tbuckley/cabot-search huggingface dataset:
Abstract IA15: Using gene expression analyses to identify MPNST therapeutics
Authors: Nancy Ratner
Journal: Clinical Cancer Research (2018)

Abstract Malignant peripheral nerve sheath tumors (MPNST) are rare soft tissue sarcomas that are a major source of mortality in neurofibromatosis type 1 (NF1) patients. In NF1 patients, these devastating sarcomas often develop in existing benign neurofibroma. We hypothesized that some over-expressed genes in solid tumors would be driver genes and/or mark critical pathways and therapeutic targets. In one approach to identify MPNST driver genes we targeted 130 genes up-regulated in neurofibroma and MPNSTs versus normal cells in a lentiviral short hairpin (sh) RNA screen. A counter-screen in RAS mutant cells excluded common RAS-pathway driven genes. We identified 7 genes specific for survival of MPSNT cells, including the transcription factor MEIS1. In a second approach, we targeted known oncogenes that were expressed at higher levels in MPNST than in normal cells, including Aurora Kinase A. MPNST responded to the Aurora A kinase inhibitor alisertib, and the combination of alisertib and HSV1716, a virus derived from HSV-1 and attenuated by deletion of RL1, exhibited significantly increased antitumor efficacy compared to either monotherapy. Supported by NIH-NS-084855 (N.R. and Largaespada, D.), NS-28840 (N.R.), and NS-086219 (N.R. and Cripe, T.P.). Citation Format: Nancy Ratner. Using gene expression analyses to identify MPNST therapeutics [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr IA15.
Ebola: new outbreak appears in Congo a week after epidemic was declared over
Authors: Owen Dyer
Journal: BMJ (2018)

The Ebola virus has reappeared in the eastern Democratic Republic of the Congo only a week after an outbreak in the western part of the country was declared over.1 Already 33 deaths are suspected of being from the virus, said the World Health Organization. An additional 43 suspected cases have been reported, of which 13 have so far been confirmed by laboratory analysis.

The new outbreak is about 1000 km to the east of the previous one and is believed not to be related but to stem from a new wildlife contact, which could be due to consumption of bush meat or contact with a fruit bat. It is the 10th outbreak in the country, which is 10 times the …
Abstract 5668: The rational design and evaluation of a peptide inhibitor of the PD-1/PD-L1 interaction
Authors: Rebecca J. Boohaker, Vijaya Sambandam, Mark Suto, Bo Xu
Journal: Cancer Research (2018)

Abstract Tumor cells exploit immune checkpoints by expressing checkpoint ligands such as PD-L1, effectively masking them from immune destruction. Programmed cell death- 1 (PD-1), plays a major role in tumor immune escape. The interaction of PD-1/PD-L1 inhibits cytotoxic T lymphocyte (CTL) proliferation, induces apoptosis of tumor-specific T cells, and promotes the resistance of tumor cells to CTL attack. Monoclonal antibodies to these proteins have been developed and approved for use in the clinic. Theoretically, peptide mimics, which have the benefit of lower half-life and significantly smaller size, are able to penetrate into solid tumors and tissues better than antibodies, and can function as inhibitors for the PD1/PD-L1 interaction. Here we report for the first time the rational design and validation of a peptide inhibitor to the PD-1/PD-L1 immune checkpoint as a viable alternative to current inhibitory antibodies. We demonstrated, by biolayer interferometry and in silico docking simulations, that a PD-L1 peptide mimetic (PL120131) can interfere with the PD-1/PD-L1 interaction by binding to PD-1. We established the binding constant for the interaction and PL120131 reduces association of PD-L1 in a dose dependent manner. We show that PL120131 is capable of inhibiting PD-1 mediated apoptotic signaling pathway and rescuing Jurkat cells and primary lymphocytes from apoptosis. Additionally, we show that PL120131 treatment allows for CTL anti-tumor activity. Furthermore, PL120131 can maintain co-culture survivability and activity of T Cells in a 3D co-culture model. Together, the characterization of this PD-1/PD-L1 inhibiting peptide provides insight regarding the ability to inhibit PD-L1 binding while maintaining CTL viability and activity. Understanding the mechanism(s) of action of this peptide has yielded information on the pathways that are drivers of immune evasion in a tumor microenvironment, which may improve and synergize with other forms of immunotherapy, thus increasing efficacy of cancer treatment. Outcomes from this study have provided a path forward to further development of small molecule inhibitors to the PD-1/PD-L1 interaction, and outlines a strategy for the design and development of small molecules to additional cell-surface checkpoint proteins. Citation Format: Rebecca J. Boohaker, Vijaya Sambandam, Mark Suto, Bo Xu. The rational design and evaluation of a peptide inhibitor of the PD-1/PD-L1 interaction [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 5668.
Abstract 3130: Immune profiling in uterine papillary serous carcinoma cancer patients reveals distinct subpopulations and clinical outcomes
Authors: Angela Rynne Vidal, Karen H. Lu, Samuel C. Mok
Journal: Cancer Research (2018)

Abstract Uterine papillary serous carcinoma (UPSC) is a rare but aggressive type of endometrial cancer (EC) that represents 10% of cases of EC but accounts for 40% of EC deaths. Patients with UPSC have poor survival rates, a high risk of recurrence and frequently metastasize to the lymph nodes and the omentum. The mechanisms that drive UPSC progression have not been elucidated yet and immune profiling can be a valuable tool to understand the different patient outcomes. In this work, we used formalin fixed paraffin embedded (FFPE) tumor samples from a cohort of 140 patients with UPSC, the largest used to date, to study a panel of 7 immune markers by multiplex immunofluorescence, using the OpalTM system (Perkin Elmer) in the same tissue section. Samples were imaged with Vectra 3.0 multispectral microscope (Perkin Elmer) and images were analyzed using Visiopharm software. Tumor samples from primary, metastatic and recurrent sites were used to study the tumor microenvironment. We observed significant differences in the tumor-infiltrating immune cells between patients that recurred and those that did not. Similarly, immune subpopulations distinguished patients with metastasis compared to those with a less aggressive form of UPSC. Spatial distribution of cytotoxic T cells (CD8+ GranzymeB+) and cancer cells was also found to significantly correlate with overall patient survival. Collectively, our work shows the immune populations play a role in patient outcomes and should be taken into account for future therapeutic strategies. Citation Format: Angela Rynne Vidal, Karen H. Lu, Samuel C. Mok. Immune profiling in uterine papillary serous carcinoma cancer patients reveals distinct subpopulations and clinical outcomes [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 3130.
ATP-Dependent Mechanism for Coordination of Intercellular Ca2+ Signaling and Renin Secretion in Rat Juxtaglomerular Cells
Authors: JianYao, MichihiroSuwa, BingLi, KazukoKawamura, TetsuoMorioka, TakashiOite
Journal: Circulation Research (2003)

A change in intracellular Ca2+ is considered to be the common final signaling pathway through which renin secretion is governed. Therefore, information relating to the generation, control, and processing of Ca2+ signaling in juxtaglomerular cells (JG) will be critical for understanding JG cell behavior. In this study, we investigated the means by which JG cells harmonize their intracellular Ca2+ signals and explored the potential role of these mechanisms in renin secretion. Mechanical stimulation of a single JG cell initiated propagation of an intercellular Ca2+ wave to up to 11.9±4.1 surrounding cells, and this was prevented in the presence of the ATP-degrading enzyme, apyrase (1.7±0.7 cells), or by desensitization of purinergic receptors via pretreatment of cells with ATP (1.8±0.9 cells), thus implicating ATP as a mediator responsible for the propagation of intercellular Ca2+ signaling. Consistent with this, JG cells were demonstrated not to express the gap junction protein connexin43, and neither did t...
Abstract 1893: The evaluation of INCB059872, an FAD-directed inhibitor of LSD1, in preclinical models of T-ALL
Authors: Melody Diamond, Yvonne Lo, Antony Chadderton, Min Ye, Valerie Roman, Michael Weber, Chunhong He, Liangxing Wu, Swamy Yeleswaram, Alan Roberts, Wenqing Yao, Gregory Hollis, Reid Huber, Peggy Scherle, Bruce Ruggeri, Sang Hyun Lee
Journal: Cancer Research (2018)

Abstract T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological tumor that is derived from the clonal expansion of immature T-cell progenitors. Multiple genetic and epigenetic alterations are attributed to the development of malignant T cell transformation. Among these, there is supporting evidence for a role of lysine specific demethylase (LSD1) in T-ALL. Oncogenic transcription factors, such as TAL-1, Notch, and ZEB2, form a complex with LSD1 to alter gene expression in T-ALL cells. In addition, LSD1 is aberrantly expressed in ALL, including B-ALL and T-ALL. Furthermore, the overexpression of LSD1 under control of the Sca-1 promoter in transgenic mice triggered T leukemogenesis via acquisition of self-renewal activity and alteration in the differentiation program to T-cell lineages. Together with the known function of LSD1 in regulating the activity of self-renewal in hematological malignancies, these studies prompted evaluation of the efficacy of the potent, selective, and orally bioavailable FAD-directed LSD1 inhibitor, INCB059872, in preclinical models of T-ALL. Expression of LSD1 was abundant in human-T-ALL cell lines as detected by immunoblotting. In vitro, INCB059872 treatment significantly inhibited the proliferation of a subset of human T-ALL cell lines. In vivo, once daily oral administration of INCB059872 inhibited tumor growth significantly in multiple human T-ALL subcutaneous xenograft models including Molt-4, RPMI-8402, CCRF-HSB-2, and CCRF-CEM, but was ineffective against DND-41 xenografts. The anti-tumor efficacy observed with INCB059872 had no clear genetic correlation with Notch mutation status of T-ALL tumors. Combination efficacy studies of INCB059872 with standard care of agents or targeted therapeutic agents in T-ALL models are currently being evaluated. These data suggest exploring the potential clinical development of INCB059872 as a therapy for T-ALL patients. Citation Format: Melody Diamond, Yvonne Lo, Antony Chadderton, Min Ye, Valerie Roman, Michael Weber, Chunhong He, Liangxing Wu, Swamy Yeleswaram, Alan Roberts, Wenqing Yao, Gregory Hollis, Reid Huber, Peggy Scherle, Bruce Ruggeri, Sang Hyun Lee. The evaluation of INCB059872, an FAD-directed inhibitor of LSD1, in preclinical models of T-ALL [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 1893.
Stem Cells as a Source of Regenerative Cardiomyocytes
Authors: KeiichiFukuda, ShinsukeYuasa
Journal: Circulation Research (2006)

The realization of regenerative cardiac medicine depends on the availability of cardiomyocytes in sufficient numbers for transplantation of cardiac tissue and the accompanying blood vessels. Embryonic stem (ES) cells, bone marrow (BM) stem cells, and tissue-derived stem cells are all potential cell sources. Although ES cells are highly proliferative and suitable for mass production, an efficient protocol is yet to be established to ensure selective cardiomyocyte induction using these cells. Recent advances in developmental biology have clarified the involvement of critical factors in cardiomyocyte differentiation, including bone morphogenic protein and Wnt signaling proteins, and such factors have the potential to improve the efficiency of stem cell induction. Initial studies of the intracoronary administration of BM mononuclear cells after myocardial infarction has yielded promising results; however, intensive investigation of the underlying molecular mechanisms at play as well as double-blinded clinical...
Abstract 1139: An shRNA screening reveals that the tumorigenic effect of FBXO11 is inversely correlated with EMT profiles in breast cancer
Authors: Jiyoung Kim, Sofie O. Bagger, Branden B. Hopkinson, René Villadsen, Ole W. Petersen
Journal: Cancer Research (2018)

Abstract Over the last decade a trend to study cancer stem cells (CSCs) has become synonymous to studying epithelial to mesenchymal transition (EMT), and has emerged in the field of breast cancer research. In turn, tumorigenesis of epithelial luminal-like breast cancer has been largely overlooked. Recently however, we and others have provided evidence that tumorigenic capacity is not always restricted to EMT-like cancer cells. Furthermore, the metastatic feature is conveyed by subclones of phenotypically differentiated non-EMT cancer cells. In this study, we aimed to identify the differential tumorigenic mechanisms of more aggressive non-EMT cells against the less aggressive EMT cells in breast cancer. By using loss of function screening, we found that a member of the E3 ubiquitin ligase complexes, FBXO11, facilitates tumor formation of non-EMT like cells by inhibiting the p53/p21 pathway. More importantly, our data showed that roles of FBXO11 in tumorigenesis are highly cell-type dependent. In conclusion, our study empathizes that it is important to understand the complexities of individual tumors in the development of personalized therapy. Citation Format: Jiyoung Kim, Sofie O. Bagger, Branden B. Hopkinson, René Villadsen, Ole W. Petersen. An shRNA screening reveals that the tumorigenic effect of FBXO11 is inversely correlated with EMT profiles in breast cancer [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 1139.
Decade of Histological Follow-Up for a Fully Biodegradable Poly-l-lactic Acid Coronary Stent (Igaki-Tamai Stent) in Humans
Authors: SojiNishio, ShinsakuTakeda, KunihikoKosuga, MasaharuOkada, EishoKyo, TakafumiTsuji, EijiTakeuchi, TsuyoshiTerashima, YasutakaInuzuka, TatsuhikoHata, YuzoTakeuchi, TakeshiHarita, JunyaSeki, ShigeruIkeguchi
Journal: Circulation (2014)
Improvement of Left Ventricular Remodeling and Function by Hydroxymethylglutaryl Coenzyme A Reductase Inhibition With Cerivastatin in Rats With Heart Failure After Myocardial Infarction
Authors: JohannBauersachs, PaoloGaluppo, DanielaFraccarollo, MichaelChrist, GeorgErtl
Journal: Circulation (2001)

Background Hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) attenuate angiotensin II-induced cellular signaling. Because angiotensin II is involved in left ventricular (LV) remodeling after myocardial infarction (MI), we examined the effects of statin treatment in an experimental model of chronic heart failure after MI. Methods and Results Rats with extensive MI were treated with placebo or cerivastatin (0.3 mg/kg per day) as a dietary supplement or via gavage for 11 weeks starting on the 7th postoperative day. Infarct size and cholesterol levels were similar among all groups. LV cavity area, an index of LV dilatation, was reduced in MI rats on cerivastatin compared with placebo. LV end-diastolic pressure was increased in MI rats on placebo (24.1±4.1 mm Hg versus sham: 5.1±0.3 mm Hg; P<0.01), and it was significantly reduced by cerivastatin treatment (13.7±2.7 mm Hg; P<0.05 versus placebo). Cerivastatin partially normalized LV dP/dtmax and dP/dtmin, indices of LV systolic and diastolic func...
Effects of Normal Blood Pressure, Prehypertension, and Hypertension on Coronary Microvascular Function
Authors: DoganErdogan, IbrahimYildirim, OzgurCiftci, IsmailOzer, MustafaCaliskan, HakanGullu, HaldunMuderrisoglu
Journal: Circulation (2007)

Background— The assessment of coronary flow reserve (CFR) by transthoracic Doppler echocardiography has recently been introduced into clinical practice, and reduced CFR has been suggested to be a sensitive indicator of hypertensive end-organ damage; however, to date, this methodology has not been used to evaluate CFR in subjects with prehypertension. Accordingly, the present study was designed to evaluate CFR in subjects with prehypertension. Methods and Results— We measured CFR of 40 subjects with prehypertension, 60 patients with hypertension, and 50 normotensive healthy volunteers using transthoracic Doppler echocardiography. None of the subjects had any systemic disease. Age, gender, body mass index, heart rate, lipid profiles, fasting glucose levels, and hemoglobin were similar among the 3 groups. CFR was significantly lower in the hypertension group than in the prehypertension and control groups; in addition, it was significantly lower in subjects with prehypertension than in control subjects (2.23±...
Abstract 17231: Loss of Zfp148 Reduces Atherosclerosis in Mice by Activating P53
Authors: Volkan I Sayin
Journal: Circulation (2014)

Rationale: Cell proliferation and cell cycle control mechanisms are believed to play central roles in the pathogenesis of atherosclerosis. The transcription factor Zinc finger protein 148 (Zfp148) was recently shown to maintain cell proliferation under oxidative conditions by suppressing p53, a checkpoint protein that arrests proliferation in response to various stressors. It is established that inactivation of p53 accelerates atherosclerosis, but whether increased p53 activation confers protection against the disease remains to be determined. Objective: We aimed to test the hypothesis that Zfp148 deficiency reduces atherosclerosis by unleashing p53 activity. Methods and Results: Mice harbouring a gene-trap mutation in the Zfp148 locus (Zfp148gt/+) were bred onto the Apoe-/- genetic background and fed a high-fat or chow diet. Loss of one copy of Zfp148 markedly reduced atherosclerosis without affecting lipid metabolism. Bone marrow transplantation experiments revealed that the effector cell is of hematopoietic origin. We next investigated whether p53 is part of the underlying mechanism. Peritoneal macrophages from Zfp148gt/+Apoe-/- mice showed increased levels of phosphorylated p53 compared to controls, and atherosclerotic lesions from Zfp148gt/+Apoe-/- mice contained fewer proliferating cells and more apoptotic cells. Zfp148gt/+Apoe-/- mice were further crossed with p53-null mice (Trp53-/-). There was no difference in atherosclerosis between Zfp148gt/+Apoe-/- mice and controls on a Trp53+/- genetic background. Conclusions: Zfp148 deficiency increases p53 activity and protects against atherosclerosis without affecting lipid metabolism. The protective effect is entirely dependent on p53 and suggests that drugs that increase p53 activity may be useful in the treatment of atherosclerosis.
Abstract 697: Comparison of tumor-infiltrating lymphocytes between primary and metastatic tumors in breast cancer
Authors: Miseon Lee, Hee Jin Lee, In Hye Song, In Ah Park, Sun-Hee Heo, Young-Ae Kim, Won Seon Bang, AReum Lee, Hyeonjin Lee, Heejae Lee, Gyungyub Gong
Journal: Cancer Research (2018)

Abstract Background: The level of tumor-infiltrating lymphocytes (TILs) and the presence of tertiary lymphoid structures (TLSs) are significant prognostic and predictive factors in primary breast cancer. However, understanding about the differences of TILs and TLSs among different metastatic sites or between primary breast tumors and metastatic sites is limited. Methods: A total of 337 cases of metastatic breast cancer with available hematoxylin and eosin slides of metastatic sites (biopsy, n=185; operation, n=152) were included. We analyzed the percentage of TILs (defined as the percentage of invasive carcinoma stroma infiltrated by lymphocytes in 10% increments; if less than 10% of stroma was infiltrated by TILs, 1% or 5% criteria were used; all available full sections were evaluated) and the presence of TLSs (defined as the lymphoid aggregation with high endothelial venules) in primary and metastatic sites. Results: The mean percentage of TILs in the lung (19.5%) was significantly higher than those in the liver (4.2%), brain (8.3%), and ovary (3.4%, p&amp;lt;0.001). The level of TILs in metastatic tumors of the lung was higher than those in primary tumors (Wilcoxon signed-rank test, p&amp;lt;0.001), while metastatic tumors of the liver (p=0.024) and brain (p=0.095) showed lower level of TILs than in primary tumors. TLSs were found only in the lung (27%) and liver (13%). Patients with lung metastasis (p&amp;lt;0.001), higher level of TILs (p=0.001), and presence of TLS (p=0.002) showed better overall survival. In patients with lung metastasis, who showed best clinical outcome, those with 10% or more of TIL had better overall survival than those with less than 10% (p=0.008). Conclusion:. Metastatic breast tumors in the lung had more TILs than other sites and matched primary tumors. Underlying mechanism of differences of TILs among metastatic sites should be investigated. Citation Format: Miseon Lee, Hee Jin Lee, In Hye Song, In Ah Park, Sun-Hee Heo, Young-Ae Kim, Won Seon Bang, AReum Lee, Hyeonjin Lee, Heejae Lee, Gyungyub Gong. Comparison of tumor-infiltrating lymphocytes between primary and metastatic tumors in breast cancer [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 697.
Abstract 16061: Epicardial Fat Volume Quantification in Acute Pericarditis: Prognostic and Therapeutic Implications
Authors: Georgios Lazaros, Alexios Antonopoulos, Evangelos K Oikonomou, Panagiotis Vasileiou, Evangelos Oikonomou, Evangelia Stroumpouli, Apostolos Karavidas, Charalambos Antoniades, Dimitris Tousoulis
Journal: Circulation (2016)

Introduction: The pathophysiology of acute pericarditis remains unknown and novel biomarkers are needed to identify patients susceptible to complications. Hypothesis: We assumed that quantification...
Calcium Preconditioning Elicits Strong Protection Against Ischemic Injury via Protein Kinase C Signaling Pathway
Authors: HiroshiMiyawaki, XiaoboZhou, MuhammadAshraf
Journal: Circulation Research (1996)

We tested the hypothesis that elevation of [Ca2+]i during Ca2+ preconditioning (CPC) is a strong activator of protein kinase C (PKC) and confers unique protection against ischemic injury. CPC consisted of three cycles of Ca2+ depletion (1 minute each) and Ca2+ repletion (5 minutes each). Langendorff-perfused rat hearts were subjected to 40 minutes of global ischemia followed by 30 minutes of reperfusion. Significant functional recovery and decreased lactate dehydrogenase release were observed in CPC hearts compared with ischemic control hearts. In addition, ATP contents were significantly higher and cell structure was better preserved in CPC hearts than in ischemic control hearts. Administration of chelerythrine, a specific PKC inhibitor, completely abolished the CPC-induced cardioprotection. In other groups, in which Ca2+ influx during CPC was inhibited with verapamil, amiloride, and low Na+ perfusion, cardioprotection was significantly reduced. The prominent increase in the membrane PKC activity after C...