tbuckley/cabot-search huggingface dataset:
Protection against malaria in mice is induced by blood stage–arresting <i>histamine-releasing factor</i> (<i>HRF</i>)–deficient parasites
Authors: Claudia Demarta-Gatsi, Leanna Smith, Sabine Thiberge, Roger Peronet, Pierre-Henri Commere, Mariette Matondo, Lionel Apetoh, Pierre Bruhns, Robert Ménard, Salaheddine Mécheri
Journal: The Journal of Experimental Medicine (2016)

Although most vaccines against blood stage malaria in development today use subunit preparations, live attenuated parasites confer significantly broader and more lasting protection. In recent years, Plasmodium genetically attenuated parasites (GAPs) have been generated in rodent models that cause self-resolving blood stage infections and induce strong protection. All such GAPs generated so far bear mutations in housekeeping genes important for parasite development in red blood cells. In this study, using a Plasmodium berghei model compatible with tracking anti-blood stage immune responses over time, we report a novel blood stage GAP that lacks a secreted factor related to histamine-releasing factor (HRF). Lack of HRF causes an IL-6 increase, which boosts T and B cell responses to resolve infection and leave a cross-stage, cross-species, and lasting immunity. Mutant-induced protection involves a combination of antiparasite IgG2c antibodies and FcγR(+) CD11b(+) cell phagocytes, especially neutrophils, which are sufficient to confer protection. This immune-boosting GAP highlights an important role of opsonized parasite-mediated phagocytosis, which may be central to protection induced by all self-resolving blood stage GAP infections.
Abstract 3673: BVES dependent regulation of YAP1 in colorectal cancer cells
Authors: Mukul K. Mittal, Anthony Bilotta, Cody E. Keating, Sarah P. Short, Christopher S. Williams
Journal: Cancer Research (2016)

Abstract Colorectal cancer (CRC) has a US incidence rate of almost 150,000 cases and accounts for over 10% of new cancer diagnoses. Dysfunction of epithelial adherens junctions and tight junctions (TJs) have long been implicated in CRC growth and metastasis The Popeye domain containing family of proteins are TJ-associated and appear to nucleate TJ formation. BVES or POPDC1 is one member of this family and is under-expressed in all stages of human colorectal carcinoma (CRC). On the other hand, YAP1 a novel oncogene in the Hippo pathway is up-regulated in many cancers including colon cancer. In the present study, we report an inverse correlation between tumor suppressor protein BVES and oncogene YAP1 in human colorectal carcinoma tumor samples and human colon cancer cell lines. We demonstrate that ectopic expression of BVES in BVES deficient cells decreases YAP1 protein while knocking down BVES in cells expressing BVES increases YAP1 levels. Cycloheximide (CHX) experiments indicate that this is likely occurring at the level of protein stability. CDK6 is a cell cycle regulator and YAP1 transcriptional target, and its levels are increased in the setting of BVES-knockdown in CACO2 cells. Concurrent with this there is increased cell growth. Conversely, when BVES is overexpressed, CDK6 transcription is reduced. Further knocking down of YAP1 in BVES knocked down cells reverses the cell growth advantage suggesting that BVES regulation of cell growth in part is dependent upon YAP1 protein levels. Co-immunoprecipitation (Co-IP) and yeast-2-hybrid (Y2H) assay also shows a direct interaction of BVES and YAP1. In sum, these findings suggest a novel mechanism underlying BVES tumor-suppressive function through regulation of a potential growth modulator, YAP1 in colorectal cancer. Citation Format: Mukul K. Mittal, Anthony Bilotta, Cody E. Keating, Sarah P. Short, Christopher S. Williams. BVES dependent regulation of YAP1 in colorectal cancer cells. [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 3673.
A network meta-analysis (NMA) of randomized controlled trials (RCT) of chemotherapy regimens for metastatic pancreatic cancer (mPC).
Authors: Gillian Gresham, Sharlene Gill, George A Wells, Derek J. Jonker
Journal: Journal of Clinical Oncology (2013)

4050 Background: Recent RCTs suggest a survival benefit for combination therapy in mPC compared to gemcitabine alone. Such combinations include FOLFIRINOX and gemcitabine plus nab-paclitaxel (G+nab-P). Survival and safety outcomes of these regimens were analyzed using gemcitabine as the reference comparator. Methods: Systematic review and NMA included data from reported phase III RCTs meeting quality standards and compared chemotherapy treatment to gemcitabine for mPC between 2000 and 2013. Excluded were trials assessing locally advanced pancreatic cancer. Following inter-trial heterogeneity assessment (patient characteristics, trial methodologies, treatment protocols), Bayesian NMAs were conducted for primary (overall survival [OS]) and secondary (progression free survival [PFS]) outcomes, overall response rate [ORR], and safety. Results: 27 studies were included involving 10 429 patients and 18 different treatments. No significant heterogeneity was observed between trials. When indirectly compared, FOLFIRINOX, PEFG and G+nab-P were top ranked for OS, PFS and ORR (Table). Comparing FOLFIRINOX and G +nab-P, there was no significant difference in odds ratios (OR) for febrile neutropenia, diarrhea or sensory neuropathy. FOLFIRINOX caused more gr3-4 neutropenia (OR 1.85 (95%Cl 1.1-3.4),p&lt;0.05), and G+nab-P trended more gr3-4 fatigue (OR 2.03 95% Cl 0.95-3.8). Conclusions: Survival and safety outcomes were comparable amongst the three regimens identified from this network meta-analysis for mPC. FOLFIRINOX tended towards a greater survival benefit over G+nab-P and PEFG although comparisons did not reach statistical significance.Head-to-head trials between FOLFIRINOX, G+nab-P and PEFG are needed to further compare the survival benefits and safety profiles of these treatments. [Table: see text]
Tolerability of dronabinol alone, ondansetron alone and the combination of dronabinol plus ondansetron in delayed chemotherapy-induced nausea and vomiting
Authors: H. Jhangiani, E. Meiri, J. Vredenburgh, L. Barbato, H. Yang, D. Li, V. Baranowski, N. Tse
Journal: Journal of Clinical Oncology (2005)

8196 Background: Dronabinol (Marinol), the synthetic version of tetrahydrocannabinol, is used to treat nausea and vomiting following cancer chemotherapy (CINV). It has a unique mechanism of action (cannabinoid receptor binding) compared to the more frequently used serotonin receptor antagonists. Tolerability of dronabinol versus ondansetron and the combination of dronabinol plus ondansetron was explored in subjects with delayed CINV. Methods: Subjects receiving moderate to high emetogenic chemotherapy were randomized in this double-blind, placebo-controlled, flexible-dose study. All subjects received dexamethasone 20mg PO and ondansetron 16mg IV prior to chemotherapy. Subjects in the dronabinol (D), ondansetron (O) and dronabinol plus ondansetron (DO) groups also received dronabinol 2.5mg pre- and post-chemotherapy (Day 1); the placebo (P) group did not. Treatment continued through Day 5. Adverse events (AEs) were coded using the MedDRA dictionary. No statistical testing was conducted on AE rates. Results: All 64 randomized subjects were in the safety population. Conclusion: Dronabinol was well tolerated and resulted in few terminations due to adverse events. The low rate of CNS-related adverse events following D treatment may make it a suitable alternative to serotonin antagonist therapy for delayed CINV. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Solvay Quintiles, Solvay Solvay
Abstract 2567: Characterizing histologic subtypes in lung cancer using principal component analysis
Authors: Jinyoung Byun, Younghun Han, Christopher I. Amos
Journal: Cancer Research (2016)

Abstract Lung cancer is the leading cause of cancer death in the United States and worldwide. The two major forms of lung cancer are small-cell lung carcinoma (SCLC) and non-SCLC (NSCLC). NSCLC is divided into three major histologic subtypes: Squamous-cell carcinoma, adenocarcinoma, and large-cell. Histological subtypes of cancers vary with respect to the genes that shows altered regulation, compared to normal bronchioepithelial cells. Lung cancer histologic diagnosis is clinically relevant because there are histology-specific treatment indications and contradictions. Principal component analysis (PCA) is one of the useful statistical tools for analyzing multivariate data and recently high-dimensional data in genetics and genomics. We demonstrated the classification between two major subtypes of lung cancer: 488 squamous cell carcinoma and 788 adenocarcinoma cases. We selected the top 20k significant SNPs using logistic regression and then conducted PCA as the unsupervised approach. We observed a distinct pattern between two major subtypes of NSCLC in genome-wide association study (GWAS). There were several publications to classify the subtypes of histology in lung cancer using gene expression data. This enables to understand the patterns for other subtypes of lung cancer in GWAS. Citation Format: Jinyoung Byun, Younghun Han, Christopher I. Amos. Characterizing histologic subtypes in lung cancer using principal component analysis. [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 2567.
A phase I study of the vascular-disrupting agent BNC105P in combination with gemcitabine-carboplatin in platinum-sensitive ovarian cancer patients in first or second relapse.
Authors: Danny Rischin, Philip James Beale, Emma Caroline Rossi, Jeffrey C. Goh, Michelle Margaret Vaughan, Meaghan Elizabeth Tenney, Julie Martyn, Dirkje Willemien Sommeijer, Jose Luis Iglesias, Gabriel Kremmidiotis, Jeremy Andrew Simpson, Elizabeth E. Doolin, Tina C. Lavranos, Annabell F. Leske, Anne-Sophie Veillard, Martin R. Stockler
Journal: Journal of Clinical Oncology (2014)

5524^ Background: BNC105P is a tubulin polymerization inhibitor and a vascular disrupting agent (VDA) selectively active against tumor endothelium. Pre-clinical data has demonstrated greater than additive activity of BNC105P when combined with platinum or with gemcitabine. The primary objective of this study was to evaluate the safety and tolerability of BNC105P in combination with gemcitabine and carboplatin in patients with recurrent ovarian cancer, and to find a dose suitable for evaluation in a randomized trial. Methods: Patients with ovarian cancer who progressed > 4 months after first or second-line platinum based chemotherapy received carboplatin AUC4 at day 1 in combination with escalating doses of gemcitabine at day 1 and 8 and escalating doses of BNC105P at day 2 and 9 every 21 days for a maximum for 6 cycles. Maintenance treatment with 16 mg/m2BNC105P treatment continued for a maximum of 6 additional cycles. Blood samples were collected at baseline and 4 hours post BNC105P to study potential pharmacodynamic biomarkers associated with BNC105P biological action in previous trials. Results: 15 patients were enrolled in the study. Adverse events were most commonly of haematological origin. Dose limiting toxicities occurred in 1 patient on dose level 1 and 2 patients on dose level 2a and consisted of thrombocytopenia and neutropenia. The recommended dose was gemcitabine 1,000 mg/m2, carboplatin AUC 4 and BNC105P 12 mg/m2. 10 patients achieved a response according to GCIG CA125 and/or RECIST 1.1 criteria. Increases in blood levels of ferritin, interleukin-8, interleukin-16 and macrophage inflammatory protein-1beta post 12 mg/m2BNC105P were consistent with a pharmacodynamic response.. Conclusions: The combination of BNC105P with gemcitabine and carboplatin is safe and tolerable in patients with potentially platinum sensitive recurrent ovarian cancer. The data supports continued development of BNC105P in this setting. Clinical trial information: ACTRN12612000522819. Dose level 1 Dose level 2a Dose Level 2b BNC105P 12 mg/m2 16 mg/m2 12 mg/m2 Gemcitabine 800 mg/m2 800 mg/m2 1000 mg/m2 Carboplatin AUC4 AUC 4 AUC 4 No. registered 6 3 6 No. DLTs 1 2 0
Reply
Authors: Carol Ann Hitchon, Hester Koppejan, Leendert A. Trouw, Tom J. W. Huizinga, René E. M. Toes, Hani S. El‐Gabalawy
Journal: Arthritis & Rheumatology (2016)

Hutchinson and colleagues in their Letter to the Editor propose a novel hypothesis in which modified-misfolded proteins such as immunoglobulin, in the setting of a permissive genetic background, might be a common link for the three autoantibody systems in RA;(Rheumatoid Factor (RF), Anti-citrullinated protein antibodies, (ACPA) and anti-carbamylated protein antibodies (antiCarP). We discuss other potential antigenic targets and pathways to the production of these antibodies in RA. This article is protected by copyright. All rights reserved.
Abstract LB-306: Molecular mechanisms of trastuzumab-mediated cardiomyopathy: Implications of autophagy in trastuzumab-induced cardiotoxicity
Authors: Nishant Mohan, Yi Shen, Wen J. Wu
Journal: Cancer Research (2016)

Abstract Trastuzumab is a humanized monoclonal antibody directed against the extracellular domain IV of human epidermal growth factor receptor 2 (HER2) and approved for the treatment of HER-2 positive breast cancer and gastric cancer. Trastuzumab therapy is associated with considerable cardiotoxicity, the mechanism of which remains unclear. Dysregulation of autophagy has been implicated in various cardiovascular diseases. In this investigation, we explored a novel mechanism by which trastuzumab dysregulates HER2 signaling and impairs basal autophagic process in human primary cardiomyocytes. Specifically, trastuzumab treatment leads to the phosphorylation of HER1-Y845 and HER2-Y1248 and the activation of Erk. This in turn results in up-regulation of mTOR/Ulk1 pathway and subsequently inhibition of autophagy in primary cardiomyocytes, by downregulating LC3I/II and increase in p62. We further demonstrate that trastuzumab-mediated inhibition of autophagy resulted in the increased production of reactive oxygen species (ROS) in cardiomyocytes. Pertuzumab, another anti-HER2 therapeutic mAb binding to HER2 domain II, fails to modulate HER2 signaling and is unable to influence autophagy in cardiomyocytes. This study provides novel mechanistic insights into trastuzumab-induced cardiotoxicity, which may assist in formulating novel approaches for clinical management of trastuzumab-induced cardiomyopathy. Citation Format: Nishant Mohan, Yi Shen, Wen J. Wu. Molecular mechanisms of trastuzumab-mediated cardiomyopathy: Implications of autophagy in trastuzumab-induced cardiotoxicity. [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-306.
Abstract SY42-01: Emerging epigenetic targets in high-risk pediatric solid tumors
Authors: Kimberly Stegmaier
Journal: Cancer Research (2016)

Abstract Pediatric cancers are typically characterized by simple genomes and key initiating events driven by aberrancy of a transcription factor or chromatin modifier. One such example is the most common extracranial solid tumor in children, neuroblastoma. Amplification of the transcription factor encoding gene MYCN is present in ∼50% of high-risk neuroblastomas, representing the best-characterized genetic marker of poor survival in these pediatric patients. We have focused on the discovery of new therapeutic strategies to targeting this recalcitrant subtype of neuroblastoma using chemical and functional genomic approaches. First, we identified BET bromodomain inhibitors as highly active in MYCN-amplified neuroblastoma in an unbiased screen of 673 diverse cancer cell lines and validated this finding using genetic suppression with shRNA and chemical inhibition with multiple BET inhibitors. Mechanistically, BET inhibitors suppress the MYCN transcriptional program and the expression of MYCN itself. Extending these studies in vivo, both to patient derived xenografts (PDX) and to genetically engineered mouse (GEM) models of MYCN-driven neuroblastoma, we demonstrated remarkable efficacy. However, this single agent approach was not curative, suggesting the need for combination therapies. In order to address this issue, we performed both gain-of-function (ORF) and loss-of-function (CRISPR/Cas9) screening of neuroblastoma cell lines treated with BET bromodomain inhibitors at an IC90 to identify potential mechanisms of resistance to treatment and to nominate targetable pathways for combination therapy. Three key pathways emerging at the intersection of these screens are under evaluation and will be presented. In parallel, we have performed a genome-wide CRISPR screen in a panel of 8 neuroblastoma cell lines, 7 of which are MYCN amplified, to identify new dependencies. In comparing neuroblastoma cell lines to over 70 non-neuroblastoma cancer cell lines, several known neuroblastoma dependencies were confirmed, including MYCN, ALK, and PHOX2B. Importantly, novel dependencies were revealed. Validated new dependencies will also be the topic of this presentation. Citation Format: Kimberly Stegmaier. Emerging epigenetic targets in high-risk pediatric solid tumors. [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 SY42-01.
Abstract 2386: Microfluidic single cell exome-seq and RNA-seq analysis of tumor composition
Authors: Ioannis Ragoussis, Paul Savage, Yu-Chang Wang, Timothee Revil, Dunarel Badescu, Sadiq Saleh, Ernesto Iacucci, Nicolas Bertos, Anie Monast, Attila Omeroglou, Dongmei Zuo, Morag Park
Journal: Cancer Research (2016)

Abstract Human breast tumors have been shown to exhibit extensive inter- and intra-tumor heterogeneity. While recent advances in genomic technologies have allowed us to deconvolute this heterogeneity, few studies have addressed the functional consequences of diversity within tumor populations. Here, we identified an index case for which we have derived a patient-derived xenograft (PDX) as a renewable tissue source to identify subpopulations and perform functional assays. On pathology, the tumor was an invasive ductal carcinoma which was hormone receptor-negative, HER2-positive (IHC 2+, FISH average HER2/CEP17 2.4), though the FISH signal was noted to be heterogeneous. On gene expression profiling of bulk samples, the primary tumor and PDX were classified as basal-like. We performed single cell RNA and exome sequencing of the PDX to identify population structure. Using a single sample predictor of breast cancer subtype, we have identified single basal-like, HER2-enriched and normal-like cells co-existing within the PDX tumor, a finding replicated in several independent experiments. Genes differentially expressed between these subpopulations are involved in proliferation and differentiation. One population was characterized by high MYC and the other high EGFR/KRT14. These findings were validated using immunohistochemistry on PDX and primary tumor material. Further functional experiments showed that that EGFR subpopulation has stem cell character istics and forms metastasis in the animal model. Microfluidic whole genome amplification followed by whole exome capture of 81 single cells, along with exome sequencing of the germline, primary and post treatment tumor and whole PDX showed that BRCA1 and TP53 are mutated in all single cells, as well as a number of sub-clonal mutations that are being investigated further. Loss of heterozygocity was observed in 16 TCGA cancer driver genes and novel mutations in 7 known cancer driver genes. Careful comparison of the exome sequencing data allowed the association of driver gene mutation prevalence with tumor progression. These findings are important in our understanding the functional consequences of intra-tumor heterogeneity with respect to clinically important phenotypes such as invasion, metastasis and drug-resistance. Citation Format: Ioannis Ragoussis, Paul Savage, Yu-Chang Wang, Timothee Revil, Dunarel Badescu, Sadiq Saleh, Ernesto Iacucci, Nicolas Bertos, Anie Monast, Attila Omeroglou, Dongmei Zuo, Morag Park. Microfluidic single cell exome-seq and RNA-seq analysis of tumor composition. [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 2386.
Abstract 5207: Comparison of subtype-specific incidence rates of lymphoid malignancies in Hong Kong and the United States
Authors: Nathaniel Rothman, Bryan A. Bassig, Wing-Yan Au, Oscar Mang, Roger Ngan, Lindsay M. Morton, Dennis K.M. Ip, Wei Hu, Tongzhang Zheng, Wei Jie Seow, Jun Xu, Qing Lan
Journal: Cancer Research (2016)

Abstract Clinical studies of lymphoid malignancies (LMs) have suggested that the descriptive patterns of these neoplasms differ in East Asia compared to Western populations. However, there are very limited available data on population-based, subtype-specific incidence rates of LMs in the East Asian population, particularly in Chinese. Using data from the Hong Kong (HK) Cancer Registry and the United States (U.S.) Surveillance, Epidemiology, and End Results Program, we calculated and compared age-adjusted incidence rates of LM subtypes in HK to those in Whites and Asians living in the U.S. Overall and sex-specific rates were calculated for the period 2001-2010. In order to formally compare the incidence rates between HK and the U.S., standardized rate ratios (SRRs) were calculated comparing the age-adjusted rates of each subtype for U.S. Whites and U.S. Asians in the SEER 13 database to HK. The incidence of most subtypes was low in the HK population, with rates &amp;lt;1 case per 100,000 for all subtypes except for diffuse large B-cell lymphoma (3.26/100,000) and plasma cell neoplasms (1.99/100,000). Age-adjusted incidence rates of all evaluated B-cell subtypes were significantly higher in U.S. Whites compared to HK, with SRRs ranging from 1.6 (Burkitt lymphoma) to 9.1 (chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL)). Rates in U.S. Asians were generally intermediate to those in U.S. Whites and HK, with SRRs for B-cell subtypes ranging from 1.0 (Burkitt) to 2.0 (CLL/SLL) comparing Asians in the U.S. to HK. For T or NK-cell subtypes, rates of extranodal NK/T-cell lymphoma were significantly lower in both U.S. Whites (SRR = 0.2) and U.S. Asians (SRR = 0.5) compared to HK. However, incidence rates of other evaluated T-cell subtypes were comparable or slightly higher in the U.S. population compared to HK. Our findings, which are based on data from population-based disease registries, provide new insight into the subtype-specific patterns of LMs in the Chinese population, and suggest the need for etiological studies of LMs in the East Asian population to elucidate the factors responsible for these differences in the geographic incidence patterns. Citation Format: Nathaniel Rothman, Bryan A. Bassig, Wing-Yan Au, Oscar Mang, Roger Ngan, Lindsay M. Morton, Dennis K.M. Ip, Wei Hu, Tongzhang Zheng, Wei Jie Seow, Jun Xu, Qing Lan. Comparison of subtype-specific incidence rates of lymphoid malignancies in Hong Kong and the United States. [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 5207.