tbuckley/cabot-search huggingface dataset:
Abstract LB-216: Protein pathway activation analysis of a panel of patient-derived epithelial tumor models identifies signatures of response to ErbB1-3 co-targeting
Authors: Valerie S. Calvert, Camilla Fröhlich, Thomas T. Poulsen, Mikkel W. Pedersen, Michael Kragh, Ivan D. Horak, Emanuel F. Petricoin
Journal: Cancer Research (2018)

Abstract Plasticity of the ErbB family of receptors and ligands is a hallmark of many human tumors and drives resistance to EGFR and HER2 targeting agents such as cetuximab or trastuzumab. Pan-HER is a unique antibody mixture designed to counter ErbB family plasticity by simultaneously targeting EGFR, HER2 and HER3. Pan-HER contains pairs of antibodies against each of the receptors, six antibodies in total, and induces efficient internalization and degradation of all three receptors. Here, the anti-tumor activity of Pan-HER was investigated in a panel of 57 patient-derived epithelial tumor models (PDXs) of various origin including pancreatic (18), colorectal (11), triple negative breast (11), lung (6), squamous head and neck (6), ovarian (3), and gastric (2) cancer, and the level of activity was correlated to baseline protein and phosphoprotein status using laser capture microdissection (LCM) and Reverse Phase Protein Arrays (RPPA). This panel has been preselected to represent hard-to-treat cancers and that are not overtly HER family positive. Pan-HER demonstrated anti-tumor activity across all indications except the gastric models and induced tumor regression in 26 of the 57 PDX models tested. The LCM-RPPA analysis of over 150 proteins and phosphoproteins that are known to be central for receptor tyrosine kinase signaling, survival, apoptosis, growth, inflammation, motility and autophagy identified both broad and indication specific signatures of response to Pan-HER and points to a key role for the KRAS/BRAF/ERK and PIK3CA/AKT pathway activation that associate with therapeutic sensitivity. In conclusion, our results demonstrate that Pan-HER has broad anti-tumor activity across indications and identify phosphoprotein pathway activation signatures predicting for sensitivity or resistance that should be explored clinically. Citation Format: Valerie S. Calvert, Camilla Fröhlich, Thomas T. Poulsen, Mikkel W. Pedersen, Michael Kragh, Ivan D. Horak, Emanuel F. Petricoin. Protein pathway activation analysis of a panel of patient-derived epithelial tumor models identifies signatures of response to ErbB1-3 co-targeting [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-216.
Mineralocorticoid Receptor Blocker Increases Angiotensin-Converting Enzyme 2 Activity in Congestive Heart Failure Patients
Authors: ShlomoKeidar, AvivaGamliel-Lazarovich, MarielleKaplan, ElsaPavlotzky, ShadiHamoud, TonyHayek, RachelKarry, ZaidAbassi
Journal: Circulation Research (2005)

Aldosterone plays an important role in the pathophysiology of congestive heart failure (CHF), and spironolactone improves cardiovascular function and survival rates in patients with CHF. We hypothesized that the mineralocorticoid receptor blockade (MRB) exerted its beneficial effects by reducing oxidative stress and changing the balance between the counter-acting enzymes angiotensin-converting enzyme (ACE) and ACE2. Monocyte-derived macrophages were obtained from 10 patients with CHF before and after 1 month of treatment with spironolactone (25 mg/d). Spironolactone therapy significantly (P<0.005) reduced oxidative stress, as expressed by reduced lipid peroxide content, superoxide ion release, and low-density lipoprotein oxidation by 28%, 53%, and 70%, respectively. Although spironolactone significantly (P<0.01) reduced macrophage ACE activity by 47% and mRNA expression by 53%, ACE2 activity and mRNA expression increased by 300% and 654%, respectively. In mice treated for 2 weeks with eplerenone (200 mg ·...
Abstract 4041: K-ras transformation leads to increased HS-degradation
Authors: Donghong Ju, Mary A. Kosir
Journal: Cancer Research (2018)

Abstract INTRODUCTION: Degradation of glycosaminoglycans in the extracellular matrix impacts cell movement, angiogenesis and other cancer cell activities. The purpose of study was to detect and measure extracellular heparan sulfate (HS)-degrading enzyme in malignant ras-transformed cells where HS degradation occurred at attachment sites. METHODS: Serum free conditioned medium (CM) and lysate from subconfluent Balb/c3T3 and KiMSV (Ki-ras-transformed 3T3) cells were collected and protease inhibitors added. CM was concentrated by ultracentrifugal filters using 3K and 30K MWCO. Heparan degrading enzyme assay kit was use with lysate and CM for each cell line. Western blot analysis of lysate and CM used anti-HPSE, anti-NAP2, and anti-PPBP antibodies with actin control. mRNA for HPSE and PPBP was determined by RTPCR. RESULTS: The heparan degrading activity of CM from KiMSV cells was 12 fold higher than from Balb/c3T3 cells with 30K MWCO concentration. Further, HPSE was detected in the lysate, but not CM. Anti-NAP2 and anti-PPBP antibody detected protein greater than 30kD in CM and lysate for KiMSV cells. However, mRNA expression of PPBP/NAP2 was less in KiMSV than Balb/c3T3 cells. CONCLUSION: HS degradation in the CM of KiMSV cells is greater than for Balb/c3T3 cells from which they are derived after Ki-ras-transformation. The HPSE is not detected in the CM, but PPBP-like proteins at higher molecular weight are detected which may be responsible for the extracellular HS degradation. Citation Format: Donghong Ju, Mary A. Kosir. K-ras transformation leads to increased HS-degradation [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 4041.
Abstract 18786: Combined Biomechanical and Pharmacological Conditioning of Mesenchymal Stem Cells for Enhancing Therapeutic Angiogenesis
Authors: Jason Lee, Kayla Henderson, Pablo Maceda, Miguel Armenta-Ochoa, Eun Yoon, Lara Samarneh, Austin Veith, Mitchell Wong, Andrew Dunn, Aaron B Baker
Journal: Circulation (2017)

Stem cell therapies have great promise for revolutionizing treatments for cardiovascular disease and other disorders. However, these therapies have not yet achieved their potential due to poor effi...
Abstract 4748: Snail1 regulates the tumor-infiltrating regulatory T cell population in breast cancer through Pglyrp3
Authors: Dongjiang Chen, Mathew Sebastian, Son Le, Nagheme Thomas, David D. Tran
Journal: Cancer Research (2018)

Abstract Breast cancer is the second-leading cause of cancer deaths in women. Nearly 30% of breast cancer patients developed recurrent and/or metastatic disease despite several effective receptor-targeting treatments. Although immunotherapy, especially immune checkpoint inhibitors, has proven to be efficacious against many cancers, they have shown more limited activities against poorly immunogenic cancers such as breast cancer. The cause of this relative resistance to immunotherapy is unclear but is thought to be due in part to an enrichment of inhibitory immune cells such as regulatory T cells (Tregs) in the tumor microenvironment (TME). Therefore there is an urgent need to have a better understanding of the underlying genetic and epigenetic determinants of immunotherapeutic resistance in breast cancer to develop methods to overcome it. To that end, using a computational algorithm that we have recently developed, we have discovered a novel gene regulatory subnetwork downstream of the master epithelial mesenchymal transition (EMT) regulator Snail1 in mouse models of human breast cancer. In advanced breast cancer, Snail1 is thought to initiate the epithelial mesenchymal transition (EMT) to promote local invasion and metastatic spread, while also maintaining tumor-initiating cells. On the contrary, this new Snail1-induced subnetwork operates independently of and possibly in place of its EMT function during early tumorigenic changes, when it is required to maintain a powerful tissue surveillance program to curtail transformed cells' ability to progress to advanced cancer. Breast-restricted deletion of Snail1 early in the course of tumorigenesis of several mouse models of breast cancer results in accelerated growth of the primary tumor in an immunocompetent TME, while in an immunosuppressed TME lack of Snail1 significantly reduced growth. We found that Snail1 suppressed regulatory T cells likely by tumor-associated cytokine production, possibly through several key nodes including Hmga2 and Pglyrp3, to promote immune surveillance and clearance of cancer cells. Ongoing experiments are aimed at validating the criticality of this new pathway as individual nodes and as a whole and to evaluate its utility as a novel therapeutic target to improve breast cancer's response to immunotherapy. Citation Format: Dongjiang Chen, Mathew Sebastian, Son Le, Nagheme Thomas, David D. Tran. Snail1 regulates the tumor-infiltrating regulatory T cell population in breast cancer through Pglyrp3 [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 4748.
Abstract 477: Targeting of ErbB3 with functional cooperative miRNAs enhances efficacy of trastuzumab in ErbB2-overexpressing breast cancer cells
Authors: Hui Lyu, Jingcao Huang, Bolun Wang, Amy Han, Bolin Liu
Journal: Cancer Research (2018)

Abstract Introduction: ErbB3 serves as a critical co-receptor of erbB2 and plays a vital role in the development of erbB2-overexpressing (erbB2+) breast cancer. It is thought to be an important compensatory target for combinatorial strategy to improve the treatments for erbB2+ breast cancer patients. MiRNAs regulate gene expression by the sequence-specific targeting of mRNAs, leading to translational repression or mRNA degradation. ErbB3 is a direct target of both miR-125a and miR-205. Here, we study the potential activity of miRNA based erbB3-targeted therapy in erbB2+ breast cancer cells. Methods: Cell growth assays were used to determine cell viability. Western blot analyses were performed to assess the expression and activation of proteins. Flow cytometry analysis was carried out to examine cell cycle progression. Lentiviral vector containing one or two miRNAs was used to ectopically express miR-125a and/or miR-205. Results: Co-expression of miR-125a and miR-205 showed a potent activity to downregulate erbB3 while single miRNA had no or little effect on erbB3 when miR-125a or miR-205 was only increased below 10-fold in BT474 cells. Combination of the two miRNAs not only resulted in a dramatic reduction of phosphorylated erbB3 (P-erbB3) and the downstream signaling kinases Akt (P-Akt) and Src (P-Scr), it also inhibited cell proliferation and increased the cells at G1 phase. More importantly, concomitant expression of the two miRNAs significantly enhanced trastuzumab-mediated growth inhibition and cell cycle G1 arrest in BT474 cells. Interestingly, the expression levels of miR-125a, but not miR-205 in the trastuzumab-resistant BT474-HR20 cells were much lower than that in the parental BT474 cells. Ectopic expression of miR-125a alone profoundly inhibited proliferation of BT474-HR20 cells. These data suggested that reduced miR-125a might be a novel mechanism leading to trastuzumab resistance; and upregulation of miR-125a could be a useful tool to abrogate the resistance. Conclusions: Co-expression of miR-125a and miR-205 is a new approach to inhibit erbB3. Specific targeting of erbB3 via the functional cooperative miRNAs enhances efficacy of trastuzumab against erbB2+ breast cancer cells. Our data support further exploration of the possible role of miR-125a in the development of trastuzumab resistance. Keywords: ErbB3, ErbB2, miRNA, Trastuzumab, Breast Cancer Citation Format: Hui Lyu, Jingcao Huang, Bolun Wang, Amy Han, Bolin Liu. Targeting of ErbB3 with functional cooperative miRNAs enhances efficacy of trastuzumab in ErbB2-overexpressing breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 477.
Localization and Function of the Medullary Vasomotor Center in Infracollicularly Decerebrated Cats
Authors: Percylindgren
Journal: Circulation Research (1961)

The medullary vasomotor centers were studied in three cats, decerebrated below the mesencephalon four to nine days before the $$$cute experiment. Exploration of the dorsal regions of the medulla oblongata revealed that the vasomotor active regions had about the same extension as in intact animals. Medullary pressor and depressor reflexes, elicited by electrical stimulation of a peripheral nerve and a sinus nerve, were also of a normal type in the decerebrated cats. The results indicate that the medullary vasomotor center constitutes a region of nuclear character with cell bodies and synapses functioning as a tonic and reflex center. In this respect, it seems to function normally even after the degeneration of vasomotor pathways from higher centers.
Prognostic Impact of Vascular Leakage in Acute Kawasaki Disease
Authors: MasaruTerai, TakafumiHonda, KumiYasukawa, KoujiHigashi, HiromichiHamada, YoichiKohno
Journal: Circulation (2003)

Background— Increased microvascular permeability is an initial step of Kawasaki disease (KD). We reported that vascular endothelial growth factor (VEGF) might play a role in the vascular leakage of KD. In fatal KD, plasma leakage was extensively documented at VEGF-positive microvessels. Increases in vascular leakage cause hypoalbuminemia and noncardiogenic edema. However, the prognostic impact of vascular leakage in KD remains unclear. Methods and Results— We compared 76 patients who became afebrile within 5 days after starting intravenous gamma globulin (IVGG) (2 g/kg over 5 days) (IVGG-responsive) with 27 patients who did not respond (IVGG-resistant). Baseline levels of serum VEGF and albumin were similar between the groups. After IVGG, VEGF levels increased (P<0.0001) and albumin levels decreased (P<0.00001) in both groups. However, the IVGG-resistant group had higher VEGF levels (P=0.029) and severe hypoalbuminemia (P<0.00001) compared with the IVGG-responsive group. Coronary aneurysms were documented...
Abstract 13572: The Mammalian Target of Rapamycin Activation is Required for Monocyte Proinflammatory Response in Patients with Coronary Artery Disease
Authors: ShanshanGao, WeiminLiu, XiaozhenZhuo, JunhuiLiu, LijunWang, YueWu, ZuyiYuan
Journal: Circulation (2014)

Introduction and Hypothesis: The regulation of nuclear factor kappa B (NF-kappaB) signaling and systematic proinflammatory response in atherosclerosis (AS) remain poorly defined. Therefore, we investigated the relationship between mammalian target of rapamycin (mTOR) and NF-kappaB signaling under proinflammatory state of circulating mononuclear cell (MNC) in coronary artery disease (CAD) patients. Methods: MNC was isolated from fasting blood samples of CAD patients (n = 31) and control subjects (n = 35). Serum interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) were measured by enzyme-linked immunosorbent assay. NF-kappaB activity, p-mTOR and mTOR expression, and p65 nuclear translocation were analyzed by western blot in the isolated MNC. In vitro, Serum extracted from CAD patients (CAD serum) was used to treat MNC isolated from the control subjects. Pharmacological and genetic inhibitors of mTOR were also applied. Results: The serum IL-6 and TNF-α concentrations, NF-kappaB activity and p65 nuclear tran...
Abstract 415: A single molecule detection system for comprehensive analysis of cancer related cellular pathways
Authors: Manohar R. Furtado, Rixun Fang, Norman Burns, Rebekah Burich, Catherine Le, Soumya Ivaturi, Rob Hartlage, Ed Zizminskas, Jim Jahncke, Philip C. Mack, Bryan P. Staker
Journal: Cancer Research (2018)

Abstract The purpose of this study was to evaluate the system capabilities of a new single-molecule detection platform capable of both genomic and proteomic analysis of cellular pathways using very small amounts of tumor material. The system has 4-color optics, single-fluorophore detection capability, localization of molecules to within a 20nm area, a flow cell with an area of 940 mm2 and the ability to detect &amp;gt; 109 molecules on the surface. NSCLC cell lines were cultured and untreated or treated with the EGFR tyrosine kinase inhibitor erlotinib. Cells were harvested and used to generate protein lysates, isolate mRNA and gDNA. Cellular molecules were covalently attached to an epoxysilane-coated surface on the flow cell and then repeatedly probed 10-15 times with labeled antibodies and oligonucleotides to detect, count and quantitate proteins, protein phosphorylation levels, mRNAs, fusion transcripts, and DNA mutations. We detected protein phosphorylation changes for EGFR, ERK, MET and MEK comparable to that observed by traditional western blots; however, the system required only 0.5 to 2 cell equivalents of protein lysate, containing sub pico-Molar levels of protein. We demonstrated robust and statistically significant detection of 2-fold changes in protein levels across 3 slides, in triplicate lanes and performed over 3 non-consecutive days by 3 operators (Tukey-Kramer tests). We also detected 8 mRNAs, with no PCR amplification required, in a multiplexed format with relative levels similar to that observed with TaqMan® qPCR tests. We demonstrated protein detection at ~ 100% recovery compared to an ELISA test and nucleic acid recovery at ~ 30% with no amplification. We also detected exon 19 deletions in EGFR, point mutations at L858R, T790M in EGFR and V600E in BRAF, at 0.5% minor allele levels, by using an oligonucleotide ligation assay off-chip and then attaching the ligated product to the surface. mRNA levels were detected using 10-20 cell equivalents of RNA. We believe the system will enable comprehensive analysis of cancer-related pathways, requiring only a few cells, to help decipher cellular pathway activity induced by driver mutations and consequently help with selection of efficacious drugs tailored for specific individuals based on comprehensive molecular analysis. Citation Format: Manohar R. Furtado, Rixun Fang, Norman Burns, Rebekah Burich, Catherine Le, Soumya Ivaturi, Rob Hartlage, Ed Zizminskas, Jim Jahncke, Philip C. Mack, Bryan P. Staker. A single molecule detection system for comprehensive analysis of cancer related cellular pathways [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 415.
Abstract 17541: SDPR/Cavin-2 Modulates Apoptosis via PTEN/Akt Signaling Pathway and Deteriorates Cardiac Function in Pressure Overload-Induced Heart Failure
Authors: Yusuke Higuchi, Takehiro Ogata, Naoki Maruyama, Masahiro Nishi, Naohiko Nakanishi, Akira Sakamoto, Hideo Tsubata, Satoaki Matoba
Journal: Circulation (2017)

Introduction: Cavins and caveolins are the principal membrane components of caveolae. Some of cavin family proteins affect cardiac function. Although the structural role of SDPR/Cavin-2 has been we...
Abstract 2995: CDK9 phosphorylates BRG1 chromatin remodeler
Authors: Somnath Pandey, Hanghang Zhang, Carlos A. Barrero, Salim Merali, Xavier Graña, Jean-Pierre Issa
Journal: Cancer Research (2018)

Abstract Cyclin-dependent kinase 9 (CDK9) belongs to the class of CDKs involved in transcription regulation along with CDK7, 8, 10-13. Earlier works have established that CDK9 is the catalytic subunit of P-TEFb, and a transcriptional activator. CDK9 inhibition holds promise for patients belonging to Chronic Lymphocytic Leukemia (CLL) and BRD4-NUT-rearranged NUT midline carcinoma (NMC) groups. It is therefore fundamentally important to understand CDK9 mediated gene regulation. CDK9 in complex with its regulatory subunit, Cyclin T1 or T2, is known to promote RNAPII promoter-proximal pause release by phosphorylating negative elongation factors. Additionally, phosphorylation of the C-terminal domain (CTD) of RNAPII on Serine-2 allows recruitment of RNA processing factors, which work on the nascent RNA as it emerges from RNAPII. It is however not known whether CDK9 has any transcriptional repression activity. Earlier work from our lab demonstrated that long-term CDK9 inhibition leads to the activation of BRG1, an ATP-dependent nucleosome-remodeling complex from the SWI/SNF family of proteins. We therefore hypothesized that CDK9 directly phosphorylates BRG1 and regulates its activity. Using Co-immunoprecipitation (Co-IP) assay we discovered that CDK9 associates with BRG1 endogenously in colon cancer cells. We tested the association of these proteins more rigorously by transiently over-expressing either FLAG-tagged or GFP-tagged CDK9 in HEK293T cells and performed immunoprecipitation using BRG1 antibody. CDK9 was found to co-precipitate with BRG1. We validated this via reciprocal Co-IPs. We performed an in vitro kinase assay using purified CDK9 and BRG1 proteins to demonstrate that CDK9 directly phosphorylates BRG1 and that inhibition of CDK9 leads to reduced phosphorylation of BRG1. We validated these results in vivo in colon cancer cells. Furthermore, our LC-MS/MS data lead to the identification of novel phosphorylation sites in BRG1 following CDK9 inhibition. These findings provide a potential mechanism for the transcriptional repressor activity associated with CDK9 and may be relevant for developing therapies targeting this transcriptional regulator. Citation Format: Somnath Pandey, Hanghang Zhang, Carlos A. Barrero, Salim Merali, Xavier Graña, Jean-Pierre Issa. CDK9 phosphorylates BRG1 chromatin remodeler [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 2995.
Natriuretic Peptide Receptor-C Regulates Coronary Blood Flow and Prevents Myocardial Ischemia/Reperfusion Injury
Authors: AdrianHobbs, PaulFoster, CraigPrescott, RamonaScotland, AmritaAhluwalia
Journal: Circulation (2004)

Background— Ischemia/reperfusion (I/R) injury complicates myocardial infarction and stroke by exacerbating tissue damage and increasing risk of mortality. We have recently identified C-type natriuretic peptide (CNP) as an endothelium-derived hyperpolarizing factor in the mesenteric resistance vasculature and described a novel signaling pathway involving activation of natriuretic peptide receptor C (NPR-C), which plays a pivotal role in the regulation of local blood flow. We tested the hypothesis that CNP/NPR-C signaling is a novel regulatory pathway governing coronary blood flow and protecting against I/R injury. Methods and Results— CNP and (Cys18)-atrial natriuretic factor (4-23) amide (cANF4–23) elicited dose-dependent decreases in coronary perfusion pressure (CPP) that were blocked by Ba2+ and ouabain in the isolated Langendorff rat heart. The endothelium-dependent vasodilator acetylcholine elicited the release of CNP from the coronary endothelium. CNP and cANF4–23 reduced infarct size after 25 minute...