tbuckley/cabot-search huggingface dataset:
Abstract 16916: Mmp14 in Vascular Smooth Muscles Protects Mice From Atherogenesis
Authors: Richard H Barnes II, Miina K Ohman, Stephen J Weiss, Daniel T Eitzman, Tae-Hwa Chun
Journal: Circulation (2015)

Rationale: The matrix metalloproteinase (MMP) family plays diverse but critical role in the remodeling of collagen-rich extracellular matrix (ECM) environment in cardiovascular diseases. A membrane-type MMP, MMP14 (MT1-MMP) plays a key role in pericellular collagen remodeling. Despite the known role played by macrophage MMP14 in collagen remodeling of atheroma, the cell type-specific role of MMP14 in atherogenesis has not been fully defined. Objective: We aimed to define the consequence of whole-body MMP14 haploinsufficiency on atherogenesis and then determine the cell type that is responsible for MMP14-dependent modification of atherogenesis. Methods and Results: MMP14(+/-)ApoE(-/-) mice displayed a significant increase in atherogenesis in the whole arterial tree compared to MMP14(+/+)ApoE(-/-) mice (18.1±0.8 vs. 14.9±0.9% in males and 23.6±1.6 vs. 15.1±1.3% in females, P &lt; 0.01). No difference in cholesterol level was found. When adipocyte MMP14 was deleted in aP2-Cre-ERT2/MMP14(f/f)/ApoE(-/-) mice (adipo-KO), profibrotic and proinflammatory changes in the visceral adipose tissue were observed; however, no significant effects on atherogenesis were noted (male Cre(-)/MMP14(f/f)/ApoE(-/-) control 8.5±1.5 vs. adipo-KO 4.6±1.5%, n = 4). On the other hand, the deletion of MMP14 from vascular smooth muscle cells (VSMCs) in SM22-Cre/MMP14(f/f)/ApoE(-/-) (VSMC-KO), markedly increased atherosclerotic area (male VSMC-KO 34.6±2.6%, P &lt; 0.0001 compared to Cre(-) control, n = 11). The histology at aortic root after 8 weeks of Western diet demonstrates the significantly increased number of VSMCs with positive Ki67 staining coupled with the infiltration of F4/80-positive macrophages in VSMC-KO mice. Primary VSMCs isolated from VSMC-KO aortas displayed augmented stress fiber formation and increased proliferation capacity in vitro. Conclusions: MMP14 expressed in VSMCs plays a protective role against atherogenesis in ApoE-null mice. The loss of MMP14 causes the proliferative response of VSMCs in atherogenic conditions.
Abstract 5087: Human melanoma exosomes induce metabolic reprogramming in human adult dermal fibroblasts
Authors: Shin La Shu, Cheryl L. Allen, Yunchen Yang, Orla Maguire, Hans Minderman, Arindam Sen, Michael J. Ciesielski, Katherine A. Collins, Peter J. Bush, Martin Morgan, Yun Wu, Richard B. Bankert, Marc S. Ernstoff
Journal: Cancer Research (2018)

Abstract The “seed and soil” hypothesis of cancer metastasis has led us to examine the role of tumor-derived exosomes on reprogramming stromal cells composing the tumor microenvironment. We used human adult dermal fibroblasts (HADF) in vitro as a model of the premetastatic niche. Specifically, we determined the role of human melanoma-derived exosomes (HMEX) on governing metabolic reprogramming of healthy HADF. HMEX from six melanoma cell lines (3 BRAF V600E mutant cell lines (526-mel, 888-mel and Hs 294T) and 3 BRAF wild-type cell lines (1300-mel, 2183-Her4 and HMCB)) were purified by size-exclusion chromatography. Using the fluorescent tag CellVue (Maroon) we demonstrated via ImageStream that HMEXs are rapidly taken up by HADF. Following 18 hours of exposure to HMEX, HADF increased aerobic glycolysis and reduced oxidative phosphorylation (OXPHOS) in vitro, as measured by Agilent Seahorse XFe96. We have also developed an immuno-biochip that captures exosomes via anti-CD63 antibodies and simultaneously detects exosomal microRNAs by cationic lipoplex nanoparticles (tCLN) containing molecular beacons. With this immuno-biochip, we demonstrated the presence of microRNAs miR-155 and miR-210 in HMEX, both of which work in concert to promote glycolysis and inhibit OXPHOS. The result has been consistent across all HMEXs from the six different melanoma cell lines. Our findings reveal a correlation between metabolic function and the presence of metabolically active microRNAs in HMEX that control aerobic glycolysis and OXPHOS of normal fibroblasts. Melanoma exosomes are potentially key players in promoting tumor progression by modulating normal stromal cell metabolism and creating an environment that is conducive to metastasis. Oxygen Consumption Rate (OCR) pmol/minHADF onlyHADF + HMEX 17.5 μgHADF + HMEX 25 μgHADF + HMEX 50μgHADF + HMEX100μgBasal OCR52.6753.5850.9638.2031.56 Citation Format: Shin La Shu, Cheryl L. Allen, Yunchen Yang, Orla Maguire, Hans Minderman, Arindam Sen, Michael J. Ciesielski, Katherine A. Collins, Peter J. Bush, Martin Morgan, Yun Wu, Richard B. Bankert, Marc S. Ernstoff. Human melanoma exosomes induce metabolic reprogramming in human adult dermal fibroblasts [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 5087.
Poly(propylacrylic acid)-peptide nanoplexes as a platform for enhancing the immunogenicity of neoantigen cancer vaccines
Authors: Feng Qiu, Kyle W. Becker, Frances C. Knight, Jessalyn J. Baljon, Sema Sevimli, Daniel Shae, Pavlo Gilchuk, Sebastian Joyce, John T. Wilson
Journal: Biomaterials (2018)
Congenital Polyvalvular Disease
Authors: Sarojabharati, Mauricelev
Journal: Circulation (1973)

Thirty-six hearts were studied in which all valves were involved in a dysplastic process. This consisted of an increase in spongiosa with vacuolar and lacunar degeneration, and a distinct lack of elastic tissue in the proximalis and in the spongiosa. This process was similar to, but more marked than that seen in a case of a single dysplastic valve as in bicuspid aortic  It was completely different than that seen in hemodynamic change. These cases clinically were often associated with trisomy 18 or trisomy 13-15, and called congenital polyvalvular disease. This disease may bear some relationship to Marfan's disease and the floppy valve.
Abstract 1090: The role of connexin43 in prostate cancer motility
Authors: Abdulaziz A. Aloliqi
Journal: Cancer Research (2018)

Abstract Prostate cancer (PC) is one of the most common male cancers in United States. PC lethality is due to metastatic growth, when cancer cells move from the primary tumor site to a secondary site. A key step in metastsis is the acquisition of motility. Connexins (Cx) play a major role in cell-cell communication and growing evidence demonstrates their contribution to cell motility. Cx43 is up-regulated in cultured PC3 metastatic prostate cancer cells. To understand the role of Cx43 in migration we asked whether silencing Cx43 would decrease PC3 cell migration. Using cells in which short interfering RNA (sh-RNA) silenced Cx43 mRNA, we showed that silencing Cx43 decreased motility of sh-Cx43 PC3 cells in Boyden chamber assays. To confirm these results in another biological system, we performed cellular wound healing assays. Silencing Cx43 decreased motility of PC3 cells reducing movement to wounded area, leaving more area open in the Cx43 inhibited cell lines. The wound healing assay showed that knockdown Cx43 altered directional movement, velocity and distance. These results supported those of our Boyden assays showing that loss of Cx43 decreases the migratory ability of PC3. Conversely, the overexpression of Cx43 in LNCaP cells, non-migratory prostate cancer cells that lack Cx43 expression, increased their motility. A comparison of cell lines engineered to overexpress or to silence Cx43 confirms the importance of Cx43 in the motility of prostate cancer cells in vitro. Although the mechanism whereby Cx43 regulates motility is still unclear, our preliminary data revealed that Cx43 co-immunoprecipitated with N-cadherin, suggesting that they form a complex in PC3 cells. Cell fractionation studies of PC3 control cells showed that N-cadherin was located in the cell membrane and not detected free in the cytoplasm, but in sh-Cx43 PC3 cells that lack Cx43, the distribution of N-cadherin protein was altered and significant levels of N-cadherin were also detected in cytoplasmic fractions. Whether changes in N-cadherin distribution is a direct or indirect result of loss of Cx43 in sh-Cx43 PC3 cells, is unclear. However, modulation of Cx43 levels in prostate cancer cells does alter motility and N-cadherin distribution. These results indicate that Cx43 and N-cadherin are in close association in PC3 cells and their interaction may play an important role in prostate cancer cell motility. A better understanding of the requirements of migratory PC cells may lead to more effective targeting of key steps in PC progression to lethal metastatic disease. Citation Format: Abdulaziz A. Aloliqi. The role of connexin43 in prostate cancer motility [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 1090.
From Myocarditis to Cardiomyopathy: Mechanisms of Inflammation and Cell Death
Authors: ChuichiKawai
Journal: Circulation (1999)

Abstract—A progression from viral myocarditis to dilated cardiomyopathy has long been hypothesized, but the actual extent of this progression has been uncertain. However, a causal link between viral myocarditis and dilated cardiomyopathy has become more evident than before with the tremendous developments in the molecular analyses of autopsy and endomyocardial biopsy specimens, new techniques of viral gene amplification, and modern immunology. The persistence of viral RNA in the myocardium beyond 90 days after inoculation, confirmed by the method of polymerase chain reaction, has given us new insights into the pathogenesis of dilated cardiomyopathy. Moreover, new knowledge of T-cell–mediated immune responses in murine viral myocarditis has contributed a great deal to the understanding of the mechanisms of ongoing disease processes. Apoptotic cell death may provide the third concept to explain the pathogenesis of dilated cardiomyopathy, in addition to persistent viral RNA in the heart tissue and an immune ...
Abstract 5613: Generation of a therapeutic monoclonal antibody for acute myeloid leukemia by employing the U937 cell line as a surrogate antigen
Authors: Bethany Chen, Evelyn Kandov, Berhane Ghebrehiwet
Journal: Cancer Research (2018)

Abstract The prognosis of acute myeloid leukemia (AML) has improved for younger patients, but it still remains grim for patients over 65 years old with a likelihood of death within a year of diagnosis. Here, we evaluated the effects of novel anti-gC1qR monoclonal antibodies (mAbs) that were generated against intact U937 cells, which are used here as a model for AML. The U937 cell line is known to overexpress gC1qR, which in turn serves not only as a proliferative molecular signal but also provides a platform for the generation of angiogenic and metastatic factors. Cell viability results reveal that all of the mAbs significantly decrease (p&amp;lt;0.05) the percentage of viable AML cells although the mixture of those mAbs was not significant when compared to the individual mAbs themselves. The anti-U937 antibodies, monoclonal and polyclonal, showed a significant difference (p&amp;lt;0.05) against the anti-purified recombinant gC1qR antibodies. The anti-U937 mAb methodology of immunizing with the mammalian cell instead of the purified protein allowed the mAbs to better target the native endogenous protein present on human cells. Our study not only provided novel and potent mAbs against AML, but also implicated a potentially more efficient technique of creating therapeutic mAbs against cancer cells. Citation Format: Bethany Chen, Evelyn Kandov, Berhane Ghebrehiwet. Generation of a therapeutic monoclonal antibody for acute myeloid leukemia by employing the U937 cell line as a surrogate antigen [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 5613.
EBS is a bivalent histone reader that regulates floral phase transition in Arabidopsis
Authors: Zhenlin Yang, Shuiming Qian, Ray N. Scheid, Li Lu, Xiangsong Chen, Rui Liu, Xuan Du, Xinchen Lv, Melissa D. Boersma, Mark Scalf, Lloyd M. Smith, John M. Denu, Jiamu Du, Xuehua Zhong
Journal: Nature Genetics (2018)
Vitamin E Reduces the Uptake of Oxidized LDL by Inhibiting CD36 Scavenger Receptor Expression in Cultured Aortic Smooth Muscle Cells
Authors: RobertaRicciarelli, Jean-MarcZingg, AngeloAzzi
Journal: Circulation (2000)

Background—Vitamin E is well known as an antioxidant, and numerous studies suggest that it has a preventive role in atherosclerosis, although the mechanism of action still remains unclear. Methods and Results—The original aim of this study was to establish whether α-tocopherol (the most active form of vitamin E) acts at the earliest events on the cascade of atherosclerosis progression, that of oxidized LDL (oxLDL) uptake and foam-cell formation. We show here that the CD36 scavenger receptor (a specific receptor for oxLDL) is expressed in cultured human aortic smooth muscle cells (SMCs). Treatment of SMCs and HL-60 macrophages with α-tocopherol (50 μmol/L, a physiological concentration) downregulates CD36 expression by reducing its promoter activity. Furthermore, we find that α-tocopherol treatment of SMCs leads to a reduction of oxLDL uptake. Conclusions—This study indicates that CD36 is expressed in cultured human SMCs. In these cells, CD36 transports oxLDL into the cytosol. α-Tocopherol inhibits oxLDL u...
Abstract 3527: Inhibition of mitochondrial pyruvate transport selectively sensitizes cancer cells to metabolic oxidative stress
Authors: Shane R. Solst, Samuel N. Rodman, Melissa A. Fath, Eric B. Taylor, Douglas R. Spitz
Journal: Cancer Research (2018)

Abstract To determine if mitochondrial pyruvate transport could represent a therapeutic target for sensitizing cancer cells to oxidative stress, lung and breast cancer cells were treated with 5 µM UK5099 to inhibit the mitochondrial pyruvate carrier (MPC). Treatment with UK5099 selectively sensitized lung and breast cancer cells to clonogenic cell killing when combined with depletion of glutathione using 1 mM buthionine sulfoximine (BSO; a glutathione synthesis inhibitor) for 48 h and 72 h, relative to normal lung and breast epithelial cells. Furthermore, cancer cell killing mediated by UK5099 combined with BSO was inhibited by the thiol antioxidant, N-acetylcysteine (NAC; 20 mM), independent of GSH levels, indicating a mechanism of toxicity involving reduced thiols and metabolic oxidative stress. In addition, treatment with UK5099 alone for 48 h also decreased levels of total glutathione in cancer cells that could be reversed by NAC. Using oxidation-sensitive fluorescent dyes (CDCFH2 and MitoSOX), treatment of lung and breast cancer cells for 24 h and 48 h with UK5099 induced increases in steady state levels of pro-oxidants (presumably hydroperoxides and mitochondrial superoxide), which were further increased with BSO. Finally, treatment of breast cancer cells with UK5099 for 24 and 48 hours significantly sensitized breast cancer cells to clonogenic cell killing mediated by paclitaxel. These data support the hypothesis that inhibition of the MPC selectively causes an impairment of antioxidant capability in cancer cells that is enhanced by depletion of glutathione. Furthermore, these results also support the hypothesis that inhibition of the MPC represents a significant target for sensitizing human breast cancer cells to chemotherapy agents thought to induce oxidative stress. Supported by R01CA182804. Citation Format: Shane R. Solst, Samuel N. Rodman, Melissa A. Fath, Eric B. Taylor, Douglas R. Spitz. Inhibition of mitochondrial pyruvate transport selectively sensitizes cancer cells to metabolic oxidative stress [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 3527.
Abstract 1487: Investigation of triple-negative breast cancer tumor conversion through high-content screening approaches
Authors: Albane Gaudeau, Véronique Lamamy, Anne-Laure Jaskowiak, Xavier Scerri, Benjamin Chanrion, Thierry Dorval, Elaine Del Nery, Franck Perez, Jacques Camonis, Jean-Philippe Stéphan
Journal: Cancer Research (2018)

Abstract Among Breast Cancer (BC) classification, Triple-Negative (TN) form is the most aggressive, lacking efficient and specific treatment. Our project aims at investigating the possibility to convert TNBC tumor cell lines in Estrogen Receptor (ER), Progesterone Receptor (PR) and/or Human Epidermal growth factor Receptor 2 (HER2)-positive cells using various modalities (siRNA, CRISPR-Cas9, small molecules). Our approach consists in optimizing a multi-parametric High-Content Screening (HCS) relying on phenotypic read-outs such as expression of TNBC positive and negative markers, cell behavior and viability. This poster will present our initial results, validation and future plans. This thesis project fits within a context of drug discovery, innovation, comparison of technologies and understanding of key biological processes and pathways, carried out in partnership between Servier Research Institute and Institut Curie. Citation Format: Albane Gaudeau, Véronique Lamamy, Anne-Laure Jaskowiak, Xavier Scerri, Benjamin Chanrion, Thierry Dorval, Elaine Del Nery, Franck Perez, Jacques Camonis, Jean-Philippe Stéphan. Investigation of triple-negative breast cancer tumor conversion through high-content screening approaches [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 1487.
A Necessary Role of miR-221 and miR-222 in Vascular Smooth Muscle Cell Proliferation and Neointimal Hyperplasia
Authors: XiaojunLiu, YunhuiCheng, ShuoZhang, YingLin, JianYang, ChunxiangZhang
Journal: Circulation Research (2009)

MicroRNAs (miRNAs) comprise a novel class of endogenous, small, noncoding RNAs that negatively regulate gene expression. Functionally, an individual miRNA is as important as a transcription factor because it is able to regulate the expression of its multiple target genes. Recently, miR-221 and miR-222 have been found to play a critical role in cancer cell proliferation. However, their roles in vascular smooth muscle cell (VSMC) biology are currently unknown. In the present study, the time course changes and cellular distribution of miR-221 and miR-222 expression were identified in rat carotid arteries after angioplasty, in which their expression was upregulated and localized in VSMCs in the injured vascular walls. In cultured VSMCs, miR-221 and miR-222 expression was increased by growth stimulators. Knockdown of miR-221 and miR-222 resulted in decreased VSMC proliferation in vitro. Using both gain-of-function and loss-of-function approaches, we found that p27(Kip1) and p57(Kip2) were 2 target genes that w...
Responsiveness of histological disease activity indices in ulcerative colitis: a post hoc analysis using data from the TOUCHSTONE randomised controlled trial
Authors: Vipul Jairath, Laurent Peyrin-Biroulet, Guangyong Zou, Mahmoud Mosli, Niels Vande Casteele, Reetesh K Pai, Mark A Valasek, Aude Marchal-Bressenot, Larry W Stitt, Lisa M Shackelton, Reena Khanna, Geert R D’Haens, William J Sandborn, Allan Olson, Brian G Feagan, Rish K Pai
Journal: Gut (2018)

Objective We evaluated the reliability and responsiveness of available but incompletely validated UC histological disease activity indices using standardised rules for centralised assessment. Design Disease activity was assessed in biopsies collected in a phase II placebo-controlled ozanimod trial by four blinded pathologists using the Geboes (GS) and modified Riley (MRS) scores, the Robarts Histopathology (RHI) and Nancy Histological (NHI) indices and a Visual Analogue Scale. Reliability was assessed with intraclass correlation coefficients (ICCs). Index responsiveness was evaluated by assessing longitudinal validity (Pearson correlations of changes in index scores and other disease measures), and effect size estimates (standardised effect size (SES)) using two criteria for change (treatment assignment and &gt;2 point decrease in total Mayo Clinic score). Area under the receiver operating characteristic (AUROC) curve estimates evaluated the probability of the indices to discriminate between treatment and placebo. Results Inter-rater reliability of the histological indices was substantial to almost perfect (ICC&gt;0.61), and responsiveness was moderate to large (SES estimates&gt;0.5); 0.81 (0.52, 1.10), 0.87 (0.58, 1.17), 0.57 (0.30, 0.84) and 0.81 (0.52, 1.09) when treatment assignment was the criterion for change and 1.05 (0.80, 1.31), 1.13 (0.87, 1.39), 0.88 (0.64, 1.12) and 1.06 (0.80, 1.31) for the change in Mayo score criterion for the GS, MRS, RHI and NHI, respectively. The indices had similar drisciminative ability based on AUROC estimates (range 0.608–0.649). Conclusion All four existing histological indices were similarly reliable and responsive based on this dataset.
Abstract 5898: A systems approach for determining the mechanism of resistance to tumor treating fields in glioblastoma
Authors: Dongjiang Chen, Son Le, Nagheme Thomas, David D. Tran
Journal: Cancer Research (2018)

Abstract Glioblastoma (GBM) is the most common and deadliest malignant brain cancer in adults despite aggressive chemoradiotherapy. Recently, Tumor Treating Fields (TTFields) was approved in combination with adjuvant temozolomide chemotherapy for newly diagnosed GBM. The addition of TTFields resulted in a significant improvement in overall survival. TTFields are low-intensity alternating electric fields that are thought to disturb mitotic macromolecules' assembly, leading to disrupted chromosomal segregation and cell death. However, the majority of GBM are not sensitive to TTFields and most of TTFields responders eventually develop resistance. However the mechanism of resistance remains largely unexplored. Understanding how cancer cells gain the ability to circumvent the biophysical forces of TTFields and their downstream effects will provide new opportunities to improve therapeutic efficacy of this novel anti-cancer treatment modality. To accomplish these objectives, we have developed several human GBM cell lines that demonstrated relative resistance to the cytotoxic effects of TTFields compared to the parental cells. Importantly TTFields-induced chromosomal instability such as the formation of micronuclei was unchanged in resistant cells compared to their sensitive counterparts, suggesting that resistance to TTFields may be conferred by a selective loss of deleterious downstream reactions to the biophysical damages. To systematically identify the mechanism of resistance, we have recently developed two innovative computational platforms, GeneRep and nSCORE and experimentally validated them in several published datasets. The tandem platforms complemented each other and allowed us to 1) interrogate large-scale gene expression profiles of pairs of TTFields resistant cells vs. sensitive counterparts to extract candidate resistance-specific gene regulatory networks, and 2) functionally rank specific core factors responsible for resistance, respectively. Once identified, biological confirmation of these factors using cell lines, mouse models and samples of patient's derived TTFields sensitive and resistant GBM. Our long-term goal is to develop targeted therapy to prevent tumor's resistance to TTFields therapy. Citation Format: Dongjiang Chen, Son Le, Nagheme Thomas, David D. Tran. A systems approach for determining the mechanism of resistance to tumor treating fields in glioblastoma [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 5898.