure laboratory information management system (LIMS) for sample accessioning and report generation. Test mutation status results were reported within 72 hours of blood shipment from the physicians’ office. To date we have processed greater than 2000 individual variant tests for patients with NSCLC. The predominant tumor type for EGFR sensitizing mutations requested was NSCLC (95%). Interestingly, even BRAF test orders were &amp;gt; 90% from NSCLC patients. Additionally, the percentage of tests requested that were positive for each mutation category were 12% for EGFR sensitizing, 20% for EGFR resistance, 14% for KRAS and 1.8% for BRAF. Significantly, T790M test orders were observed to have increased five-fold over the last three months of testing. We have developed highly sensitive, 72 hour test to results blood-based assays as a part of the GeneStratTM panel, that expand the utility of laboratory testing for patients previously diagnosed with cancer. Citation Format: Hestia Mellert, Scott Thurston, Trudi Foreman, Westen Hahn, Nicholas Dupuis, Gary Pestano. Blood-based profiling of patients with NSCLC using CLIA certified cell-free DNA tests for EGFR, KRAS and BRAF point mutations and test use in clinical practice. [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 485.
Abstract 1329: Intravenous delivery of Erlotinib-loaded PLA-PEG nanoparticles for treatment of GB
Authors: Lauren K. Hartman, Harshil D. Dhruv, Kyle T. Householder, Jeffrey E. Roth, Allison N. Schorzman, William Zamboni, Rachel Sirianni, Michael E. Berens
Journal: Cancer Research (2016)

Abstract Amplification, overexpression, and mutation of the epidermal growth factor receptor (EGFR) gene represent common genetic signature abnormalities (&amp;gt;50%) in primary glioblastomas (GBs) that arise de novo. Although activated EGFR signaling represents the most common genetic abnormality in GB, targeted therapeutics against EGFR, such as Erlotinib and Gefitinib, have found very limited clinical success mainly because of restricted access to the tumor cells behind the blood brain barrier. Nanoparticles, such as those composed of poly(lactic acid)-poly(glycolic acid) (PLA-PEG), may be capable of overcoming delivery barriers to expand the armamentarium of drugs useful against GB. PLA-PEG is one of only two polymer NP formulations in phase II clinical trial for intravenous administration (NCT01812746). In this study, we tested the ability of Erlotinib-loaded PLA-PEG nanoparticles to inhibit the EGFR signaling pathway in short-term cultures of GB patient derived xenograft (PDX) models. We also tested the ability of systemically administered PLA-PEG nanoparticles to deliver Erlotinib payload to intracranial GB PDX cells by pharmacokinetic (PK) analysis. Potency of Erlotinib-loaded PLA-PEG was determined in four PDX models (GBM6, GBM12, GBM39, and GBM59) with known EGFR and PTEN status using immunoblot analysis and CellTiterGlo® assay. Our results demonstrate that Erlotinib PLA-PEG inhibits EGFR signaling in all PDX models tested with potency equal to free Erlotininb (EC50 range 4.9 - 16.8 μM). Pharmacokinetic measurements were done in plasma and brain tissue samples (tumor-bearing hemisphere and contralateral hemisphere were analyzed separately) collected from intracranial GBM12 tumor bearing mice at 5 min, 1 hr, 6hr, and 24 hr after intravenous (IV) dose of free Erlotinib at 7.5 mg/Kg and Erlotininb PLA-PEG at 13.125 mg/Kg. PLA-PEG-mediated brain penetration (AUCplasm:AUCBrain) of Erlotinib is ∼7.5%. Using orthotopic PDX implants, perivascular/intratumoral penetration by PLA-PEG is being measured. Additional improvements in PLA-PEG to heighten uptake into brain, as well as tumor-specific targeting and enriched payload density will foster improved clinical utility of EGFR targeted therapies against GB. Supported by a grant from the Ben &amp; Catherine Ivy Foundation. Citation Format: Lauren K. Hartman, Harshil D. Dhruv, Kyle T. Householder, Jeffrey E. Roth, Allison N. Schorzman, William Zamboni, Rachel Sirianni, Michael E. Berens. Intravenous delivery of Erlotinib-loaded PLA-PEG nanoparticles for treatment of GB. [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 1329.
The Crohn’s Disease–Ulcerative Colitis Clinical Appraisal Update: Emerging Trends in Clinical Practice
Authors: William Sandborn, Jean-Frédéric Colombel, Geert D’Haens, Subrata Ghosh, Remo Panaccione, Julian Panés, Simon Travis, Laurent Peyrin-Biroulet
Journal: Clinical Gastroenterology and Hepatology (2016)
Abstract 1284: Lurbinectedin reduces tumor-associated macrophages and the production of inflammatory cytokines, chemokines, and angiogenic factors in preclinical models
Authors: Paola Allavena, Cristina Belgiovine, Manuela Liguori, Ezia Bello, Roberta Frapolli, Carlos M. Galmarini, Maurizio D’Incalci
Journal: Cancer Research (2016)

Abstract Lurbinectedin, currently undergoing clinical evaluation in ovarian, breast and small-cell lung cancer patients, inhibits active transcription. The drug is structurally related to trabectedin containing the same pentacyclic skeleton of the fused tetrahydroisoquinoline rings, but differing by the presence of a tetrahydro-B-carboline replacing the additional tetrahydroisoquinoline of trabectedin. We investigated whether lurbinectedin has the ability to regulate the inflammatory tumor microenvironment in vitro and in vivo. Human purified monocytes were highly sensitive to lurbinectedin (IC50: 5-10 nM) and, after drug treatment, underwent caspase-8-dependent apoptosis. Furthermore, in vitro, lurbinectedin significantly inhibited the production of selected inflammatory chemokines (CCL2, CXCL8) and VEGF by stimulated monocytes and liposarcoma cell lines. Administration of lurbinectedin to mice bearing a murine fibrosarcoma -resistant to this compound in vitro- resulted in significant anti-tumor activity (T/C value around 50%). The analysis of immune cells of blood spleen and tumor tissues during treatment with lurbinectedin revealed a significant and selective decrease in the subset of monocytes and macrophages, including tumor-associated macrophages (TAM). A gene expression analysis of monocytes treated with lurbinectedin indicated a modulation of the transcriptional program in LPS-stimulated human monocytes. Overall, these results indicate that lurbinectedin affects the inflammatory micro-environment, with a selective apoptotic-inducing effect on mononuclear phagocytes and a specific inhibition of production of inflammatory cytokines. Citation Format: Paola Allavena, Cristina Belgiovine, Manuela Liguori, Ezia Bello, Roberta Frapolli, Carlos M. Galmarini, Maurizio D’Incalci. Lurbinectedin reduces tumor-associated macrophages and the production of inflammatory cytokines, chemokines, and angiogenic factors in preclinical 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 1284.
High‐Resolution Magnetic Resonance Imaging of Scalp Arteries for the Diagnosis of Giant Cell Arteritis: Results of a Prospective Cohort Study
Authors: Maxime Rhéaume, Ryan Rebello, Christian Pagnoux, Simon Carette, Marie Clements‐Baker, Violette Cohen‐Hallaleh, David Doucette‐Preville, B. Stanley Jackson, Samih Salama Sargious Salama, George Ioannidis, Nader A. Khalidi
Journal: Arthritis & Rheumatology (2016)

To examine the concordance between high-resolution magnetic resonance imaging (MRI) of the scalp arteries and temporal artery biopsy for the diagnosis of giant cell arteritis (GCA).We conducted a prospective cohort study of patients with suspected GCA. Participants underwent high-field 3T MRI of the scalp arteries followed by temporal artery biopsy. Arterial wall thickness and enhancement on multiplanar postcontrast T1-weighted spin-echo images were graded according to a published severity scale (range 0-3). MRI findings were compared with temporal artery biopsy results and the American College of Rheumatology (ACR) criteria for GCA.One hundred seventy-one patients were included in the study. Temporal artery biopsy findings were positive in 31 patients (18.1%), and MRI findings were abnormal in 60 patients (35.1%). ACR criteria were met in 137 patients (80.1%). With temporal artery biopsy as the reference test, MRI had a sensitivity of 93.6% (95% confidence interval [95% CI] 78.6-99.2) and a specificity of 77.9% (95% CI 70.1-84.4). The corresponding negative predictive value of MRI was 98.2% (95% CI 93.6-99.8) and positive predictive value was 48.3% (95% CI 35.2-61.6).In patients with suspected GCA, normal findings on scalp artery MRI are very strongly associated with negative temporal artery biopsy findings. This suggests that MRI could be used as the initial diagnostic procedure in GCA, with temporal artery biopsy being reserved for patients with abnormal MRI findings.
Abstract 2925: Anti-tumor activity of a MYC-targeting dicer substrate siRNA in combination with BRD4/CDK7 inhibitors
Authors: Edmond Chipumuro, Zakir Siddiquee, Shanthi Ganesh, Serena Shui, Anee Shah, Boyoung Kim, Dongyu Chen, Purva Pandya, Rachel Storr, Weimin Wang, Hank Dudek, Cheng Lai, Marc Abrams, Bob Brown
Journal: Cancer Research (2016)

Abstract MYC is a well-characterized driver of numerous tumor types. Since the protein encoded by this gene is challenging to target via conventional modalities, progress in new therapeutic agents has been slow despite decades of research. RNA interference technology has enabled the inhibition of previously-undruggable genetic targets at the mRNA level, and has advanced to clinical development for several indications. DCR-MYC, a lipid nanoparticle (LNP)-formulated Dicer substrate siRNA (DsiRNA) targeting MYC mRNA, is currently in Phase Ib/II clinical trials and showing promising results. In this study we used an improved EnCore LNP and MYC DsiRNA, which demonstrated MYC mRNA silencing activity and efficacy in mouse models of human hepatocellular carcinoma (HCC). Small molecule inhibitors that target BRD4; JQ1 and CDK7; THZ1 has previously reported anti-proliferative effects in various cancer types and efficacy in several tumor mouse models including HCC. Treatment with both JQ1 and THZ1 induced cell cycle arrest and apoptosis in various cancer cells by repressing MYC expression. Here we observed striking anti-proliferative effects in vitro when MYC-DsiRNA was combined with THZ1 in cancer cells. In addition, when mice bearing HCC tumors were treated with MYC-DsiRNA combined with either THZ1 or JQ1, the antitumor efficacy was additive or synergistic relative to either single agent alone. We observed significantly more MYC mRNA knockdown in the tumors that had the combination treatment compared to the tumors that received either of the single agent treatment. These preclinical data suggests the possibility of a significant and practical benefit of combining MYC-DsiRNA and small molecule inhibitors that target an epigenetic regulator BRD4 (JQ1) and a global gene regulator CDK7 (THZ1). Citation Format: Edmond Chipumuro, Zakir Siddiquee, Shanthi Ganesh, Serena Shui, Anee Shah, Boyoung Kim, Dongyu Chen, Purva Pandya, Rachel Storr, Weimin Wang, Hank Dudek, Cheng Lai, Marc Abrams, Bob Brown. Anti-tumor activity of a MYC-targeting dicer substrate siRNA in combination with BRD4/CDK7 inhibitors. [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 2925.
Mitochondrial dysfunction in Parkinson’s disease
Authors: Qingsong Hu, Guanghui Wang
Journal: Translational Neurodegeneration (2016)

Parkinson's disease (PD) is the second most common neurodegenerative disease, which is characterized by loss of dopaminergic (DA) neurons in the substantia nigra pars compacta and the formation of Lewy bodies and Lewy neurites in surviving DA neurons in most cases. Although the cause of PD is still unclear, the remarkable advances have been made in understanding the possible causative mechanisms of PD pathogenesis. Numerous studies showed that dysfunction of mitochondria may play key roles in DA neuronal loss. Both genetic and environmental factors that are associated with PD contribute to mitochondrial dysfunction and PD pathogenesis. The induction of PD by neurotoxins that inhibit mitochondrial complex I provides direct evidence linking mitochondrial dysfunction to PD. Decrease of mitochondrial complex I activity is present in PD brain and in neurotoxin- or genetic factor-induced PD cellular and animal models. Moreover, PINK1 and parkin, two autosomal recessive PD gene products, have important roles in mitophagy, a cellular process to clear damaged mitochondria. PINK1 activates parkin to ubiquitinate outer mitochondrial membrane proteins to induce a selective degradation of damaged mitochondria by autophagy. In this review, we summarize the factors associated with PD and recent advances in understanding mitochondrial dysfunction in PD.
Circulating tumor DNA (ctDNA) in nonmetastatic colorectal cancer (CRC): Potential role as a screening tool.
Authors: Jeanne Tie, Yuxuan Wang, Isaac Kinde, Malcolm Steel, Hany Elsaleh, Madhu Sudan Singh, Natalie Heather Turner, Ben Tran, Robert Strausberg, Luis A. Diaz, Nickolas Papadopoulos, Kenneth W. Kinzler, Bert Vogelstein, Peter Gibbs
Journal: Journal of Clinical Oncology (2015)

518 Background: CRC screening significantly reduces cancer incidence and mortality. Participation rates in screening, both stool based and endoscopic, are often low. The value and safety of endoscopic screening in older individuals is also uncertain. Preliminary data indicate ctDNA can be detected in a high proportion of patients with early stage CRC, suggesting promise as a screening test that should have broad community acceptance. Methods: Plasma samples were collected at diagnosis from 100 patients (pts) with newly diagnosed CRC. Surgical, clinicopathologic and outcome data were prospectively captured. All samples were sent to Johns Hopkins Kimmel Cancer Center, where tumors were sequenced using a panel of 15 genes frequently mutated in CRC to identify candidate mutations for ctDNA analysis. For each pt, one tumor mutation was selected to assess for ctDNA in plasma samples using the Safe-SeqS digital genomic assay. Results: Preliminary data is available on 68 pts. Median follow-up is 15.2 months. Candidate mutations for ctDNA analysis were identified in all cases, with a matching mutation detectable in the plasma cell-free DNA in 41 pts (60%). Median mutant allele fraction was 0.24% (range 0.11% - 8.39%). Tumor stage did not appear to have a major impact on the detection rate of ctDNA (Table), and ctDNA detection was independent of CEA levels. Five pts have recurred, all of whom had detectable ctDNA at diagnosis, whereas CEA was elevated in only 1 of these cases. Conclusions: Preliminary data suggests ctDNA is detectable at diagnosis in the majority of pts with non-metastatic CRC. The potential for ctDNA as a CRC screening tool, and as a prognostic marker for patients with early stage cancer, should be further explored. [Table: see text]
Abstract LB-134: Sequential validation of blood-based protein biomarker candidates for early-stage pancreatic cancer
Authors: Michela Capello, Leonidas E. Bantis, Ghislaine Scelo, Yang Zhao, Dilsher S. Dhillon, Hong Wang, James L. Abbruzzese, Anirban Maitra, Margaret A. Tempero, Randall Brand, Matthew A. Firpo, Sean Mulvihill, Matthew H. Katz, Paul Brennan, Ziding Feng, Samir M. Hanash, Ayumu Taguchi
Journal: Cancer Research (2016)

Abstract Purpose: CA19-9, which is currently in clinical use as a pancreatic ductal adenocarcinoma (PDAC) biomarker, has limited performance in detecting early stage disease. We and others have identified protein biomarker candidates that have the potential to complement CA19.9. We have carried out sequential validations starting with 32 protein biomarker candidates to develop a marker panel to improve detection of early stage disease compared with CA19.9 alone. Patients and Methods: Multiple independent sample sets consisting of PDAC cases, benign pancreatic disease and healthy controls were utilized for immunoassays of candidate markers which after sequential validations yielded a panel of three markers that was further tested in a blinded setting. Results: The 32 biomarker candidates were initially tested in a sample set consisting of 75 PDAC cases, 29 healthy controls, and 19 chronic pancreatitis cases which narrowed the list to seven biomarker candidates. A second independent set of 73 early-stage PDAC cases, 60 healthy controls, and 74 benign pancreatic disease cases (60 chronic pancreatitis cases and 14 benign pancreatic cyst cases) yielded a panel of three markers, including CA19-9, with an AUC (95%CI) of 0.949 (0.917-0.981) and sensitivity of 0.849 at 95% specificity. Additional blinded testing of the model was done using an independent set of plasma samples from 39 resectable PDAC patients and 82 matched healthy controls, yielding an AUC of 0.887. The performance of the biomarker panel was significantly improved compared to CA19-9 alone (P &amp;lt; 0.001) in both plasma sample sets. Conclusion: We validated a protein-based three marker panel with significantly improved performance compared to CA19-9 with the potential to contribute to strategies for detecting early-stage PDAC. Citation Format: Michela Capello, Leonidas E. Bantis, Ghislaine Scelo, Yang Zhao, Dilsher S. Dhillon, Hong Wang, James L. Abbruzzese, Anirban Maitra, Margaret A. Tempero, Randall Brand, Matthew A. Firpo, Sean Mulvihill, Matthew H. Katz, Paul Brennan, Ziding Feng, Samir M. Hanash, Ayumu Taguchi. Sequential validation of blood-based protein biomarker candidates for early-stage pancreatic 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 LB-134.
Abstract 845: Diet stamps on bugs: early life dietary energy intake impacts gut microbiota
Authors: Jinyu Xu, Jeffrey Galley, Michael Bailey, Jennifer Thomas-Ahner, Steven Clinton, Susan Olivo-Marston
Journal: Cancer Research (2016)

Abstract The complex and dynamic interactions between diet, gut microbiota (GM) structure and function, and colon carcinogenesis are only beginning to be elucidated. We examined the colonic microbiota and aberrant crypt foci (ACF) in C57BL/6N female mice fed various dietary interventions (control, energy restricted and high-fat) provided during two phases (initiation and progression) of azoxymethane (AOM)-induced early colon carcinogenesis. During progression (wks. 22- 60), a high-fat diet enhanced ACF formation compared to a control or energy restricted diet. In contrast, energy restriction during initiation phase (wks. 3-21) enhanced ACF burden at 60 weeks, regardless of the diet in progression phase. Alterations in GM structure during the initiation phase diet were partially maintained after changing diets during the progression phase. However, diet during the progression phase had major effects on the mucosal GM that energy restriction in progression phase increased Firmicutes and reduced Bacteroidetes compared to a high-fat diet, regardless of initiation phase diet, suggesting that diet may have both transient effects as well as a lasting impact on GM composition. Integration of early life and adult dietary impacts on the colonic microbial structure and function with host molecular processes involved in colon carcinogenesis will be key to defining preventive strategies. Citation Format: Jinyu Xu, Jeffrey Galley, Michael Bailey, Jennifer Thomas-Ahner, Steven Clinton, Susan Olivo-Marston. Diet stamps on bugs: early life dietary energy intake impacts gut microbiota. [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 845.
Decreased Rate of β-GlobinL1 Allele Transcription Due to Intronic LINE-1 Insertion In the β-Globin gene Is Associated with β-globinL1 Promoter and Enhancer Hypermethylation Which Is Not Reverted by Decitabine
Authors: Lucie Piterkova, Jana Kucerova, Karel Indrak, Vladimir Divoky
Journal: Blood (2010)
Response To First-Line Treatment In Stem Cell Transplant (SCT) and Non-SCT Patients With Newly Diagnosed Multiple Myeloma Who Are Enrolled In The Connect MM Registry
Authors: Rafat Abonour, Jatin J. Shah, Brian Durie, Howard Terebelo, Cristina J Gasparetto, Jayesh Mehta, Mohit Narang, Sachdev P Thomas, Kathleen Toomey, Kristen A Sullivan, Shankar Srinivasan, Yasir Nagarwala, Robert M Rifkin
Journal: Blood (2013)