tbuckley/cabot-search huggingface dataset:
Lymphoproliferative disorders in patients with chronic myeloproliferative neoplasms: A systematic review
Authors: Monia Marchetti, Alessandra Carobbio, Enrica Capitoni, Tiziano Barbui
Journal: American Journal of Hematology (2018)

Patients with a Ph-negative myeloproliferative neoplasm (MPN) may harbor or develop lymphoproliferative disorders (LPD), however, the clinical and molecular determinants of MPN and LPD co-occurrence are still uncertain. To systematically pool the available knowledge, we conducted a scoping review of literature published since January 2005 and analyzed single-patient clinical data from 50 papers reporting 214 individuals harboring both MPN and LPD. Patients had been diagnosed essential thrombocythemia (44%), polycythemia vera (29%), or myelofibrosis (23%) at a median age of 67 years (26-94): half of them incurred a LPD after a median of 72 months from MPN diagnosis, while in 20% the LPD diagnosis was antecedent or synchronous. Patients mainly incurred indolent LPD, particularly chronic lymphocytic leukemia (CLL), while aggressive lymphomas and multiple myeloma were a relevant portion of the LPDs occurring in the follow-up of MPN. CLL was preferentially diagnosed in PV patients and was associated with a very high male-to-female ratio, as well as an older age at MPN diagnosis. On converse, multiple myeloma was rarely reported in PV patients and was preferentially diagnosed in female patients not harboring the JAK2 V617F mutation. Based on the 46 cases reporting follow-up data, median survival after MPN diagnosis was 96 months. This thorough review of published evidence confirms that LPD are relevant clinical events in the history of MPN patients. Controlled studies are needed to better refine individuals at higher risk of developing LPD, to support surveillance programs and to avoid therapies possibly favoring LPD.
Abstract 5430: Evaluating a novel phytobiologic mixture against breast cancer cell lines: Effect on glycolytic enzymes and EMT gene expression profile
Authors: Aliaa A. Alamoudi, Afnan A. Alqarni, Ghada Ajabnoor, Aleksandra Niedwiecki, Matthias Rath, Steve M. Harakeh, Ahmed M. Al-Abd
Journal: Cancer Research (2018)

Abstract Background: Recently, there has been a growing evidence proposed regarding role of phytobiological compounds against various malignancies. One of the novel phytobiological mixture (PB), which is a mixture composed of the following: quercetin, resveratrol, cruciferex, epigallocatechin-3-gallate and curcumin at different proportions. To the best of our knowledge, this is the first study to evaluate the effects of a PB on breast cancer cell lines and its impact on the expression profile of these cells. Aim: Herein, we investigated the anti-proliferative effects of PB against two breast cancer cell lines: MDA-MB-231 and MCF-7, in addition, to investigating whether PB may alter the expression profile of glycolytic enzymes and epithelial mesenchymal transition (EMT) genes in these cell lines. Method: The anti-proliferative effect of PB was evaluated in vitro against MCF-7 and MDA-MB-231 cell lines using SRB assay. The effect of PB on the relative expression profile of some of the glycolytic enzymes and EMT genes was conducted using TaqMan gene expression assays via reverse transcription-quantitative PCR (RT-qPCR). Results: At 72 hrs, treatment with PB showed cytotoxic effects against MDA-MB-231 and MCF-7 cells with an IC50's of 25.9±3 µg/ml and 29.5± 0.9 µg/ml, respectively. At 24 hrs post PB treatment, there was a significant increase in the gene expression of most glycolytic enzymes such as; Phosphofructokinase muscle type (PFKM) (1.4± 0.1, p&amp;lt;0.01) and Pyruvate dehydrogenase kinase isoenzyme 1 (PDK-1) (1.6± 0.2 fold, p&amp;lt; 0.001). PB did not seem to alter the EMT gene expression profile with both cadherin 1 and 2 showing no significant changes. Interestingly, however, a significant up-regulation was seen with ZEB2 member of the zinc finger E-box binding homeobox 2, post PB treatment. Conclusion: In conclusion PB showed a promising anti-proliferative effect against two breast cancer cell lines. However, we postulate that the drug could be modulating glycolytic enzymes expression, which ultimately can affect key molecules in cell differentiation. Further studies are needed to elucidate the exact underlying mechanism and to better understand the most beneficial drug combinations that can work synergistically with PB to interfere with different tumor hallmarks. Citation Format: Aliaa A. Alamoudi, Afnan A. Alqarni, Ghada Ajabnoor, Aleksandra Niedwiecki, Matthias Rath, Steve M. Harakeh, Ahmed M. Al-Abd. Evaluating a novel phytobiologic mixture against breast cancer cell lines: Effect on glycolytic enzymes and EMT gene expression profile [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5430.
Abstract 20576: Reporterless Reprogrammed Cardiac Progenitor Cells Attach, Migrate, and Repopulate Decellularized Whole Mouse Hearts
Authors: Ruben A Alexanian, Pratik A Lalit, Di Lang, Martin R Lea, Ravi Vaidyanathan, Yogananda S Markandeya, Andrew J Zhai, Eric G Schmuck, L L Eckhardt, Alexey Glukhov, Timothy J Kamp
Journal: Circulation (2016)

Cardiac progenitor cells hold great promise for cardiac repair due to their expandability and multipotency. Recently, we have reprogrammed fibroblasts (fibs) from transgenic mice with an Nkx2.5-YFP...
Abstract LB-088: Cytokine-transgenic NOG mice engrafted with human peripheral blood cells support natural killer cell expansion
Authors: Paul Volden
Journal: Cancer Research (2018)

Abstract Harnessing natural killer (NK) cells and their ability to mediate antibody-dependent cellular cytotoxicity (ADCC) forms the basis for many ongoing immuno-oncology efforts. Currently, most preclinical in vivo studies of ADCC-dependent efficacy rely on syngeneic models, which mandate the generation and use of surrogate therapies to overcome differences between mouse and human immune systems. These steps add time and cost, and can be particularly challenging for advanced antibody therapeutics (e.g. bispecific antibodies and antibody-drug conjugates). A humanized immune system (HIS) model that supports human NK cells could improve evaluations of human NK cell-dependent cancer therapies. However, HIS models have largely failed to support human NK cell-engraftment, rendering them inadequate for ADCC studies. Prior work has shown that human cytokine-transgenic hIL2-NOG and hIL15-NOG mice support the development of human NK cells from engrafted human hematopoietic stem cells (HSCs). Furthermore, the hIL15-NOG model has been shown to support in vivo expansion and long-term engraftment of isolated human NK cells. These properties suggest hIL2-NOG and/or hIL15-NOG might also sufficiently support NK cells following engraftment of peripheral blood mononuclear cells (PBMCs). Such a model could enable cost-effective and efficient in vivo studies of human NK cells and therapeutic human antibodies. To test this hypothesis, NOG, hIL-2 NOG, and hIL-15 NOG mice were engrafted with PBMCs from a single donor and at one of three increasing cell doses. The onset of graft vs host disease and peripheral blood human immune cell subsets were monitored through the duration of this study. Results showed that hIL15-NOG mice had a slightly diminished survival compared to conventional NOG. Nevertheless, hIL15-NOG survived up to 7 weeks after PBMC engraftment without any signs of graft vs host disease. Although hIL2-NOG mice showed the best engraftment rate for NK cells and other immune cell subpopulations, the overall survival was severely decreased post engraftment. Comparing NK cell-engraftment in hIL15-NOG and conventional NOG mice, we observed a tenfold increase of NK cell numbers in hIL15-NOG mice, independent of engrafted PBMC numbers, making it a highly suitable HIS model for studying NK cells. Citation Format: Paul Volden. Cytokine-transgenic NOG mice engrafted with human peripheral blood cells support natural killer cell expansion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-088.
Prolonged Observations of the Cardiovascular Status in Essential Hyperlipemia
Authors: Alfredsoffer, Martinmurray
Journal: Circulation (1954)

Study of the natural course of essential hyperlipemia discloses that this disease is frequently associated with premature atherosclerosis. It is, therefore, our contention that we can no longer regard essential hyperlipemia as a benign disease. Heparin administered intravenously to patients with essential hyperlipemia produces dramatic though transient lowering of total lipids. This is due predominantly to heparin's effect upon neutral fat. Normal controls show no significant differences in their lipid response to heparin, though of course the degree of these changes is comparatively smaller.
Risk of Major Malformations in Infants Following First-Trimester Exposure to Quetiapine
Authors: Lee S. Cohen, Lina Góez-Mogollón, Alexandra Z. Sosinsky, Gina M. Savella, Adele C. Viguera, David Chitayat, Sonia Hernández-Díaz, Marlene P. Freeman
Journal: American Journal of Psychiatry (2018)

Second-generation antipsychotics are commonly prescribed to reproductive-age women for the treatment of a spectrum of psychiatric disorders. Quetiapine is the most commonly prescribed medication in this class, and therefore a better understanding of its reproductive safety profile is critical. The goal of this study was to determine the risk of major malformations among infants exposed to quetiapine during pregnancy compared with a group of infants whose mothers had a history of psychiatric morbidity but who did not use a second-generation antipsychotic during pregnancy.The National Pregnancy Registry for Atypical Antipsychotics interviews pregnant women ages 18-45 during pregnancy and the postpartum period. Obstetric, labor, and delivery medical records and pediatric medical records from the first 6 months of life were screened for evidence of major malformations, followed by adjudication by a blinded dysmorphologist. Women with first-trimester exposure to quetiapine were compared with control subjects without exposure to second-generation antipsychotics.As of March 2017, 888 women had enrolled prospectively and 357 were eligible for analysis. Of these, 152 women with first-trimester exposure to quetiapine were compared with 205 control subjects without any second-generation antipsychotic exposure. For the 155 infants born to women in the exposed group (including three sets of twins), two major malformations were confirmed (1.3%), compared with three major malformations among the 210 infants born in the unexposed group (including five sets of twins) (1.4%). The unadjusted odds ratio for major malformations between infants with and without quetiapine exposure was 0.90 (95% CI=0.15, 5.46), which is consistent with the pooled estimate of the available controlled data on fetal exposure to quetiapine.These data regarding the safety of fetal exposure to quetiapine in a small sample of well-characterized participants are reassuring given that the confidence interval does not exceed a fivefold increased risk of major malformations relative to psychiatric control subjects. Future analyses based on ongoing data collection will produce more precise estimates.
Abstract SY18-02: The relationship between Batf3-DC and antitumor T-cell responses
Authors: Stefani Spranger
Journal: Cancer Research (2018)

Abstract Cancer immunotherapy has attracted enormous attention and investment, stimulated by successes of immune checkpoint blockade drugs, such as anti-CTLA4 and anti-PD-1. Despite the potential of immunotherapy to eradicate even metastatic cancer, only a minority of cancer patients respond to checkpoint blockade agents. Clinical and preclinical data provide evidence that the presence of tumor-specific CD8 T cells within the tumor microenvironment (TME) is critical for the response to checkpoint blockade. Another major component of tumor-infiltrating immune systems is the mononuclear phagocytic cell compartment, which provides both pro- and antitumoral properties, depending on its composition. A rare subset of conventional dendritic cells, marked by CD103 and the transcription factor Batf3, is required for the uptake, transport, and presentation of tumor-derived antigens to CD8 T cells in the tumor-draining lymph node. Tumors lacking CD103+ dendritic cells do not mount spontaneous antitumor immune responses and fail to respond to checkpoint blockade therapy. Moreover, we observed that absence of this subset of DC is mediating resistance to adoptive T-cell transfer. Analysis of tumor-residing CD103+ dendritic cells revealed that this small subset of cells provides the predominant source of effector T-cell recruiting chemokines (CXCL9 and 10) and is a critical component of the TME. This observation imposes a more detailed and refined analysis of the contribution of tumor-residing dendritic cells to the local antitumor immune response. Citation Format: Stefani Spranger. The relationship between Batf3-DC and antitumor T-cell responses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr SY18-02.
Abstract 785: Application of CRISPR/Cas9 gene editing to primary T cells
Authors: Xi Li, Wanbing Tang, Chenjie Zhou, Yulin Yang, Zhengang Peng, Wenrong Zhou, Qunsheng Ji, Yong Cang
Journal: Cancer Research (2018)

Abstract T cells mediate a broad range of immune responses, especially generation of adaptive immunity for cancer cell clearance. Identification of genetic components that modulate T cell proliferation, differentiation, migration and cytotoxicity would facilitate development of more effective cancer immunotherapy. CRISPR/Cas9, as a tool, could generate gene knockout with high specificity and efficiency and has been widely used in genome-wide screening for therapeutic targets in many tumor cell models. However, its application to primary cells especially T cell has not been extensively investigated. Here, we described how to employ the CRISPR/Cas9 tools for immune-oncology target identification in primary mouse T cells. Cas9/sgRNA could be transduced into T cells with high efficiency and low toxicity using a lentivirus based delivery system. The transduced T cells acquired Cas9 expression but no DNA editing was observed. However, we achieved gene editing in primary T cells isolated from a Cas9 transgenic mouse strain after lentiviral delivery of guide RNA's. In summary, we provide a new method to generate DNA editing in primary T cell using CRISPR/Cas9 technology. It could be used for gene knockout, knockin and even genome-wide screening in primary T cell for immune checkpoint regulators. Citation Format: Xi Li, Wanbing Tang, Chenjie Zhou, Yulin Yang, Zhengang Peng, Wenrong Zhou, Qunsheng Ji, Yong Cang. Application of CRISPR/Cas9 gene editing to primary T cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 785.
Abstract 5492: Inhibition of ERK MAPK signaling increases pancreatic cancer dependency on autophagy
Authors: Kirsten Bryant, Sen Peng, Andrey Tikunov, Mariaelena Pierobon, Venugopal Gunda, Garima Tomar, Pankaj Singh, Emanuel Petricoin, Jeffrey Macdonald, Nhan Tran, Alec Kimmelman, Channing Der
Journal: Cancer Research (2018)

Abstract Pancreatic ductal adenocarcinoma (PDAC) cell growth is dependent on altered biochemical and cellular activities that facilitate increased metabolic dependencies. We determined the role of mutationally activated KRAS, found in ~95% of PDAC, in supporting autophagy. Surprisingly, acute KRAS suppression, which blocks proliferation, was associated with increased rather than decreased autophagic flux. Similarly, KRAS transformation of immortalized human pancreatic epithelial cells showed decreased autophagic flux. Pharmacologic inhibition of ERK MAPK phenocopied the genetic silencing of KRAS and also increased autophagic flux. Addressing a mechanism for ERK suppression increased autophagy, we found increased AMPK activity, decreased mTOR activity, and increased expression of autophagic proteins. We speculated that increased autophagy may be a compensatory mechanism caused by the loss of KRAS- and ERK-dependent metabolic processes. To address this possibility, we performed RNA-seq analyses to monitor gene expression changes in response to ERK inhibition. We observed increased transcription of genes responsible for the metabolic processes of autophagy and β-oxidation, with concurrent decreased transcription of glycolysis and mitochondrial-associated genes. These changes were validated in metabolomic analyses following either genetic silencing of KRAS or ERK inhibition. Thus, the loss of ERK-driven metabolic processes may induce compensatory mechanisms to increase autophagy. We then addressed whether ERK inhibition increased PDAC dependence on autophagy. Supporting this possibility, we found that cotreatment with the autophagy inhibitor chloroquine synergistically enhanced ERK inhibitor mediated antiproliferative activity. Similarly, genetic or pharmacologic inhibition of specific regulators of autophagy also enhanced ERK inhibitor activity. We conclude that concurrent suppression of multiple metabolic processes, to block compensatory rebound activities, will be needed for effective PDAC treatment. Citation Format: Kirsten Bryant, Sen Peng, Andrey Tikunov, Mariaelena Pierobon, Venugopal Gunda, Garima Tomar, Pankaj Singh, Emanuel Petricoin, Jeffrey Macdonald, Nhan Tran, Alec Kimmelman, Channing Der. Inhibition of ERK MAPK signaling increases pancreatic cancer dependency on autophagy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5492.
Hemodynamic, Renal, and Hormonal Effects of Adrenomedullin Infusion in Patients With Congestive Heart Failure
Authors: NoritoshiNagaya, ToruSatoh, ToshioNishikimi, MasaakiUematsu, ShinichiFuruichi, FumioSakamaki, HideoOya, ShingoKyotani, NorifumiNakanishi, YoichiGoto, YoshiakiMasuda, KunioMiyatake, KenjiKangawa
Journal: Circulation (2000)

Background—Experimental studies have shown that adrenomedullin (AM) causes vasodilatation, diuresis, and a positive inotropic effect. In humans, however, whether infusion of AM has beneficial effects in congestive heart failure (CHF) remains unknown. Methods and Results—Hemodynamic, renal, and hormonal responses to intravenous infusion of human AM (0.05 μg · kg−1 · min−1) were examined in 7 patients with CHF and 7 normal healthy subjects (NL). In NL group, AM significantly decreased mean arterial pressure (−16 mm Hg, P<0.05) and increased heart rate (+12 bpm, P<0.05). In CHF group, AM also decreased mean arterial pressure (−8 mm Hg, P<0.05) and increased heart rate (+5 bpm, P<0.05), but to a much lesser degree (P<0.05 versus NL). AM markedly increased cardiac index (CHF, +49%; NL, +39%, P<0.05) while decreasing pulmonary capillary wedge pressure (CHF, −4 mm Hg; NL, −2 mm Hg, P<0.05). AM significantly decreased mean pulmonary arterial pressure only in CHF (−4 mm Hg, P<0.05). AM increased urine volume (CHF,...
Abstract LB-164: Global study of chromatin interactions reveals biologically relevant candidate target genes at endometrial cancer risk loci
Authors: Dylan M. Glubb, Pik Fang Kho, Endometrial Cancer Association Consortium, Deborah Thompson, Amanda Spurdle, Tracy O'Mara
Journal: Cancer Research (2018)

Abstract We have previously used genome-wide association studies and meta-analyses to uncover 17 genetic risk loci for endometrial cancer. However, the regulatory gene targets of these loci have not been systematically evaluated. To identify candidate gene targets at endometrial cancer risk loci, we have assessed chromatin looping interactions between endometrial cancer risk variants and neighboring genes using the global HiChIP chromatin conformation capture technique. To perform HiChIP, estrogen-stimulated Ishikawa endometrial cancer cells were cross-linked and proximity ligation performed. Chromatin associated with RNA polymerase II was isolated and HiChIP libraries prepared before sequencing using the Illumina HiSeq 4000 system. HiChIP paired-end reads were aligned using the HiC-Pro pipeline and filtered for valid reads. The hichipper package was used to identify and characterise global chromatin interactions (FDR &amp;lt; 0.01). At 11 of the 17 endometrial cancer risk loci, we identified chromatin interactions between risk variants and genes (37 coding and 10 non-coding). Interaction distances ranged from 8 kb to 1.7 Mb. Expression of candidate target genes CUX2, CYP19A1, SKAP1, SNX11 and EIF2AK4 was found to associate with endometrial cancer risk in whole blood transcriptome-wide association studies (TWAS). Ingenuity Pathway Analysis revealed that candidate genes were enriched for relevant functional annotations such as tumorigenesis, cell migration, necrosis and viability. Furthermore, enrichment of candidate genes (p=0.001) was observed in the CXCR4 signaling pathway, which is involved with endometrial cancer development, invasion and progression. In summary, we have performed the first global study of chromatin interactions in endometrial cancer cells. This analysis has revealed biologically relevant candidate target genes at endometrial cancer risk loci, five of which are supported by TWAS. Transcriptional regulation of candidate target genes by endometrial cancer risk variants will be verified in future studies. Citation Format: Dylan M. Glubb, Pik Fang Kho, Endometrial Cancer Association Consortium, Deborah Thompson, Amanda Spurdle, Tracy O'Mara. Global study of chromatin interactions reveals biologically relevant candidate target genes at endometrial cancer risk loci [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-164.