tbuckley/cabot-search huggingface dataset:
Abstract 18151: NIH-Funded Cardiac Arrest Research: A 10-Year Trend Analysis
Authors: Ryan A Coute, Ashish R Panchal, Timothy J Mader, Robert W Neumar
Journal: Circulation (2016)

Background:  Cardiac  (CA) is a leading cause of death in the U.S., claiming over 500,000 lives annually. Improving survival depends largely on the ability to conduct CA research, and the translation of research findings into practice. Our objective was to provide a descriptive analysis of annual NIH-funding for CA research over the past decade.   Methods:  An advanced search within NIH RePORTER for the years 2006-2015 was performed using the following terms:   arrest or “cardiopulmonary resuscitation” or “heart arrest” or “circulatory arrest” or “pulseless electrical activity” or “ventricular fibrillation” or “resuscitation.  Grants were reviewed and categorized as CA research (yes/no) using predefined criteria. The annual number of CA grants, principal investigators, newly funded grants, trainee grants, non-human subject grants, human-subject grants, and pediatric grants were tabulated. The total NIH investment in CA research was calculated and compared to other leading causes of death within the U.S. The data were analyzed descriptively. Inter-rater reliability between three independent reviewers for funding year 2015 was assessed using Fleiss’s Kappa calculation.   Results:  The search yielded 2,693 NIH-funded grants, of which 749 (27.8%) were classified as CA research (Kappa = 0.86). Comparing 2006 to 2015, an increase was seen in the annual number of CA grants (69-81), principal investigators (60-75), individual trainee grants (5-16), and pediatric CA grants (6-16). The total funding for CA research increased from $32.8 M in 2006 to $40.8 M in 2015. This NIH investment in CA research represents approximately 0.13% of the 2015 NIH budget, while stroke and heart disease represent 0.95% and 4.2%, respectively. Per annual death, this investment equates to ~$2,200 for stroke, ~$2,100 for heart disease, and ~$81 for cardiac arrest.   Conclusion:  A modest increase in the annual number of NIH-funded CA grants, principal investigators, trainee grants, and pediatric CA grants has occurred over the past decade. Our data suggests that the NIH investment in CA research is substantially less than other leading causes of death in the U.S.
Abstract 939: Single cell mRNA expression profiling reveals heterogeneity of normal and malignant breast stem cell populations
Authors: Shamileh Fouladdel, Justin Colacino, Ebrahim Azizi, Max S. Wicha
Journal: Cancer Research (2017)

Abstract The normal breast contains epithelial populations which are hierarchically organized, a profile recapitulated in breast cancer. At the apex of these hierarchies are "stem like" cells defined by their capacity to self-renew as well as to generate more differentiated progeny. In breast cancer these "cancer stem cells" (CSCs) have been shown to be important mediators of tumor metastasis and treatment resistance. Although the phenotypes of normal rodent and human mammary stem cells have been characterized, CSC populations are operationally defined by their capacity for tumor initiation. In addition, putative breast CSC markers such as CD44+/CD24low/- and or ALDH+ have proven useful in enriching for cells capable of tumor initiation and previous studies have suggested that these markers identify alternative mesenchymal and epithelial stem cell states, respectively. However, it remains unclear whether CSCs exist in discrete states or whether these cells actually represent a continuum reflected in heterogeneity of cell populations defined by expression of these markers. To address this question we utilized single cell mRNA expression profiling of normal and malignant breast stem cells. We first generated a panel of 96 genes representing stem cell and developmental pathways and analyzed expression of these 96 genes utilizing Fluidigm’s C1 and BioMark HD technologies and TaqMan gene expression assays. We also utilized Fluidigm’s Polaris to selectively isolate single cells that were then analyzed by illumina RNA-Seq method. Utilizing these advanced technologies, we demonstrated that both normal and malignant breast stem cells characterized by CD44+/CD24low/- and or ALDH+ expression are highly heterogeneous. For example, the ALDH isoforms ALDH1A1 and ALDH1A3 were each expressed in some single cells and co-expressed in others. ALDH1A1 expressing single cells appeared to express a unique gene pattern characterized by SLIT/ROBO, PLXNA2, RHOU and HNF1a. These results suggest that at the level of mRNA expression, normal and malignant breast stem cells display a greater heterogeneity than has previously been reported. These results have important implications for breast carcinogenesis as well as for the development of therapeutic strategies designed to target CSCs in breast cancer. Citation Format: Shamileh Fouladdel, Justin Colacino, Ebrahim Azizi, Max S. Wicha. Single cell mRNA expression profiling reveals heterogeneity of normal and malignant breast stem cell populations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 939. doi:10.1158/1538-7445.AM2017-939
NHS director who was arrested on suspicion of voyeurism resigns
Authors: Abi Rimmer
Journal: BMJ (2017)

Jonathan Fielden, NHS England’s deputy medical director and director of specialised commissioning services, has resigned. In February he was arrested by police on suspicion of voyeurism.1

In a statement issued on 26 July, NHS England said that Fielden had resigned from his post “to pursue other opportunities, effective 10 September 2017.” Formerly one of four medical directors at University College Hospital London NHS Foundation Trust, …
Abstract 4232: Gastrointestinal stromal tumor: Retrospective analysis of 44 cases of center of reference in eastern Algeria
Authors: Soufyane Ali Boukhalfa, Tah Filali
Journal: Cancer Research (2017)

Abstract Aim: To analyze the clinicopathologic characteristics, prognostic factors, and treatment of gastrointestinal stromal tumors (GISTs). Methods: We conducted a retrospective analysis of all cases of GISTs treated in the Medical Oncology Unit from 2010 through 2015. Results: We analyzed 44 patients with a median age of 49.43 years (17-76 years) with sex ratio 1:1. The main symptom was abdominal pain. Thirty patients had limited-stage disease and 14 patients had metastatic disease. We observed 90% of the immunohistochemistry exams were positive for CD117 (c-Kit+). The most frequent location was in the stomach (45%), the high-risk group was predominant (50%) and the average tumor size is 12.84 cm. Surgery was considered R0 (extensive) in 75% of the cases and the main sites of metastases were liver and peritoneum.25 patients received imatinib 400 mg qDay in adjuvant setting,5 patients in neoadjuvant, 13 patients in palliative and 1 patient had best supportive care. A total of 44 patients were followed up for 1 to 78 months.6 patients (13 %) developed recurrence or metastasis during or after adjuvant treatment. Two patients had surgery after neoadjuvant treatment(40%). 4 patients treated in second line with imatinib 800 mg qDay, 5 patients with sunitinib and 2 patients rechallenged in third line with imatinib 800 mg qDay. Conclusion: Our patients presented mainly in the form of high-risk disease, Surgery is the mainstay treatment when GISTs are localized, Adjuvant therapy is used depending their risk of relapse. In the advanced disease, tyrosine kinase inhibitors have substantially improved the prognosis of GISTs. Note: This abstract was not presented at the meeting. Citation Format: Soufyane Ali Boukhalfa, Tah Filali. Gastrointestinal stromal tumor: Retrospective analysis of 44 cases of center of reference in eastern Algeria [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4232. doi:10.1158/1538-7445.AM2017-4232
Abstract 2843: DNMT3B mediated DNA methylation and epigenetic reprogramming of metastatic cancer cells
Authors: Jae Young So, Nicolas Skrypek, Xiang Wang, Anand Merchant, Howard Yang, Wei-Dong Chen, Gangqing Hu, Bhagelu R Achyut, Meggie Cam, Keji Zhao, Maxwell Lee, Li Yang
Journal: Cancer Research (2017)

Abstract Approximately 90% of cancer patients die from metastasis. In many cases, current therapies are designed based on the primary tumor characterization and are ineffective against metastatic disease. It is not clear whether metastatic cancer cells acquire additional genetic and epigenetic alterations, if so, what are the underlying mechanisms. Using several tumor models, we demonstrated that DNMT3B, de nova DNA methyltransferase, was increased in metastatic nodules in comparison to that from the primary tumors. DNMT3B knockdown or overexpression significantly inhibited or increased metastatic colonization of cancer cells. To understand the underlying molecular mechanisms of DNMT3B regulation, we performed DNMT3B ChIP-seq, RNA-seq, and DNA methylation-seq comparing lung metastases with primary tumors and 4T1 cells. We identified genes that are differentially methylated and expressed. Ingenuity Pathway Analysis revealed DNMT3B targeting multiple oncogenic signaling pathways. Bioinformatics analysis of human databases demonstrated significantly higher expression levels of DNMT3B in metastases than primary tumors in breast, prostate and melanoma cancer patients. In summary, our study demonstrated that DNMT3B as a key epigenetic regulator which plays critical roles for tumor metastasis. Our work suggests DNMT3B as potential therapeutic targets for breast cancer patients with metastatic disease. Citation Format: Jae Young So, Nicolas Skrypek, Xiang Wang, Anand Merchant, Howard Yang, Wei-Dong Chen, Gangqing Hu, Bhagelu R Achyut, Meggie Cam, Keji Zhao, Maxwell Lee, Li Yang. DNMT3B mediated DNA methylation and epigenetic reprogramming of metastatic cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2843. doi:10.1158/1538-7445.AM2017-2843
Abstract 1865: Enhancing the in vivo detection of cancer by manipulating magnetic fields applied to tumor targeting superparamagnetic iron oxide nanoparticles
Authors: Todor Karaulanov, Erika C. Vreeland, Andrew Gomez, Kayla E. Minser, Caroline L. Weldon, William H. Anderson, Christopher Nettles, Giulio Paciotti
Journal: Cancer Research (2017)

Abstract Superparamagnetic Relaxometry (SPMR) is combination technology for the early detection of cancer. Conceptually, PEGylated superparamagnetic iron oxide (Fe3O4) nanoparticles (NPs) coupled with a tumor targeting monoclonal antibody are systemically administered and target solid tumors by both passive (EPR) and active (receptor targeting) mechanisms. Once bound to the target cells, the NPs are magnetized by a brief, low field magnetic pulse to create macroscopic magnetization. Once the field is removed, the particle’s magnetization decays and is measurable by superconducting quantum interference device (SQUID) detectors. The pattern of decay, known as Néel relaxation, exhibits a difference in latency specific to bound nanoparticles and differs from the Brownian decay exhibited by free/unbound particles. As a proof of concept, we developed PEGylated NPs that are covalently bound to an anti-Her-2 monoclonal antibody. In vitro, the nanoconstruct exhibits specific binding to the Her-2 overexpressing BT-474 breast cancer cells, with little to no binding to Her-2 negative MCF-7cells. Similar patterns of selective targeting were observed in vivo. To improve the specific detection of SPMR signals in tumors we developed a novel system that selectively enhances the magnetic signal at tumor sites and reduces the contribution of similar signals at off target sites such as the liver and spleen. For these studies, we created phantoms of varying strength to mimic tumor and non-specific signals. We observed that by creating non-homogenous excitation magnetic field patterns, we reduced the contribution of the non-specific signals by an order of magnitude, effectively increasing the signal to noise ratio of the tumor signal. These results are clinically relevant and support the use of SPMR in the detection of small tumors in cancer patients. Citation Format: Todor Karaulanov, Erika C. Vreeland, Andrew Gomez, Kayla E. Minser, Caroline L. Weldon, William H. Anderson, Christopher Nettles, Giulio Paciotti. Enhancing the in vivo detection of cancer by manipulating magnetic fields applied to tumor targeting superparamagnetic iron oxide nanoparticles [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1865. doi:10.1158/1538-7445.AM2017-1865
Abstract 3683: Melphalan stimulates dendritic cell and CD8+ T cell expansion by inducing immunogenic cell death in melanoma cells
Authors: Junko Johansson, Roberta Kiffin, Per Lindnér, Peter Naredi, Roger Olofsson Bagge, Anna Martner
Journal: Cancer Research (2017)

Abstract Background: Regional hyperthermic perfusion with the alkylating agent melphalan is a treatment option for patients with metastatic melanoma confined to the limbs or the liver. Following a single perfusion, tumors often decrease gradually in size during several months, suggesting an immune-mediated mechanism of action, in addition to the direct cytotoxic effects of melphalan. This study was designed to characterize the immunogenic effects of melphalan. Materials and methods: We have established an in vitro model of regional hyperthermic perfusion where human melanoma cell lines are exposed to melphalan at 40oC for 1 h, thus mimicking the currently employed clinical protocol. The melphalan-exposed melanoma cells were analyzed for markers of immunogenic cell death and were co-cultured with peripheral blood mononuclear cells (PBMCs) in the presence or absence of IL-2. The number and activation status of various immune populations were analyzed by flow cytometry. Results: Melphalan exposure triggered the expression of several immune-related markers on melanoma cells, including calreticulin, MHC class I, Hsp70 and PD-L1. Melphalan-treated, but not untreated melanoma cells, triggered an increase in dendritic cell (DC) numbers along with a dramatic expansion of CD8+ T cells in co-cultured PBMCs. The expanded CD8+ T cells showed an activated phenotype with the majority of cells belonging to the effector memory subtype. Conclusions: Melanoma cells exposed to melphalan undergo immunogenic cell death and trigger DC expansion with subsequent expansion and activation of CD8+ T cells. We propose that these events may contribute to the anti-tumor efficacy of regional hyperthermic perfusion with melphalan in metastatic melanoma. Citation Format: Junko Johansson, Roberta Kiffin, Per Lindnér, Peter Naredi, Roger Olofsson Bagge, Anna Martner. Melphalan stimulates dendritic cell and CD8+ T cell expansion by inducing immunogenic cell death in melanoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3683. doi:10.1158/1538-7445.AM2017-3683
Abstract 4996: The m6A hallmark of cancer: RNA demethylase ALKBH5 maintains tumorigenicity of glioblastoma stem-like cells by sustaining FOXM1 expression and cell proliferation
Authors: Sicong Zhang, Aidong Zhou, Oliver Bogler, Sadhan Majumder, Suyun Huang
Journal: Cancer Research (2017)

Abstract N6-methyladenosine (m6A) is the most prevalent internal modification on mRNA, but its functions in human diseases are poorly understood. The dynamic and reversible m6A modification installed and erased by N6-methyltransferases and demethylases regulates cell fate and gene expression. We show that the m6A demethylase ALKBH5 is highly expressed in patient-derived glioblastoma stem-like cells (GSCs) and informs poor survival of patients with glioblastoma. Silencing ALKBH5 suppresses the proliferation of GSCs in vitro and in vivo. Results of integrated transcriptome and m6A-seq analyses reveal a global change of gene expression enriched in cell cycle and altered expression of select ALKBH5 targets. Among these targets, Ingenuity’s upstream regulator analysis identified FOXM1, an essential transcription factor for GSC proliferation, as a key mediator responsible for the disrupted proliferation program. Using multiple molecular and biochemical approaches, we demonstrate that ALKBH5 binds to and demethylates FOXM1 nascent transcripts. This promotes the interaction of FOXM1 pre-mRNA with HuR, thereby maintaining FOXM1 expression. Further, a long noncoding RNA antisense to the FOXM1 (FOXM1-AS) interacts with ALKBH5 as well as FOXM1 pre-mRNA and promotes their interaction. Depleting ALKBH5 and FOXM1-AS abolishes GSC tumorigenesis through the FOXM1 axis. The vulnerability of GSCs to disruptions in ALKBH5-dependent gene expression suggests that m6A has a central role in tumor development and provides a rationale for therapeutically targeting epitranscriptomic modulators in patients with glioblastoma. Citation Format: Sicong Zhang, Aidong Zhou, Oliver Bogler, Sadhan Majumder, Suyun Huang. The m6A hallmark of cancer: RNA demethylase ALKBH5 maintains tumorigenicity of glioblastoma stem-like cells by sustaining FOXM1 expression and cell proliferation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4996. doi:10.1158/1538-7445.AM2017-4996
Abstract 3459: BRCA1 controls the cell division axis and governs ploidy and phenotype in human mammary cells
Authors: Zhengcheng He, Oksana Nemirovsky, Nagarajan Kannan, Connie Eaves, Christopher A. Maxwell
Journal: Cancer Research (2017)

Abstract BRCA1 deficiency alters the relative proportions of progenitor cells in preneoplastic mammary tissue, and typically associates with breast cancers characterized by genomic instability and a basal-like cell phenotype. Oriented division of progenitor cells is one mechanism these cells use to maintain tissue homeostasis, and to suppress tumor formation. We now show that shRNA-mediated reduction of BRCA1 levels in non-tumorigenic and immortalized or freshly isolated, normal human mammary cells alters their plane of division with graded consequences that include the induction of aneuploidy in progeny cells, perturbation of polarity in spheroid cultures, and inhibition of clonal growth with favored expression of basal features. We also demonstrate a requirement for BRCA1 in establishing cortical asymmetry of NUMA-dynein complexes. Mutation of a single BRCA1 allele (BRCA1 185delAG/+) altered the division axis of isolated cells but their deficient spindle positioning was supervised by CDH1-positive adherens, which sustained oriented divisions and produced colonies with luminal features. These findings reveal a previously unrecognized consequence of mutant BRCA1 on the cell division axis, post-mitotic integrity and phenotype control in normal human mammary epithelial cells. Note: This abstract was not presented at the meeting. Citation Format: Zhengcheng He, Oksana Nemirovsky, Nagarajan Kannan, Connie Eaves, Christopher A. Maxwell. BRCA1 controls the cell division axis and governs ploidy and phenotype in human mammary cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3459. doi:10.1158/1538-7445.AM2017-3459
Abstract 636: Comprehensive analysis of T cells responsive to neoantigens derived from tumor-specific genetic mutations
Authors: Tetsuro Sasada, Junya Ohtake, Satoshi Wada, Erika Yada, Shintaro Yoshida
Journal: Cancer Research (2017)

Abstract Neoantigens derived from tumor-specific genetic mutations can be recognized as foreign by the host immune system, and might be suitable as target for cancer immunotherapy possibly due to their higher immunogenicity. In this study, to really know the immunogenicity of tumor-specific neoantigens, we comprehensively investigated T cell responses against neoantigens derived from genetic mutations in gastric cancer. Using next-generation sequencing, 156 missense mutations were identified in tumor cells from two gastric cancer patients. From them, we selected 30 potentially immunogenic amino acid sequences, which were derived from the mutations and predicted to potentially bind to HLA-class I (A*0201, A*0206, or A*2402) by an epitope prediction server, IEBD. We synthesized 30 kinds of 27mer long peptides, in which the mutated sequences were located in the center, and then cultured peripheral blood mononuclear cells (PBMC) from healthy donors in the presence of the synthetic peptides to evaluate whether they could really induce antigen-specific T cell responses. In the analysis with PBMC from 18 healthy donors, 27/30 (90%) synthetic peptides showed an ability to induce antigen-specific T cell responses in at least one donor, assessed by cytokine production assay. Among them, 15 peptides were immunogenic in more than one donor. The antigen-specific T cell responses were detected more frequently in CD4+ T cells (70%) than in CD8+ T cells (43%). The specificity of T cell responses to mutated sequences, but not to the corresponding wild type sequences, were confirmed in 5 of 8 (63%) peptides examined. In addition, antigen-specific T cell responses induced by mutated peptides were shown to be much higher than those induced by the corresponding wild type peptides. These findings clearly demonstrated high immunogenicity and specificity of neoantigens derived from tumor-specific genetic mutations. Further studies would be recommended to develop a novel immunotherapeutic approach, “personalized cancer vaccination”, targeting mutation-derived neoantigens. Citation Format: Tetsuro Sasada, Junya Ohtake, Satoshi Wada, Erika Yada, Shintaro Yoshida. Comprehensive analysis of T cells responsive to neoantigens derived from tumor-specific genetic mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 636. doi:10.1158/1538-7445.AM2017-636