tbuckley/cabot-search huggingface dataset:
Abstract 3568: Phosphatidylserine targeting antibody enhances antitumor activity of CAR T cells in mouse melanoma
Authors: Sara Schad, Daniel Hirschhorn-Cymerman, Sadna Budhu, Hong Zhong, Xia Yang, Joseph Shan, Steven King, Taha Merghoub, Jedd Wolchok
Journal: Cancer Research (2018)

Abstract A viable strategy to treat advanced cancers includes transferring of tumor-specific T cells. T cells that recognize tumor antigens can be expanded and reinvigorated ex-vivo. Furthermore, autologous T cells can be genetically modified to express antitumor T cell receptors or chimeric antigen receptors (CARs). Although the potency and specificity of tumor-specific T cells can be manipulated ex vivo, once reinfused into patients, the T cells are subjected to immunosuppressive mechanisms established by the tumor. An important immune checkpoint regulator within tumors is phosphatidylserine (PS), a phospholipid that is exposed on apoptotic cells, tumor cells and tumor endothelium. Innate immune cells exposed to PS secrete suppressive cytokines and chemokines that can significantly impair the function and activation of antitumor T cells. Antibodies that target PS have been shown to reactivate antitumor immunity by polarizing tumor-associated macrophages into a proinflammatory M1 phenotype, reducing the number of MDSCs in tumors and promoting the maturation of dendritic cells into functional APCs. Our lab has previously shown that a PS targeting monoclonal antibody (mch1N11), in combination with transgenic CD4+ T cells that recognize the melanoma antigen Trp1, can regress very advanced melanomas in all treated mice. Here, we further those studies with data showing that a 2nd-generation CAR T cell that binds Trp1 on the surface of B16 melanoma, in combination with mch1N11 can improve antitumor activity and overall survival in B16 tumor-bearing mice. Additionally, in vitro killing assays with antigen-specific T cells sorted from the tumor reveal that mch1N11 enhances the cytolytic function of these T cells against B16 melanoma. Flow cytometry analysis of local immune responses in the tumors of animals treated with tumor-specific T cells and mch1N11 showed a decrease in anti-inflammatory (M2) macrophages and FoxP3+ regulatory T cells. These findings highlight that diminishing suppressive mechanisms locally with mch1N11 can enhance the efficacy of transgenic TCR and CAR T cells to improve the outcome in patients with advanced-stage melanoma. Our studies may inform the design of clinical trials combining PS targeting antibodies with CAR T cell therapy in solid tumors. Citation Format: Sara Schad, Daniel Hirschhorn-Cymerman, Sadna Budhu, Hong Zhong, Xia Yang, Joseph Shan, Steven King, Taha Merghoub, Jedd Wolchok. Phosphatidylserine targeting antibody enhances antitumor activity of CAR T cells in mouse melanoma [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 3568.
Abstract 14157: Periodontal Microbiome Induces Inflammation and Atherosclerosis in Hyperlipidemic Atherogenic ApoeNull Mice
Authors: SasankaChukkapalli, IrinaVelsko, MercedesRivera-Kweh, DonghangZheng, AlexandraLucas, KesavaluLakshmyya
Journal: Circulation (2015)

Introduction: Periodontal disease (PD) is a polymicrobial dysbiotic chronic inflammatory disease produced by a complex subgingival microbiome, and is linked to systemic inflammatory atherosclerotic vascular disease (ASVD). American Heart Association supported the association between PD and ASVD but not causal association. Prior reports investigated the associations between these two diseases PD and ASVD. But the complex signaling molecules and mechanisms establishing a causal association are not well defined. Methods: To investigate how polybacterial infections initiate atherosclerotic plaque growth, ApoEnull mice were orally infected with a polybacterial consortium of 4 well-characterized periodontal pathogens Porphyromonas gingivalis, Treponema denticola, Tannerella forsythia and Fusobacterium nucleatum. We assessed PD characteristics, hematogenous dissemination of bacteria, peripheral T cell response, serum inflammatory cytokines, atherosclerosis risk factors, atherosclerotic plaque development, and al...
Abstract A25: Tissue transglutaminase interacts with Frizzled 7 in ovarian cancer stem cells
Authors: Salvatore Condello, Livia Sima, Cristina Ivan, Horacio Cardenas, Gary Schiltz, Rama K Mishra, Daniela Matei
Journal: Clinical Cancer Research (2018)

Abstract Increasing evidence correlates the metastatic progression and post-chemotherapy recurrence of ovarian cancer (OC) to a small population of cancer stem cells (CSCs), resistant to traditional chemotherapy and responsible for tumor relapse. Tissue transglutaminase (TG2) is a multifunctional protein, with enzymatic and scaffold functions, overexpressed in ovarian carcinomas, where it promotes metastasis. Independently of its enzymatic function, TG2 can be secreted in the extracellular compartment where it increases cell adhesion to the fibronectin (FN) matrix by regulating integrins clustering and matrix reorganization. We hypothesized that by binding to the integrins and FN, TG2 promotes survival of CSCs and supports OC spheroid formation. Our data demonstrate that TG2, β1 integrin, and FN1 expression are markedly increased in OC spheroids compared with monolayers and are enriched in successive sphere generations. Immunofluorescence (IF) staining supports that TG2 forms abundant complexes with β1 integrin and FN in cells grown as spheroids. TG2 expression is strongly correlated with β1 integrin (ITGB1) (R=0.23, P&amp;lt;0.0001) and with FN1 (R=0.39, P&amp;lt;0.0001) in the TCGA ovarian cancer database, which houses gene expression data of 560 clinically annotated HGSOC tumors. Patients with high TG2 and ITGB1 expression levels had an increased estimated risk of death when compared to those with low TG2 and ITGB1 expression levels (P=0.00652). Use of function-inhibiting antibody against the FN-binding domain of TG2 (4G3) dramatically suppressed TG2/FN/β1 integrin complex formation, spheroid proliferation, and tumor growth in a xenograft model. Furthermore, disruption of TG2/FN complex formation altered key oncogenic signaling pathways, and in particular blocked the canonical Wnt/β-catenin signaling pathway essential to sustaining cancer cell stemness. The Wnt receptor Frizzled genes (Fzd1, Fzd7 and Fzd8) showed the greatest difference in gene expression, indicating a direct correlation between TG2/FN complex and Wnt pathway activation. By co-immunoprecipitation and IF staining we demonstrated that TG2 colocalizes and directly binds to Fzd7 receptor. In conclusion, our data support that TG2/FN/β1 integrin complex formation is essential to promoting ovarian CSCs survival by acting as coreceptor complex with Fzd7 in regulating β-catenin signaling and represents a new target to eradicate chemotherapy-resistant tumors. Citation Format: Salvatore Condello, Livia Sima, Cristina Ivan, Horacio Cardenas, Gary Schiltz, Rama K Mishra, Daniela Matei. Tissue transglutaminase interacts with Frizzled 7 in ovarian cancer stem cells. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr A25.
Dual Effect of Ceramide on Human Endothelial Cells
Authors: HuigeLi, PeterJunk, AndreaHuwiler, ChristianBurkhardt, ThomasWallerath, JosefPfeilschifter, UlrichFörstermann
Journal: Circulation (2002)

Background— Generation of the second-messenger molecule ceramide by stimulated sphingomyelinase activity has been implicated in the inflammatory processes contributing to the pathogenesis of atherosclerosis. However, reports of stimulatory effects of ceramide on endothelial NO production in animal models suggest antiatherosclerotic effects of the molecule. Therefore, we investigated long-term effects of ceramide on NO generation in human endothelial cells. Methods and Results— In human umbilical vein endothelial cells (HUVECs) and in HUVEC-derived EA.hy 926 endothelial cells, C6-ceramide (N-hexanoyl-d-erythro-sphingosine) reduced the generation of bioactive NO (RFL-6 reporter-cell assay). At the same time, the signaling molecule increased endothelial NO synthase (eNOS) mRNA (RNase protection assay) and protein expression (Western blot). C6-ceramide stimulated eNOS transcription by a signaling mechanism involving protein phosphatase PP2A but did not modify the stability of the eNOS mRNA. Endothelial genera...
Nerve Growth Factor Is Critical for Cardiac Sensory Innervation and Rescues Neuropathy in Diabetic Hearts
Authors: MasakiIeda, HideakiKanazawa, YasuyoIeda, KensukeKimura, KeisukeMatsumura, YuichiTomita, TakashiYagi, TakeshiOnizuka, KenichiroShimoji, SatoshiOgawa, ShinjiMakino, MotoakiSano, KeiichiFukuda
Journal: Circulation (2006)

Background— Molecular mechanisms regulating the cardiac sensory nervous system remain poorly understood. Cardiac sensory nerve impairment causes silent myocardial ischemia, a main cause of sudden death in diabetes mellitus (DM). The present study focused on the roles of nerve growth factor (NGF) in the regulation of the cardiac sensory nervous system and analyzed the mechanism of silent myocardial ischemia in DM. Methods and Results— We screened neurotrophic factors and found that cardiac sensory nerves developed in parallel with NGF synthesized in the heart. Cardiac nociceptive sensory nerves that were immunopositive for calcitonin gene-related peptide, dorsal root ganglia (DRG), and the dorsal horn were markedly retarded in NGF-deficient mice, whereas cardiac-specific overexpression of NGF rescued these deficits. DM was induced with streptozotocin in wild-type and transgenic mice overexpressing NGF in the heart. Downregulation of NGF, calcitonin gene-related peptide–immunopositive cardiac sensory denerv...
Adrenergic Modulation of Ultrarapid Delayed Rectifier K+ Current in Human Atrial Myocytes
Authors: Gui-RongLi, JianlinFeng, ZhiguoWang, BernardFermini, StanleyNattel
Journal: Circulation Research (1996)

Abstract The ultrarapid delayed rectifier K+ current (IKur) in human atrial cells appears to correspond to Kv1.5 cloned channels and to play an important role in human atrial repolarization. Kv1.5 channels have consensus sites for phosphorylation by protein kinase A and C, suggesting possible modulation by adrenergic stimulation. The present study was designed to assess the adrenergic regulation of IKur in human atrial myocytes. Isoproterenol increased IKur in a concentration-dependent manner, with significant effects at concentrations as low as 10 nmol/L. The effects of isoproterenol were reversible by washout or by the addition of propranolol (1 μmol/L). Isoproterenol’s effects were mimicked by the direct adenylate cyclase stimulator, forskolin, and by the membrane-permeable form of cAMP, 8-bromo cAMP. Isoproterenol had no effect on IKur when the protein kinase A inhibitor peptide, PKI(6-22)amide, was included in the pipette solution; in a separate set of experiments in which isoproterenol alone increas...
Abstract 5337: The epigenetic feedback loop of the CpG demethylase TET family genes in head and neck cancers
Authors: Kiyoshi Misawa, Atsushi Imai, Daiki Mochizuki, Takeharu Kanazawa
Journal: Cancer Research (2018)

Abstract Purpose: The aim of this study is that clarifying the epigenetic regulation of TET family genes can provide insights into the mechanisms of tumorigenesis and the risk of disease recurrence in HNSCC. Experimental Design: We generated methylation profiles of TET family genes in tumor samples obtained from 233 patients with head and neck squamous cell carcinoma (HNSCC); these included 57 hypopharynx, 44 larynx, 69 oral cavity, and 63 oropharynx tumor samples. TET family genes mRNA expression and promoter DNA methylation were examined via quantitative reverse transcription (Q-RT-PCR) and methylation-specific PCR (Q-MSP), respectively. Promoter methylation was compared with various clinical characteristics and methylation index. Results: The TET methylation index (TE-MI) as the number of TET family genes methylation events was positively correlated with alcohol consumption (P = 0.004), HPV status (P = 0.004) and disease recurrence (P = 0.002). Simultaneous methylation analysis of TET family genes significantly correlated with reduced disease-free survival in unfavorable event groups (log-rank test, P = 0.026). In the multivariate Cox proportional hazards analysis, TET3 methylation of T1/2 patients, oropharyngeal cancer patients and oral cancer patients exhibited the high association with poor survival (hazard ratio: 2.64, P = 0.014; 3.55, P = 0.048; 2.63, P = 0.028, respectively). Joint analysis of tumor suppressor genes methylation index (TS-MI) showed a significant trend toward higher TE-MI increased. Conclusions: TET family genes methylation status was independently associated with aggressive tumor behavior and forming a DNA methylation feedback loop in patients with HNSCC. Citation Format: Kiyoshi Misawa, Atsushi Imai, Daiki Mochizuki, Takeharu Kanazawa. The epigenetic feedback loop of the CpG demethylase TET family genes in head and neck cancers [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 5337.
Abstract 4314: Chromatin state alterations during melanoma progression
Authors: Kunal Rai, Christopher Terranova, Mayinuer Maitituoheti, Ming Tang, Kadir Akdemir, Elias Orouji, Lynda Chin, Petko Fiziev, Mayura Dhamdhere, Neha S. Samant, Amikhsha Shah, Sneha Sharma, Jason Ernst
Journal: Cancer Research (2018)

Abstract The extent and nature of epigenomic changes associated with melanoma progression is poorly understood. To determine chromatin state patterns of human metastatic melanomas, we defined epigenome of melanoma by profiling 6 histone modification marks (H3K4me, H3K27Ac, H3K4me3, H3K79me2, H3K27me3 and H3K9me3) in 48 metastatic melanoma tumors, cell lines and short-term cultures. Computation of chromatin states identified specific chromatin state aberrations in human tumors and their relationship with specific genotypes. Specifically, we defined patterns of enhancer elements, broad H3K4me3 domains and bivalent chromatin states enriched in specific genotypes of BRAF, NRAS, and WT groups of melanomas. Importantly, we identified switch from specific bivalent chromatin states in melanocytes to active states leading to upregulation of EMT genes in NRAS mutant melanomas. Similarly, we noted gains of broad H3K4me3 domains in particular classes of oncogenes in specific gentoypes as well as during transitions from melanocytes to melanomas. Finally, we identified clusters of enhancers that are specifically enriched in subset of melanoma samples defining intertumor epigenetic heterogeneity in melanoma tumors. In addition, to investigate chromatin state changes associated with early stages of melanoma progression, we systematically profiled 35 epigenetic modifications in a cell phenotypic model of non-tumorigenic and tumorigenic states (and verified in human nevi and melanoma samples). Specific chromatin state transitions featuring loss of histone acetylations and H3K4me2/3 were observed on specific promoter and enhancer elements targeting cancer-regulatory genes in important melanoma-driving cell signaling pathways. Intriguingly, only a small fraction of chromatin state transitions correlated with expected changes in gene expression patterns. Restoration of acetylation levels on deacetylated loci by histone deacetylase (HDAC) inhibitors selectively blocked excessive proliferation in tumorigenic cells and human melanoma cells, suggesting functional roles of observed chromatin state transitions in driving hyperproliferative phenotype. Overall, our study reveals principles of epigenetic reprogramming in melanoma progression stages and how they may establish transcriptional programs that impart aggressive characteristics to melanomas. Citation Format: Kunal Rai, Christopher Terranova, Mayinuer Maitituoheti, Ming Tang, Kadir Akdemir, Elias Orouji, Lynda Chin, Petko Fiziev, Mayura Dhamdhere, Neha S. Samant, Amikhsha Shah, Sneha Sharma, Jason Ernst. Chromatin state alterations during melanoma progression [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 4314.
Abstract 538: ASPM promotes prostate cancer tumorigenesis by bolstering cancer stemness through Wnt-Dvl-3-<i>b</i>-catenin signaling
Authors: Kelvin K. Tsai, Vincent C. Pai, Chung-Chi Hsu, Tze-Sian Chan
Journal: Cancer Research (2018)

Abstract Metastasis is the major cause of cancer mortality in androgen-independent prostate cancer (PCA) and understanding it is crucial to improving the outcome of patients. Recent evidence suggests that activation of Wnt signaling in cancer stem cells (CSCs) contributes to cancer progression in malignant tumors. Here we report that a novel Wnt activator ASPM (Abnormal spindle-like microcephaly associated) maintains the prostate CSC subpopulation through augmenting the Wnt-β-catenin signaling in PCA. Functional studies showed that downregulation of ASPM expression attenuated the proliferation and invasive of PCA cells and reduced the number of prostate CSCs and inhibited cancer stemness and tumorigenesis. Mechanistically, ASPM interacts with dishevelled-3 (Dvl-3) and inhibits its proteasome-dependent degradation, thereby increasing the protein stability of Dvl-3 and enabling the β-catenin transcriptional activity in PCA cells. The clinical significance of the above findings was credentialed by the profound up-regulation of ASPM in metastatic PCA and the strong correlation of cytoplasmic ASPM expression with poor metastasis-free survival of patients with resected PCA. Collectively, our data points to ASPM as a novel oncoprotein and an essential regulator of cancer stemness in PCA, which has important clinical and therapeutic significance (supported by Ministry of Science and Technology grants MOST 104-2314-B-400-022 and MOST 105-2314-B-400-018 and National Health Research Institutes NHRIs grant CA-106-PP-09 to K.K.T). Citation Format: Kelvin K. Tsai, Vincent C. Pai, Chung-Chi Hsu, Tze-Sian Chan. ASPM promotes prostate cancer tumorigenesis by bolstering cancer stemness through Wnt-Dvl-3-b-catenin signaling [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 538.
Abstract 450: Unveiling Human Cardiac Stem Cells Role in Myocardial Ischemia-reperfusion Injury
Authors: Maria J Sebastião, Margarida Serra, Rute Pereira, Catarina Brito, Itziar Palacios, Patrícia Gomes-Alves, Paula M Alves
Journal: Circulation Research (2016)

After an Acute Myocardial Infarction (AMI), Ischemia-Reperfusion (I/R) injury is responsible for a critical decrease in the number of viable cardiomyocytes (hCMs). Human adult myocardium harbors a population of endogenous cardiac stem cells (hCSCs) that is activated upon I/R injury, contributing to myocardial repair through the establishment of an auto/paracrine molecular crosstalk between hCSCs and hCMs in stress. Our work aims at setting up the first in vitro human I/R injury model in order to decipher the role of hCSCs and correspondent cross talk between hCSCs and hCMs upon AMI using proteomic tools. Human CSCs, hCMs cultures and co-cultures were established using human donor derived CSCs (c-kit + , CD45 - ) and hCMs derived from human induced pluripotent stem cells at different maturation stages (hiPSC-CMs). Ischemia was mimicked by substituting growth media by Ischemia Mimetic Solution (including nutrient depletion, lactate accumulation, acidosis and hyperosmosis) and placing the cells at 0% O 2 for 5 hours. In the reperfusion step, cells were placed back in their physiological culture conditions (3% O 2 ). The effect of I/R injury on growth factor secretion, cells’ viability, as well as on hCSC proliferation was accessed in both mono- and co-culture systems. In addition, hCSCs total proteome analysis was performed at different timepoints (before injury, after ischemia and after 1h and 16h of reoxygenation) by LC-MS. Important features of I/R injury were successfully captured in our model, namely hCSC proliferation activation upon insult, the increase in HGF secretion during the first hour after reoxygenation, and the protective role of hCSCs on hiPSC-CMs. The maturation stage of hiPSC-CM showed to be of high relevance in the response to injury. More than 2000 proteins were identified in hCSCs per experimental time point; proteins associated with mitochondrial dysfunction and oxidative stress response were identified in hCSCs exposed to injury. This system will allow further understanding on the molecular landscape of the myocardium during AMI, namely regarding hCSC regenerative response and hCM survival. The knowledge gained in this work will potentiate the development of novel therapies for myocardium regeneration.
Katherine Mary Donnelly
Authors: Brian Donnelly
Journal: BMJ (2018)

One of 11 children (including six doctors), Katherine Mary Donnelly (“Maura”) McLoughlin met her future husband, Brian Donnelly, as a fourth year medical student on an anaesthetics placement at Daisy Hill Hospital, Newry.

Married shortly after qualifying, Maura completed her house job in the Mater Hospital in Belfast, and …
Effect of Catecholamines and Adrenergic Blocking Agents on Oxidative Phosphorylation in Rat Heart Mitochondria
Authors: Burtonsobel, Ericjequier, Albertsjoerdsma, Walterlovenberg
Journal: Circulation Research (1966)

Polarographic methods were used to examine oxidative phosphorylation in mitochondria isolated from hearts of rats treated with 5 mg/kg epinephrine, norepinephrine, or isoproterenol in oil given subcutaneously. Uncoupling of oxidative phosphorylation occurred (P/O ratio 2.1 ± .04 compared to P/O ratio of controls, 2.9 ± .03). Other indices of mitochondrial function, including oxygen consumption, respiratory control, adenosinetriphosphatase activity, and swelling were normal. The time course of depression of P/O ratio was parallel to that of myocardial catecholamine uptake, yet normal mitochondria were not affected by catecholamines in vitro (10-3M). Adrenergic blocking agents in vitro did not improve the function of mitochondria from catecholamine-treated animals. No free fatty acids were detectable in extracts of mitochondria from either group by gas liquid chromatography, and the lipid profiles of extracts from each were similar by thin layer chromatography. The data indicate a means by which large quant...