tbuckley/cabot-search huggingface dataset:
Abstract 1119: S100A4 alters mitochondrial metabolism to promote invasion and metastasis of non-small cell lung cancer cells through upregulation of NDUFS2
Authors: Lili Liu, Lei Qi, Teresa Knifley, Dava W. Piecoro, Piotr Rychahou, Jinpeng Liu, Mihail I. Mitov, Jeremiah Martin, Chi Wang, Jianrong Wu, Heidi L. Weiss, D. Allan Butterfield, B. Mark Evers, Kathleen L. O'Connor, Min Chen
Journal: Cancer Research (2019)

Abstract It is generally accepted that alterations in metabolism are critical for the metastatic process; however, the mechanisms by which the metabolic changes are controlled by the major drivers of the metastatic process remain elusive. Here, we find that S100A4, a major metastasis-promoting protein, alters metabolic plasticity to drive tumor invasion and metastasis. Investigating how S100A4 regulates metabolism, we find that depletion of S100A4 decreases oxygen consumption rate, mitochondrial activity, and ATP production, and shifts cell metabolism to be more glycolytically active. We further identify that the 49 KD mitochondrial complex I subunit NADH dehydrogenase (ubiquinone) Fe-S protein 2 (NDUFS2) is regulated in an S100A4-dependent manner and that S100A4 and NDUFS2 exhibit co-occurrence at significant levels in various cancer types (cBioPortal). Importantly, we find that knockdown of NDUFS2 inhibits mitochondrial complex I activity, reduces cellular ATP level, and decreases the invasive capacity in three-dimensional (3D) growth, thus mimicking the biological effect resulting from S100A4 knockdown in A549 cells. Likewise, silencing S100A4 and NDUFS2 dramatically decreases the rate of metastasis as well as tumor growth in vivo. Finally, we provide evidence that cells with S100A4 and NDUFS2 depletion shift metabolism toward glycolysis through upregulating hexokinases expression and that suppressing S100A4 signaling sensitizes lung cancer cells to glycolysis inhibition. Together, our findings uncover a novel function of S100A4 in mitochondrial metabolism and highlight the importance of NDUFS2 in regulating the plasticity of mitochondrial metabolism by S100A4 to promote the invasion and metastasis in lung cancer. Citation Format: Lili Liu, Lei Qi, Teresa Knifley, Dava W. Piecoro, Piotr Rychahou, Jinpeng Liu, Mihail I. Mitov, Jeremiah Martin, Chi Wang, Jianrong Wu, Heidi L. Weiss, D. Allan Butterfield, B. Mark Evers, Kathleen L. O'Connor, Min Chen. S100A4 alters mitochondrial metabolism to promote invasion and metastasis of non-small cell lung cancer cells through upregulation of NDUFS2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1119.
Abstract 13326: Multilayer Appearance as a Finding of Mural Thrombosis is Associated with Subsequent Plaque Progression in Cardiac Transplant Patients
Authors: Yoshiki Matsuo, Andrew Cassar, Jing Li, Andreas J Flammer, Rajiv Gulati, Sudhir Kushwaha, Amir Lerman
Journal: Circulation (2012)

Background: Cardiac allograft vasculopathy (CAV) is a major limitation to long-term survival following heart transplantation. The pathogenesis of CAV remains to be established although multiple mec...
Correcting Meta-analyses and Reviews Affected by Retracted Research—Reply
Authors: Craig A. Garmendia, Purnima Madhivanan
Journal: JAMA Internal Medicine (2019)

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Abstract 435: Adrenergic Deficiency Disrupts Glucose Metabolism and ATP/NADH Production During Embryonic Heart Development
Authors: Jessica Peoples, Timmi Maxmillian, Quynh Le, Sergiy M Nadtochiy, Paul Brookes, George Porter, Steven Ebert
Journal: Circulation Research (2017)

Cardiac energy demands increase during embryonic development, requiring activation of oxidative phosphorylation to convert ADP to ATP in mitochondria. We have recently shown that adrenergic hormones are required to maintain sufficient cardiac energy metabolism during embryonic development, but the specific mechanism(s) underlying this regulation are not known. Mouse embryos lacking the adrenergic hormones, norepinephrine (NE) and epinephrine (EPI), due to targeted loss of the dopamine β-hydroxylase ( Dbh ) gene, have markedly (&gt;50-fold) decreased steady-state ATP/ADP ratios. Rates of ATP synthesis and hydrolysis did not differ between adrenergic-deficient and competent embryos suggesting the enzymatic machinery required for ATP production/consumption is functional. We hypothesized that adrenergic-deficient embryonic hearts are metabolically starved of nutrients leading to energy depletion. To identify changes in metabolism in adrenergic-deficient hearts, we performed LC-MS metabolomics, which showed decreases in all nucleotide triphosphates (NTPs) and NAD(H) confirming energy depletion. Additionally, products of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), glucose-6-phosphate dehydrogenase (G-6-PDH), and pyruvate dehydrogenase (PDH) were significantly diminished compared to controls, suggesting impaired activity. Enzymatic activities of GAPDH, G-6-PDH, PDH, and glycogen phosphorylase (GP); a well-known enzyme under adrenergic regulation, were measured from the rate of NAD(P)H production. GAPDH, G-6-PDH, and GP activities were significantly decreased (~80%, 40%, and 70% reduction, respectively) compared to controls. Interestingly, GAPDH, G-6-PDH, and GP protein levels, examined by western blot, did not differ from adrenergic-competent controls, thereby suggesting that adrenergic hormones regulate posttranslational activity of these enzymes. These results indicate that mitochondria are metabolically starved due to impairments in glycogenolysis, glycolysis, and pentose phosphate pathways. These findings reveal new mechanistic insights into global adrenergic regulation of major metabolic pathways during embryonic heart development.
Activation of the VEGFC/VEGFR3 Pathway Induces Tumor Immune Escape in Colorectal Cancer
Authors: Carlotta Tacconi, Federica Ungaro, Carmen Correale, Vincenzo Arena, Luca Massimino, Michael Detmar, Antonino Spinelli, Michele Carvello, Massimiliano Mazzone, Ana I. Oliveira, Federica Rubbino, Valentina Garlatti, Salvatore Spanò, Enrico Lugli, Federico S. Colombo, Alberto Malesci, Laurent Peyrin-Biroulet, Stefania Vetrano, Silvio Danese, Silvia D’Alessio
Journal: Cancer Research (2019)

Abstract Colorectal cancer is a major cause of cancer-related death in Western countries and is associated with increased numbers of lymphatic vessels (LV) and tumor-associated macrophages (TAM). The VEGFC/VEGFR3 pathway is regarded as the principal inducer of lymphangiogenesis and it contributes to metastases; however, no data are available regarding its role during primary colorectal cancer development. We found that both VEGFC and VEGFR3 were upregulated in human nonmetastatic colorectal cancer, with VEGFR3 expressed on both LVs and TAMs. With the use of three different preclinical models of colorectal cancer, we also discovered that the VEGFC/VEGFR3 axis can shape both lymphatic endothelial cells and TAMs to synergistically inhibit antitumor immunity and promote primary colorectal cancer growth. Therefore, VEGFR3-directed therapy could be envisioned for the treatment of nonmetastatic colorectal cancer. Significance: The prolymphangiogenic factor VEGFC is abundant in colorectal cancer and activates VEGFR3 present on cancer-associated macrophages and lymphatic vessels; activation of VEGFR3 signaling fosters cancer immune escape, resulting in enhanced tumor growth.
Abstract SY42-01: Chemical biology-based approach to understanding and overcoming resistance of cancers to therapies
Authors: Stuart L. Schreiber
Journal: Cancer Research (2019)

Abstract The ability of cancer cells to resist apoptotic death induced by radiation, chemotherapy, targeted therapies and immunotherapy has been a primary impediment to achieving long-lasting clinical responses. Cancer resistance is often studied through the lens of genetics, and thus on a drug-by-drug basis. I will discuss an alternative approach - studying resistance through the lens of cellular plasticity. As part of the NCI’s Cancer Target Discovery &amp; Development Network, we use the Cancer Therapeutics Response Portal (CTRP), which enables small molecule sensitivity-cancer cell feature relationships to be explored on a broad basis. One insight gained from this resource suggests that a similar form of plasticity appears recurrently in multiple cancer contexts, and in response to multiple modalities (chemotherapy; targeted therapy; immunotherapy) thus opening the possibility of a pan-cancer explanation of resistance. Here, cell plasticity provides access to an apoptosis-deficient state and thus resistance, and then subsequent cancer mutations, rather than being the basis of resistance, are needed to optimize the fitness of the resistant state for growth. We found that this myofibroblastic-like cell state has profound changes in lipid biology that result in a novel vulnerability to ferroptotic cell death and a dependency on the activity of GPX4, a potentially druggable lipid hydroperoxidas. We hope this research will provide a blueprint for the cure of cancers in the future. Citation Format: Stuart L. Schreiber. Chemical biology-based approach to understanding and overcoming resistance of cancers to therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr SY42-01.
Integrated next-generation sequencing and patient-derived xenografts to personalized cancer treatment.
Authors: Elena Garralda, Antonio Calles, Fernando López-Ríos, Siân Jones, Lisa M. Kann, Samuel V. Angiuoli, Luis A. Diaz, Victor E. Velculescu, Pedro P. López-Casas, Francesca Sarno, Raquel Martinez, Carlos Gomez-Martin, Esther Conde, Cristobal Belda-Iniesta, Alfonso Valencia, Manuel Hidalgo
Journal: Journal of Clinical Oncology (2012)

3068 Background: The knowledge of actionable somatic genomic alterations present in each tumor is making possible the era of personalized cancer treatment. Methods: Using massively parallel sequencing we performed whole exome sequencing analysis of tumor and matched normal blood samples of 8 patients (2 pancreatic adenocarcinoma, 1 neuroendocrine tumor, 1 glioblastoma, 1 uveal melanoma, 1 colon cancer) to identify putatively actionable tumor specific genomic alterations. We used 2 in silico methods (Polyphen and SIFT) to estimate the functional significance of a given confirmed mutation. Primary xenografts (PDX), generated by direct engraftment of tumor samples from the patients into immunocompromised mice, were used as an in vivo platform that provided the opportunity to test proposed personalized medicine strategies. Results: At this time exome sequencing analyses have been performed for 5 patients (1 patient died prematurely, 1 tumor sample was insufficient, 1 result is pending). More than 30 million bases of target DNA were analyzed in the tumor and normal samples in every case, with at least 70 distinct reads at each base. Tumor specific mutations (Muts) and copy number variations (CNVs) were identified: 5 Muts in the neuroendocrine tumor; 62Muts/6CNVs and 38Muts/10CNVs in the pancreatic tumors; 63Muts/23CNVs in the glioblastoma; 5 Muts in the melanoma. All samples profiled contained actionable alterations with the most relevant mutations affecting NF1, PTPN11, EPHA3, CDKN2A, FAS (glioblastoma); PI3KCA, ARID1A, ARID1B, DDR2, SMAD4, TP53, KRAS, PTCHD3 (pancreatic); CREB3L3, ITPR2 (neuroendocrine); GNA11, TAOK3 (melanoma). PDX from the pancreatic cancer patient was treated with a PI3K inhibitor and dasatinib, reported to be effective in discodin domain receptor 2 (DDR2) mutant cancer with no effect. Accordingly treatment of that patient with dasatinib was not effective and the level of this mutation in the tumor was observed to be low. Conclusions: Detection of actionable tumor-specific genomic alterations in the clinical setting is feasible. In silico methods and primary xenografts can help in the challenge of linking confirmed mutations to protein function and ultimately to clinical utility.
Abstract 15181: Machine Learning Identifies Heterogeneity of Treatment Effect for the Use of Spironolactone in Heart Failure With Preserved Ejection Fraction: Insights From the TOPCAT Trial
Authors: Usman A Tahir, Yang Hu, Marwa Sabe, Robert W Yeh, Changyu Shen
Journal: Circulation (2018)

Background: Spironolactone has been shown to potentially benefit patients with HFpEF, however given the heterogeneity of this patient population, it is unclear which patients are more likely to ben...
The Effect of Measurable Residual Disease at the Time of Allogeneic Hematopoietic Cell Transplantation on Outcomes in Patients with Acute Myeloid Leukemia: A Meta-Analysis
Authors: Sarah A. Buckley, Brent L. Wood, Megan Othus, Christopher S. Hourigan, Celalettin Ustun, Michael A. Linden, Todd E. DeFor, Michele Malagola, Christopher G. Kanakry, Bernd Gruhn, Beth Devine, Roland B. Walter
Journal: Blood (2016)
Anti‐C1q antibodies in scleroderma
Authors: C. Liaskos, S. Rentouli, T. Simopoulou, A. Gkoutzourelas, G.L. Norman, A. Brotis, I. Alexiou, C. Katsiari, D.P. Bogdanos, L.I. Sakkas
Journal: British Journal of Dermatology (2019)

Systemic sclerosis (SSc) is an autoimmune condition which means that the body's immune system, which usually fights off disease, wrongly targets healthy parts of the body, and SSc patients produce antibodies to their own tissues (‘autoantibodies’). Extensive thickening and scarring of tissues (fibrosis) is the main feature of the condition and is due to over‐production of collagen. Changes in small blood vessels also occur. When fibrosis occurs in the lungs (pulmonary fibrosis) it can lead to high blood pressure in the arteries going to the lungs, and this may be life‐threatening. The condition is commoner in women. SSc can be localised or disseminated (generalised), depending on the extent of skin involvement. Although the cause of SSc has not been fully worked out, many of the autoantibodies associated with the condition are believed to be involved in one way or another. Autoantibodies called ‘anti‐C1q’ are certainly found in another autoimmune condition called systemic lupus erythematosus, so the aim of this study from Greece and the USA was to see if they were also present in SSc. Anti‐C1q autoantibodies were found in 16.1% of the 124 SSc patients in the study, occurring as often as the third most frequently found autoantibody, known as anti‐RNA polymerase III. They were found particularly in men and in patients with disseminated SSc. Presence of anti‐C1q antibodies was associated with pulmonary fibrosis but not with any of the other features of SSc. The authors therefore suggest that anti‐C1q autoantibodies could be looked at as a marker for (sign of) pulmonary fibrosis in SSc patients.
Abstract 1029: Metastatic cancer cells activate endothelial RhoA-ROCK pathway for trans-endothelial migration
Authors: Md Sanaullah Sajib, Fatema Tuz Zahra, Jee Hyun Park, Paul Tullar, Sanjay K. Srivastava, Ulrich Bickel, Constantinos M Mikelis
Journal: Cancer Research (2019)

Abstract Metastasis is the process through which tumor cells disseminate from the primary tumor and colonize in distant parts of the body. Two of the steps in the metastatic process are the trans-migration of cancer cells through the endothelial lining of blood and lymphatic vessels, during entrance (intravasation) and exit (extravasation) from the vascular system. We and others have shown that the endothelial RhoA pathway plays important role in endothelial permeability. Translating these findings in the metastasis context we aim to explore the role of endothelial RhoA signaling pathway on cancer cell trans-endothelial migration and metastasis. In vitro, we have established a quantifiable, highly reproducible, transwell-based, two-cell co-culture model of trans-endothelial migration, where fluorescently-labeled cancer cells transmigrate through an endothelial monolayer. Pharmacological and molecular biology approaches were incorporated to dissect the role of endothelial RhoA signaling pathway. Primary and immortalized endothelial cells were used and cancer cells of both mouse and human origin were tested. In all cases, conditioned media from the cancer cells activated endothelial RhoA. Blockade of the RhoA pathway inhibited cancer cell trans-endothelial migration. In vivo, syngeneic and human cancer cell lines were tested in tail-vein and intra-cardiac models of experimental metastasis. We observed decreased lung metastatic nodules in endothelial-specific RhoA-deficient mice, compared to the littermate controls. Treatment with a clinically-relevant inhibitor of the RhoA pathway, Fasudil, also decreased the metastatic colonization of both human and cancer cells. The above findings demonstrate that the endothelial RhoA pathway has a pivotal role on cancer cell trans-endothelial migration. Citation Format: Md Sanaullah Sajib, Fatema Tuz Zahra, Jee Hyun Park, Paul Tullar, Sanjay K. Srivastava, Ulrich Bickel, Constantinos M Mikelis. Metastatic cancer cells activate endothelial RhoA-ROCK pathway for trans-endothelial migration [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1029.
Abstract 5299: Role of short chain free fatty acid receptors in colorectal cancer
Authors: Amal AlGhamdi, Saeed AlMahri, Maaged AlAkiel, Sameer Mohammad, Mohammad Aziz
Journal: Cancer Research (2019)

Abstract One of the well established risk factors for colorectal cancer is dietary profile. A well recognized negative association of dietary fiber with colorectal cancer warrants further understanding of the underlying mechanism. Bacterial fermentation of dietary fibre results in formation of short chain free fatty acids in the gut. There are two receptors for these fatty acids one of which has been implicated in colorectal cancer. Free fatty acid receptor 2 has been associated with development of colorectal adenoma in a mouse model. We analyzed the differential expression of FFAR2 gene in colorectal cancer patients. Further, we generated genetically engineered colorectal cancer cell line with reduced level of expression of these receptors. These engineered cells were found to have enhanced rate of cell proliferation. In order to understand the mechanism of increased proliferation, we explored the involevement of glucose uptake and cAMP pathways. While there was an increased level of glucose uptake in engineered cells, there was no evidence of involvement of Protein kinase A mediated cAMP pathway. Further studies are needed to fully establish the connection between dietary fibre, gut microbiota and colorectal cancer. Citation Format: Amal AlGhamdi, Saeed AlMahri, Maaged AlAkiel, Sameer Mohammad, Mohammad Aziz. Role of short chain free fatty acid receptors in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5299.
Abstract 4222: Omega-3 fatty acids produce DNA methylation changes in inflammation-related genes and pathways with implication of toll-like receptor signaling
Authors: David E. Frankhouser, Sarah Woelke, Michael Sovic, Ralf Bundschuh, Pearlly Yan, Lisa D. Yee
Journal: Cancer Research (2019)

Abstract Introduction Omega-3 polyunsaturated fatty acids (n-3 PUFA) have been studied for potential health benefits in many diseases including breast cancer. The preventive effects of n-3 PUFAs may relate in part to inhibition of chronic, low-grade inflammation. Of interest is the role of n-3 PUFAs in modulating pro-inflammatory gene expression via epigenetic factors such as DNA methylation (DNAm). Methods DNA methylation of PBMCs obtained at 0 and 6 months of n-3 PUFA supplementation was assessed via reduced representation bisulfite sequencing (RRBS). PBMC samples were obtained from women at high risk for breast cancer during a randomized clinical trial investigating the effects of different n-3 PUFA doses. The dosing arm selected for this study was 5 g of EPA+DHA/day, with baseline and 6 month samples (n=10). DNAm was quantified using Bismark from trimmed, pass filter reads and analyzed with MethylKit to determine n-3 PUFA treatment specific DNAm changes. Results Global DNAm showed no change after 6 months of n-3 PUFA treatment; however, we detected 30,974 differentially methylated CpGs (DMCs) across the genome. DMCs, both genome-wide and in gene promoters, where DNAm can regulate gene expression, were significantly enriched for hypermethylation events after treatment. Focusing the analysis on pro-inflammatory signaling mediators led to identification of candidate gene promoter DMCs involved in several inflammation-related pathways. Four pathways were significantly enriched for both DMCs and DMC hypermethylation events even when accounting for the genome-wide trend toward hypermethylated DMCs (hypergeometric test p-value &amp;lt; 0.001). The Toll-Like Receptor Pathway (TLR) genes harbored the most DNAm changes post n-3 PUFA treatment. Conclusion Our findings demonstrate that n-3 PUFA supplementation can result in inflammation-related changes stemming from PBMC methylome perturbation. The results suggest the TLR pathway as a potential mechanism for the anti-inflammatory effects of EPA and DHA. Functional studies are needed to confirm our current observation. Citation Format: David E. Frankhouser, Sarah Woelke, Michael Sovic, Ralf Bundschuh, Pearlly Yan, Lisa D. Yee. Omega-3 fatty acids produce DNA methylation changes in inflammation-related genes and pathways with implication of toll-like receptor signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4222.