tbuckley/cabot-search huggingface dataset:
Abstract 4478: The tumor suppressive function of HPP1 is mediated by its EGF-like domain
Authors: Abul Elahi, Abidemi Ajidahun, Leah Hendrick, S. Mazher Husain, Irina Getun, Andreas Becker, Evan S. Glazer, David Shibata
Journal: Cancer Research (2018)

Abstract Introduction: HPP1 is a putative tumor suppressor gene that has had significant interest as a potential serum- and stool-based biomarker in colorectal cancer. It is an Epidermal Growth Factor (EGF)-like ligand that we have previously demonstrated to mediate its effects via an erbB4-JAK-STAT signaling cascade. HPP1 is a secreted transmembrane protein comprised of two follistatin modules, a cytosolic tail with a potential G - protein-activating motif and an EGF-like domain which differs from EGF by replacement of arginine (R) by a histidine (H) residue at the critical 299 position. The exact component of HPP1 responsible for its biologic function has yet to be elucidated. We sought to examine the specific role of the EGF-like domain and the contribution of the H299R alteration. Methods: Synthetic wild-type (WT; H299) and mutant (R299) peptides were prepared at our crystallographic core facility. The change in amino acid did not alter the predicted 3D structure of the peptide. A total of 50ng/ml of each peptide per well (6-well plate) were used to treat the HPP1 non-expressing HCT116 colon cancer cell line. Cells were starved for 24 hours with a peptide exposure time of 7 minutes. Using immunoblot analyses, we examined alterations in the expression and activation status of erbB4, and STAT family proteins. Results: Delivery of the WT peptide into the HCT116 cell line resulted in increased activation/phosphorylation of erbB4, STAT1 and STAT2 with a concomitant downregulation of STAT3 activation as compared to controls. These findings are identical to the signaling profile that we have previously described for full length HPP1 and required for its tumor suppressive activity. The mutant peptide did not result in any change in the phosphorylation status of erbB4, STAT1 or STAT2 but was associated with an increase in STAT3 activation as compared to controls. Conclusion: The EGF-like domain of HPP1 is the key moiety responsible for triggering its tumor suppressive erbB -STAT signaling cascade. Furthermore, the histidine residue at position 299 is critical and differentiates it from the oncogenic function of EGF. Our findings may have implications for the further understanding of EGF-related signaling in cancer progression. Citation Format: Abul Elahi, Abidemi Ajidahun, Leah Hendrick, S. Mazher Husain, Irina Getun, Andreas Becker, Evan S. Glazer, David Shibata. The tumor suppressive function of HPP1 is mediated by its EGF-like domain [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 4478.
Abstract 2373: ADA-07 suppresses solar ultraviolet-induced skin carcinogenesis by directly inhibiting TOPK
Authors: Tianshun Zhang, Qiushi Wang, Ge Gao, Bode Ann, Zigang Dong
Journal: Cancer Research (2018)

Abstract Cumulative exposure to solar ultraviolet (SUV) irradiation is regarded as the major etiologic factor in the development of skin cancer. The activation of the mitogen-activated protein kinase (MAPK) cascades occurs rapidly and is vital in the regulation of SUV-induced cellular responses. The T-LAK cell-originated protein kinase (TOPK), an upstream activator of MAPKs, is heavily involved in inflammation, DNA damage, and tumor development. However, the chemopreventive and therapeutic effects of specific TOPK inhibitors in SUV-induced skin cancer have not yet been elucidated. In the current study, ADA-07, a novel TOPK inhibitor, was synthesized and characterized. Pull-down assay results, ATP competition and in vitro kinase assay data revealed that ADA-07 interacted with TOPK at the ATP-binding pocket and inhibited its kinase activity. Western blot analysis showed that ADA-07 suppressed SUV-induced phosphorylation of ERK1/2, p38, and JNKs, and subsequently inhibited AP-1 activity. Importantly, topical treatment with ADA-07 dramatically attenuated tumor incidence, multiplicity, and volume in SKH-1 hairless mice exposed to chronic SUV. Our findings suggest that ADA-07 is a promising chemopreventive or potential therapeutic agent against SUV-induced skin carcinogenesis that acts by specifically targeting TOPK. Citation Format: Tianshun Zhang, Qiushi Wang, Ge Gao, Bode Ann, Zigang Dong. ADA-07 suppresses solar ultraviolet-induced skin carcinogenesis by directly inhibiting TOPK [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 2373.
Abstract 5113: Spontaneous tumors in aging colonies of C57BL/6J mice
Authors: Andrew Schile, Stephanie Dion, Denise Imai-Leonard, Rosalinda Doty
Journal: Cancer Research (2018)

Abstract The C57BL/6J inbred mouse strain is widely used to study the effects of aging. We have documented 51 spontaneous tumors (39 malignant and 12 benign) as part of a recent effort to establish large colonies of male and female C57BL/6J mice for aging research. Forty six of the tumors were diagnosed in mice submitted for histopathology from typical aging colonies maintained throughout a range of ages (6-18 months) that roughly correspond to 30 - 56 years of age in humans; the remaining cases were from much smaller cohorts aged past 18 months. Sarcomas represented the largest category of malignant tumors (20/51). There were 6 cases (5 male, 1 female) of hemangiosarcoma (4 on the neck, 1 on the liver, and 1 on the ear) and 6 multicentric histocytic sarcomas (4 male, 2 female). Four cases (1 male, 3 female) of rhabdomyosarcoma (2 on the head, 2 on the leg) were also seen. The remaining sarcoma diagnoses included one osteosarcoma (female; leg), one chondrosarcoma (male; ear), and two sarcomas not otherwise specified (both female; one leg, one lateral abdomen). Hematological malignancies constituted the second largest category (9/51), including 7 multicentric lymphomas (3 male, 4 female), a uterine lymphoma, and a multicentric plasma cell tumor (1 male). The four skin malignancies included two melanomas (male: head; female: tail/anus) and two squamous cell carcinomas (male: jaw; female: leg). Three mammary cancers were observed in females, including an adenoacanthoma and two adenocarcinomas, one of which had lung metastases. An ovarian dysgerminoma was the only germ cell tumor documented. The Harderian gland (a lacrimal duct of the eye) was the site of two carcinomas (male) and six adenomas (5 male, 1 female). Other benign tumors included a tail fibroma (male), two pulmonary adenomas (1 male, 1 female), one mammary fibroadenoma (female), a myoepithelioma of the leg (female), and a keratoacanthoma of the paw (female). Tumor incidence was very low overall, representing &amp;lt;0.1% of the mice present on an average week during the typical range of ages (6-18 months) in the aging colonies. Overall, the median age of diagnosis was 239 days for females and 427 days for males. These results should help to define the spectrum of tumors that develop in colonies of C57BL/6J mice that approximately correspond in age to middle-aged humans. Citation Format: Andrew Schile, Stephanie Dion, Denise Imai-Leonard, Rosalinda Doty. Spontaneous tumors in aging colonies of C57BL/6J mice [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 5113.
Abstract 1419: Dissection of single-cell transcriptional and translational regulation by digital mRNA and protein quantification
Authors: Gretchen Lam, Eleen Shum, Christina Chang, Hemi Shah, Devon Jensen, James Ghadiali, Jody Martin, David Rosenfeld, Christina H. Fan
Journal: Cancer Research (2018)

Abstract The immune system consists of complex gene regulatory networks that allow a rapid transition of different cellular states during an immune response. Cell-surface marker analysis using flow cytometry or single cell RNA-seq has allowed characterization of immune subpopulations and a greater understanding of the complexity of immune cells. However, restrictions on protein-only or RNA-only analysis can greatly limit the understanding of how genes are regulated in cells. For example, many cell surface markers - such as CD4 in T cells - has thousands of protein copies per cell using antigen density calculations, yet is fueled by a small number of mRNA transcripts per CD4+ T cell. Moreover, conventional whole-transcriptome analysis of mRNA can further mute the expression detection of CD4 mRNA in T cells due to the abundance of housekeeping ribosomal genes. To bridge the understanding of protein and mRNA expression differences, we used Ab-Seq on BD RhapsodyTM platform to provide digital quantification of both protein and mRNA expression level in single cells. An oligo-conjugated antibody panel against immune-relevant cell-surface markers was created and used for this multi-omic gene expression profiling effort. This approach is coupled with mRNA analysis using the BD Rhapsody Immune Response Panel, a targeted method of RNA-seq that allows a higher sensitivity of immune markers than conventional whole transcriptome assays. We studied the dynamics of early T cell activation in vitro to understand this response on transcriptional, post-transcriptional, and translational levels. Different time points following anti-CD3 and anti-CD28 treatment were collected and multiplexed on to BD Rhapsody cartridge for single cell capture and analysis. Using Ab-Seq on BD Rhapsody, we were able to detect the difference in mRNA and protein levels of crucial markers, allowing us to dissect the intricate gene regulatory pathways during an immune response in a single cell level. Citation Format: Gretchen Lam, Eleen Shum, Christina Chang, Hemi Shah, Devon Jensen, James Ghadiali, Jody Martin, David Rosenfeld, Christina H. Fan. Dissection of single-cell transcriptional and translational regulation by digital mRNA and protein quantification [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 1419.
Aldosterone-Induced Coronary Dysfunction in Transgenic Mice Involves the Calcium-Activated Potassium (BKCa) Channels of Vascular Smooth Muscle Cells
Authors: Marie-LoryAmbroisine, JulieFavre, PatriciaOliviero, CamilleRodriguez, JiGao, ChristianThuillez, Jane-LiseSamuel, VincentRichard, ClaudeDelcayre
Journal: Circulation (2007)

Background— Cardiomyocyte-specific overexpression of aldosterone synthase in male (MAS) mice induces a nitric oxide–independent coronary dysfunction. Because calcium-activated potassium (BKCa) channels are essential for vascular smooth muscle cell (VSMC) relaxation, we hypothesized that aldosterone alters their expression and/or function in VSMCs. Methods and Results— Left coronary artery segments were isolated from MAS or male wild-type mice and mounted in a wire myograph. Responses to acetylcholine were assessed (in the presence of a nitric oxide synthase inhibitor) without or with the cyclooxygenase inhibitor diclofenac, the KCa inhibitors charybdotoxin plus apamin, or the BKCa inhibitor iberiotoxin. Expression of BKCa was quantified in hearts by real-time quantitative polymerase chain reaction and Western blot and in isolated coronary arteries by polymerase chain reaction. The effect of aldosterone on BKCa expression also was studied in cultured rat aortic VSMCs. Acetylcholine-mediated coronary relaxa...
Abstract 20053: Ps100 Helps Predict Neurological Statue for Ecpr Patient ?
Authors: Alice Hutin, Boualem Hammadi, Romain Jouffroy, Christelle Dagron, Kim An, Jean-Louis Beaudeux, Pierre Carli, Lionel Lamhaut
Journal: Circulation (2016)

Introduction: Prognostication for cardiac arrest requires time.Neuroproteins can help prognosticate neurological outcome. Early prognostication for patients treated by ECPR could help identify those with poor neurological prognosis in order to consider termination of care or organ donation. Hypothesis: Our objective was to investigate the prognostic value of S-100 protein in patients treated by ECPR for refractory cardiac arrest (RCA). Methods: We conducted a retrospective single center observational study during 17 months. We included patients presenting a RCA treated by ECPR. All patients admitted had daily blood samples (day 1 to day 4) in order to evaluate S100 protein. Patients were separated into 2 groups according to their neurological outcome at ICU discharge: favorable outcome (CPC 1-2) and unfavorable outcome (CPC 3-5). We compared mean daily S-100 protein concentrations for these 2 groups using a Student T test. Results: During the study period, 37 patients were included; 13 were discharged wit...
Abstract 5591: Analytical and clinical validation of blood-based NGS panel for detection of genomic alterations in DNA repair pathways
Authors: Zhixin Zhao
Journal: Cancer Research (2018)

Abstract Circulating cell-free DNA (cfDNA) and cell-free RNA (cfRNA) in cancer patients are valuable resource of biomarkers for early detection, diagnosis, treatment and monitoring of disease progression. Compared to cfDNA, cfRNA is more labile to degrade and fluctuate, and thus more challenging to be detected in blood. In the present study, we reported PrediSeq, a validated NGS-based liquid biopsy assay to detect fusions, splicing and mutation events using cfRNA. By using Predicine proprietary ultra-sensitive DeepSeaTM (Deterministic, Efficient, Precise, Sensitive Algorithm) variant detection algorithm, pre-analytical study demonstrated RNA-based detection of fusion, RNA splicing, and mutations using reference materials. In a LOD study, PrediSeq NGS assay is more sensitive than the digital PCR based assay in terms of mutation detection. In clinical validation study, tissue and plasma samples from various types of cancer patients (lung, breast, prostate etc) were used, where concordant fusion events with tissue were observed and RNA mutations confirmed variants detected at DNA level. In conclusion, a highly sensitive and accurate RNA-based liquid biopsy test has been developed to complement the use of cfDNA for detection of fusion, splicing and mutations. Citation Format: Zhixin Zhao. Analytical and clinical validation of blood-based NGS panel for detection of genomic alterations in DNA repair 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 5591.
Abstract 13: Anti-angiogenic action of leukotriene-C4induced 15-hydroxyprostaglandin dehydrogenase in colon cancer cells is a TNF-α dependent phenomenon
Authors: Shakti R. Satapathy, Anita Sjölander
Journal: Cancer Research (2018)

Abstract Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths worldwide. Cyclooxygenase-2 (COX-2), which plays a key role in the biosynthesis of prostaglandin E2 (PGE2), is often up-regulated in CRC and in other types of cancer. PGE2 induces angiogenesis and tumor cell survival, proliferation and migration. The tumor suppressor 15-hydroxyprostaglandin dehydrogenase (15-PGDH) is a key enzyme in PGE2 catabolism, converting it into its inactive metabolite 15-keto-PGE2 and is often down-regulated in cancer. Interesting enough, CRC patients expressing high levels of Cysteinyl leukotriene receptor 2 (CysLTR2) have a good prognosis and therefore, we investigated a potential link between CysLTR2-signaling and the tumor suppressor 15-PGDH in colon cancer cells. TNF-α is considered as the main regulators of COX-2 and mPGES-1 that contribute to the increased synthesis of PGE2, which is inhibited by overexpressed 15-PGDH. Level of the pro-tumorigenic PGE2 are increased in CRC, previously attributed to increased production via TNF-α mediated COX-2 up-regulation but more recently attributed to decreased catabolism due to down-regulation of 15-PGDH. Elevation of 15-PGDH expression by leukotriene C4 (LTC4), a CysLTR2 ligand, exhibited anti-tumor activity in colon cancer cells with significant phosphorylation of β-catenin and down-regulation of anti-apoptotic marker Bcl-2 with concurrent activation of CASPASE-3 expression. We also observed a dramatic down-regulation of TNF-α on mRNA level and NF-κβ on both mRNA as well as protein level with LTC4 induced 15-PGDH in a TNF-α dependent manner. Moreover, TNF-α regulated anti-angiogenic action of 15-PGDH in HT-29 and Caco-2 colon cancer cells by depleting the mRNA level of MMP-2 and MMP-9 and protein level of VEGFR-1. Furthermore, our preliminary observation also suggested disrupted tube formation in HUVEC with LTC4 induced 15-PGDH which is mediated by TNF-α. Hence, restoration of 15-PGDH expression through CysLTR2-signaling promotes the anti-angiogenic action against colon cancer cells, indicating an anti-tumor as well as the anti-metastatic efficacy of CysLTR2-signaling. Citation Format: Shakti R. Satapathy, Anita Sjölander. Anti-angiogenic action of leukotriene-C4induced 15-hydroxyprostaglandin dehydrogenase in colon cancer cells is a TNF-α dependent phenomenon [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 13.
Gene Expression in Fibroblasts and Fibrosis
Authors: IchiroManabe, TakayukiShindo, RyozoNagai
Journal: Circulation Research (2002)

Structural remodeling of the ventricular wall is a key determinant of clinical outcome in heart disease. Such remodeling involves the production and destruction of extracellular matrix proteins, cell proliferation and migration, and apoptotic and necrotic cell death. Cardiac fibroblasts are crucially involved in these processes, producing growth factors and cytokines that act as autocrine and paracrine factors, as well as extracellular matrix proteins and proteinases. Recent studies have shown that the interactions between cardiac fibroblasts and cardiomyocytes are essential for the progression of cardiac remodeling. This review addresses the functional role played by cardiac fibroblasts and the molecular mechanisms that govern their activity during cardiac hypertrophy and remodeling. A particular focus is the recent progress toward our understanding of the transcriptional regulatory mechanisms involved.
Mitogen-Activated Protein Kinases in Heart Development and Diseases
Authors: YibinWang
Journal: Circulation (2007)

Mitogen-activated protein (MAP) kinases belong to a highly conserved family of Ser-Thr protein kinases in the human kinome and have diverse roles in broad physiological functions. The 4 best-characterized MAP kinase pathways, ERK1/2, JNK, p38, and ERK5, have been implicated in different aspects of cardiac regulation, from development to pathological remodeling. Recent advancements in the development of kinase-specific inhibitors and genetically engineered animal models have revealed significant new insights about MAP kinase pathways in the heart. However, this explosive body of new information also has yielded many controversies about the functional role of specific MAP kinases as either detrimental promoters or critical protectors of the heart during cardiac pathological processes. These uncertainties have raised questions on whether/how MAP kinases can be targeted to develop effective therapies against heart diseases. In this review, recent studies examining the role of MAP kinase subfamilies in cardiac...
Role of the RANK/RANKL Pathway in Multiple Myeloma
Authors: Noopur S. Raje, Sumita Bhatta, Evangelos Terpos
Journal: Clinical Cancer Research (2018)

Receptor activator of nuclear factor-kappa B (RANK) and its ligand, RANKL, are expressed in a variety of tissues throughout the body; their primary role is in the regulation of bone remodeling and development of the immune system. Consistent with these functions, evidence exists for a role of RANK/RANKL in all stages of tumorigenesis, from cell proliferation and carcinogenesis to epithelial-mesenchymal transition to neoangiogenesis and intravasation to metastasis to bone resorption and tumor growth in bone. Results from current studies also point to a role of RANK/RANKL signaling in patients with multiple myeloma, who have increased serum levels of soluble RANKL and an imbalance in RANKL and osteoprotegerin. Current therapies for patients with multiple myeloma demonstrate that RANKL may be released by tumor cells or osteoprogenitor cells. This article will review currently available evidence supporting a role for RANK/RANKL signaling in tumorigenesis, with a focus on patients with multiple myeloma.
Abstract 14465: Obesity Paradox on Outcome in Atrial Fibrillation Maintained Even Considering the Prognostic Influence of Biomarkers: Insights From the ARISTOTLE Trial
Authors: Roopinder K Sandhu, Justin Ezekowitz, Ziad Hijazi, Johan Westerbergh, John H Alexander, Christopher B Granger, Sigrun Halvorsen, Michael S Hanna, Renato D Lopes, Lars Wallentin
Journal: Circulation (2017)

Background: Studies have shown that obese patients with atrial fibrillation (AF) have a favorable prognosis compared to those with a lower body mass index (BMI); however, the underlying cause for t...