tbuckley/cabot-search huggingface dataset:
Suppression of metastasis through inhibition of chitinase 3-like 1 expression by miR-125a-3p-mediated up-regulation of USF1
Authors: Ki Cheon Kim, Jaesuk Yun, Dong Ju Son, Ji Young Kim, Jae-Kyung Jung, Jeong Soon Choi, Yu Ri Kim, Ju Kyung Song, Sun Young Kim, Sin Kook Kang, Dae Hwan Shin, Yoon-Seok Roh, Sang-Bae Han, Jin Tae Hong
Journal: Theranostics (2018)

Rationale: Chitinase 3-like 1 (Chi3L1) protein is up-regulated in various diseases including solid cancers. According to Genome-Wide Association Study (GWAS)/Online Mendelian Inheritance in Man (OMIM)/Differentially Expressed Gene (DEG) analyses, Chi3L1 is associated with 38 cancers, and more highly associated with cancer compared to other oncogenes such as EGFR, TNFα, etc. However, the mechanisms and pathways by which Chi3L1 is associated with cancer are not clear. In current study, we investigated the role of Chi3L1 in lung metastasis. Methods: We performed the differentially expressed gene analysis to explore the genes which are associated with Chi3L1 using the web-based platform from Biomart. We investigated the metastases in lung tissues of C57BL/6 mice injected with B16F10 melanoma following treatment with Ad-shChi3L1. We also investigated the expression of USF1 and Chi3L1 in Chi3L1 KD mice lung tissues by Western blotting and IHC. We also analyzed lung cancer cells metastases induced by Chi3L1 using migration and cell proliferation assay in human lung cancer cell lines. The involvement of miR-125a-3p in Chi3L1 regulation was determined by miRNA qPCR and luciferase reporter assay. Results: We showed that melanoma metastasis in lung tissues was significantly reduced in Chi3L1 knock-down mice, accompanied by down-regulation of MMP-9, MMP-13, VEGF, and PCNA in Chi3L1 knock-down mice lung tissue, as well as in human lung cancer cell lines. We also found that USF1 was conversely expressed against Chi3L1. USF1 was increased by knock-down of Chi3L1 in mice lung tissues, as well as in human lung cancer cell lines. In addition, knock-down of USF1 increased Chi3L1 levels in addition to augmenting metastasis cell migration and proliferation in mice model, as well as in human cancer cell lines. Moreover, in human lung tumor tissues, the expression of Chi3L1 was increased but USF1 was decreased in a stage-dependent manner. Finally, Chi3L1 expression was strongly regulated by the indirect translational suppressing activity of USF1 through induction of miR-125a-3p, a target of Chi3L1. Conclusion: Metastases in mice lung tissues and human lung cancer cell lines were decreased by KD of Chi3L1. USF1 bound to the Chi3L1 promoter, however, Chi3L1 expression was decreased by USF1, despite USF1 enhancing the transcriptional activity of Chi3L1. We found that USF1 induced miR-125a-3p levels which suppressed Chi3L1 expression. Ultimately, our results suggest that lung metastasis is suppressed by knock-down of Chi3L1 through miR-125a-3p-mediated up-regulation of USF1.
Abstract 462: Hyperactivation of ERK/MAPK pathway reduces pancreatic cancer cells' proliferation and tumor progression through phosphoproteome reprogramming
Authors: Marie-Camille Rowell, Xavier Deschênes-Simard, Benjamin Le Calvé, Stéphane Lopes-Paciência, Ana Fernandez Ruiz, Filippos Kottakis, Nabeel Bardeesy, Gerardo Ferbeyre
Journal: Cancer Research (2018)

Abstract This study aims to better understand the loss of tumor -uppression functions of ERK in pancreatic cancer progression. Pancreatic cancer is the 4th leading cause of death by cancer in Canada and USA with a 5-year survival rate below 7%. We have identified a high level of phosphorylation of the MAP kinase ERK in benign pancreatic intraepithelial neoplasms (PanIN), followed by a reduction in phospho-ERK levels in pancreatic ductal adenocarcinoma (PDAC) both in human patient samples and KRas-driven mouse models for pancreatic cancer. Since PanINs are considered senescent lesions, we hypothesized that phospho-ERK levels were reduced in PDAC to bypass oncogene-induced senescence and allow tumor initiation. We propose that reactivating high ERK in PDAC could restore tumor-suppression mechanisms lost during progression. To do so, we use a tamoxifen-inducible constitutive allele of RAF1 kinase, which acts upstream of ERK (ΔRAF1-ERT). In human (PANC-1, KP-4) and murine PDAC cell lines, activated RAF1 slows cell proliferation and induces cellular senescence in vitro in an ERK-dependent and p53/p16-independent manner. Activation of ERK kinases by this system in subcutaneous PDAC xenografts slows tumor growth in nude mice. To characterize key mediators of ERK-dependent tumor suppression, we did phosphoproteomics by mass spectrometry and identified a reprogramming of nuclear vs. cytoplasmic phosphoproteome, involving key ribosome biogenesis factors. Depletion of these nucleolar targets by shRNAs and nucleolar stress inducers such as RNA polymerase I inhibitor CX-5461 recapitulates ERK-dependent tumor suppression. At the same time, we are also investigating autophagy-related processes involved in RAF/MEK signaling blockade in PDAC cells. In summary, we suggest that high levels of p-ERK1/2 in early PanIN stage act as a tumor-suppressor mechanism, which is lost with cancer progression. Our future work aims to better understand the mechanism by which high ERK signaling exerts tumor suppression in order to find downstream effectors that could be used as therapeutic targets in pancreatic cancer. Citation Format: Marie-Camille Rowell, Xavier Deschênes-Simard, Benjamin Le Calvé, Stéphane Lopes-Paciência, Ana Fernandez Ruiz, Filippos Kottakis, Nabeel Bardeesy, Gerardo Ferbeyre. Hyperactivation of ERK/MAPK pathway reduces pancreatic cancer cells' proliferation and tumor progression through phosphoproteome reprogramming [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 462.
Abstract 1472: The role of the BAF complex in Wnt signaling-mediated transcriptional regulation in colorectal cancer
Authors: Madhobi Sen, Feda H. Hamdan, Xin Wang, Jacobe Rapp, Steven A. Johnsen
Journal: Cancer Research (2018)

Abstract Recent genome- and exome-wide sequencing studies have revealed a close association between the epigenome and the pathogenesis of cancer. Not only were chromatin regulators found to be commonly mutated in a wide range of cancers, but a class of these regulators, the ATP-dependent chromatin remodelers, especially subunits of the mammalian BAF complex, were among the most frequently mutated group of genes across cancer types, mutated in over 20% of cancers. Among these subunits, loss of function mutations in ARID1A (AT-rich interactive domain-containing protein 1A) are most frequent across cancer types including 10% of colorectal cancer (CRC). Very interestingly, a recent publication described the pivotal role of the loss of ARID1A in driving CRC wherein its inactivation alone led to the formation of invasive adenocarcinomas in mice. However, surprisingly, in contrast to the expected tumor suppressive role of ARID1A in CRC, we observe that the knockout (KO) of ARID1A in CRC cell lines leads to impaired proliferation. Moreover, subcutaneous xenografts in SCID/SHO mice using ARID1A KO CRC cells did not form more aggressive tumors than their wild type counterparts. One of the most commonly occurring mutations in CRC is in the APC gene, which leads to hyperactive Wnt signaling. Thus CRC progression is typically highly dependent on this pathway. Notably, it is reported that loss of ARID1A in the context of APC mutations results in diminished tumor formation in mice and increased differentiation. This led us to hypothesize that ARID1A is required for Wnt signaling-mediated transcriptional (de)regulation in CRC. To uncover this further, we utilized several publically available ChIP-seq, RNA-seq and ATAC-seq datasets as well as our own ChIP-seq data for ARID1A in the HCT116 cell line. We observe a substantial co-localization of the BAF complex with TCF7L2, a downstream effector of the Wnt signaling pathway, suggesting cooperation between these factors. Further, these sites are also co-occupied by AP1 transcription factors. A crosstalk between the TCF7L2 and AP1 factors has been reported in intestinal tumors. From data available in the ARID1A KO system, we observe a downregulation of potential target genes which are co-occupied at neighboring sites by these factors. Therefore, we suggest that ARID1A plays an important role in the regulation of colorectal cancer relevant genes that are targets of TCF7L2/AP1, thus facilitating a pathway that is most commonly hijacked in colorectal cancer. Citation Format: Madhobi Sen, Feda H. Hamdan, Xin Wang, Jacobe Rapp, Steven A. Johnsen. The role of the BAF complex in Wnt signaling-mediated transcriptional regulation in colorectal cancer [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 1472.
Adipocyte-Derived Plasma Protein, Adiponectin, Suppresses Lipid Accumulation and Class A Scavenger Receptor Expression in Human Monocyte-Derived Macrophages
Authors: NoriyukiOuchi, ShinjiKihara, YukioArita, MakotoNishida, AkifumiMatsuyama, YoshihisaOkamoto, MasatoIshigami, HiroshiKuriyama, KenKishida, HitoshiNishizawa, KikukoHotta, MasahiroMuraguchi, YasukazuOhmoto, ShizuyaYamashita, TohruFunahashi, YujiMatsuzawa
Journal: Circulation (2001)

Background—Excessive lipid accumulation in macrophages plays an important role in the development of atherosclerosis. Recently, we discovered an adipocyte-specific plasma protein, adiponectin, that is decreased in patients with coronary artery disease. We previously demonstrated that adiponectin acts as a modulator for proinflammatory stimuli and inhibits monocyte adhesion to endothelial cells. The present study investigated the effects of adiponectin on lipid accumulation in human monocyte-derived macrophages. Methods and Results—Human monocytes were differentiated into macrophages by incubation in human type AB serum for 7 days, and the effects of adiponectin were investigated at different time intervals. Treatment with physiological concentrations of adiponectin reduced intracellular cholesteryl ester content, as determined using the enzymatic, fluorometric method. The adiponectin-treated macrophages contained fewer lipid droplets stained by oil red O. Adiponectin suppressed the expression of the class...
Abstract 10879: Efficacy and Safety of Rivaroxaban in Patients With Venous Thromboembolism and Active Malignancy - A Single Center Registry
Authors: RayyaSaadiq, DaleneBott-Kitslaar, CharlesLoprinzi, RobertMcBane, WaldemarWysokinski
Journal: Circulation (2015)

Background: Active malignancy accounts for 20% of venous thromboembolism (VTE) in the community and is the second leading cause of death among cancer patients. Rivaroxaban offers a convenient alternative to conventional anticoagulation for VTE in cancer patients but its efficacy and safety for this group of patients is not well documented. Patients and Methods: All patients with cancer-associated deep vein thrombosis (DVT) or pulmonary embolism (PE), enrolled into Mayo Rochester Thrombophilia Clinic Direct Oral Anticoagulants Registry between November 1, 2012 and April 30, 2015, were followed prospectively to provide an estimate of the efficacy and safety of this form of therapy. Follow up was obtained in person or by mailed or telephone survey. Results: Out of the 377 patients in the registry, 118 (31%) patients (51% female, mean age 66±10 years) had active malignancy related VTE (62% DVT, 24% PE, and 14% DVT/PE) treated with rivaroxaban. The most common malignancies in this group were: gastrointestinal ...
Abstract 17875: Association of Cumulative Social Risk With Mortality and Adverse Cardiovascular Disease Outcomes
Authors: Sebhat Erqou, Justin B Echouffo-Tcheugui, Kevin E Kip, Aryan Aiyer, Steven E Reis
Journal: Circulation (2016)

Background: Quantification of the cumulative effect of social risk factors on cardiovascular disease (CVD) risk can provide insight into the effects of social disadvantage on and contributors to ra...
Abstract 16436: The Relationship Between Radiation Dose Volume and Adverse Cardiovascular Events in Cancer Survivors Who Received Thoracic Radiation
Authors: Carolyn M Reilly, Melinda Higgins, Eduard Schreibmann, Natia Esiashvili
Journal: Circulation (2015)

Objective: The purpose of this retrospective case-controlled study was to examine the contribution of radiation therapy (RT) dose distribution on the development of significant CVD events in cancer patients within the previous 5 years. Methods: Patients receiving initial cancer and subsequent medical care at a large Southeastern medical center were culled from medical records and databases for a sample of 28 with and 28 without secondary CVD development. All demographic and clinical variables including CVD risk and outcome data were gleaned through medical record and billing review. The risk due to RT was isolated from known CVD risk factors present at the initiation of cancer treatment. Secondly, a novel means of applying dose volume histograms (DVHs) to summarize the radiation dose delivered to the heart and each of the three main coronary arteries was calculated by a medical physicist and radiation oncologist. Analysis used paired t-tests and Logistic Regression Modeling. Results: Case to control matching was made based upon age at cancer diagnosis [cases 62.29 +/- 8.9; controls: 61.93 +/- 9.0; (p=.571)]; gender; and cancer type. There were no significant differences between the RT dose statistics or delivery between pairs. A significant difference was observed with more cases having multiple risk factors at the time of cancer diagnosis: Cases had significantly higher BMIs (p=.009), systolic blood pressure (p=.028), glucose levels (p=.022), and calculated Framingham risk (w/BMI), (p=.001). More cases than controls were observed to have a history of CVD (McNemar’s p=.022), and diabetes (McNemar’s p=.003). No significant differences between cases and controls was observed for: ethnicity; marital status; comorbidities; smoking history; hyperlipidemia; alcohol abuse; chemotherapy type; nor use of hormone therapy. Conclusion: The cases all had significantly greater typical CVD risk factors upon cancer diagnoses and did not receive any greater or differing amounts of thoracic radiation. A logistic regression model revealed subjects with high systolic BP, CVD history and diabetes had much higher odds of being a CVD case. After accounting for these variables, no other radiation parameters (dose, DVH, nor shape) entered the model.
Abstract 2745: EpCAM targeted immunotoxin prolongs survival of metastatic colorectal cancer patients by a previously unknown immunostimulatory mechanism
Authors: Øystein Fodstad, Svein Dueland, Kjersti Flatmark, Else Marit Inderberg, Gunnar Kvalheim, Yvonne Andersson
Journal: Cancer Research (2018)

Abstract A first-in-man study of the anti-EpCAM immunotoxin MOC31PE with and without parallel immunosuppression with Cyclosporin A (CsA) was performed in metastatic colorectal cancer (CRC) patients. The safety and maximum tolerable doses in patients with EpCAM-positive tumors were determined, and only mild and reversible dose-limiting liver toxicity was seen, with no subjective side effects to the patients. Although no complete or partial responses were observed on CT scans at eight weeks, upon evaluation of the overall survival (OS) of the patients we surprisingly found that CRC patients treated with immunotoxin alone (n=15) had a median OS of 16.3 months (95% CI=5.6-27.0) compared to 6.0 months (CI=5.8-6.2) (p&amp;lt;0.001) for the combination group (n=18) (hazard ratio (HR): 0.248, 95% credible interval (CrI): 0.109-0.564). The 6.0 months OS for the patients treated with CsA in addition to the immunotoxin is comparable to OS of patients with progressive disease on last line of standard chemotherapy. The Th1 cytokine profile in sera from patients treated with MOC31PE alone indicated that the immuntoxin induces an immunogenic cell death resulting in T-cell activation, and that this effect disappeared in the patients who had received simultaneous treatment with CsA. Further, we demonstrate in in vitro experiments that the immunogenic cell death factors ATP and HMGB1 were secreted from CRC cell lines treated with MOC31PE alone. Finally, conditioned media from MOC31PE treated CRC cells induced maturation of dendritic cells and promoted activation of killer (CD8+) and helper (CD4+) T cells, showing that MOC31PE treatment induces release of immune stimulating factors. The present results demonstrate the novel and exciting finding that MOC31PE induces an immunogenic effect resulting in prolonged overall survival of patients with metastatic CRC, an effect obliterated by the parallel immunosuppression of CsA. Citation Format: Øystein Fodstad, Svein Dueland, Kjersti Flatmark, Else Marit Inderberg, Gunnar Kvalheim, Yvonne Andersson. EpCAM targeted immunotoxin prolongs survival of metastatic colorectal cancer patients by a previously unknown immunostimulatory mechanism [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 2745.
Abstract 68: Caveolae-specific Phosphorylation of L-type Calcium Channel β2a Subunit exaggerates Cardiac Hypertrophic Responses after α1 Adrenergic Stimulation in Mice
Authors: HiroyukiNakayama, ShoheiKumagai, SachiMatsunami, NaoHayamizu, KotaTonegawa, WataruOtsuka, YasushiFujio
Journal: Circulation Research (2014)

Rationale: Ca2+ influx via L-type Ca2+ channels (LTCCs) plays a pivotal role in excitation-contraction coupling and cardiac hypertrophy. Phosphorylation of LTCC β2a subunit (β2a) by CaMKII enhances channel activity. LTCCs are localized in both T-tubules and caveolae, but the functional role of phosphorylation of β2a in caveolae remains unelucidated. Objective: To develop a novel tool to analyze caveolae specific activation of CaMKII and to determine the functional roles of caveolae-specific CaMKII signaling in LTCC-related cardiac hypertrophy. Methods and Results: To evaluate caveolae-specific activation of CaMKII, we generated a fusion protein composed of the cytosolic domain of phospholamban (PLN) as a phosphopeptide tag and caveolin3 (cPLN-Cav3). Activation of CaMKII was assessed by phospho-specific antibody for PLN (Thr17). To inhibit caveolae-specific activation, we generated a GFP fusion protein with caveolae-targeting sequences fused to CaMKII inhibitory peptide (CTS-GFP-AIP). In neonatal rat cardi...
Re: Response Assessment of 223Ra Treatment: Should a Fluorocholine PET/CT Be Performed?
Authors: Laura Evangelista, Alessandra Zorz
Journal: Clinical Nuclear Medicine (2018)

*Nuclear Medicine and Molecular Imaging Unit Veneto Institute of Oncology IOV–IRCCS Padua, Italy [email protected] †Medical Physic Unit Veneto Institute of Oncology IOV–IRCCS Padua, Italy Conflicts of interest and sources of funding: none declared.
Abstract 475: Characterization of miR-21 expression in budding colon cancer cells using digital images of multiplex fluorescence stained slides obtained by confocal scanning microscopy
Authors: Boye Schnack Nielsen, Kirsten Nguyen Knudsen, Jan Lindebjerg, Alexandra Kalmár, Béla Molnár, Flemming Sorensen, Torben Hansen
Journal: Cancer Research (2018)

Abstract This study was undertaken to analyze the presence and prevalence of microRNA-21 (miR-21) positive budding cancer cells in colon cancer using confocal scanning microscopy. Budding cancer cells are locally invasive cancer cells with increased metastatic properties and characteristics of epithelial to mesenchymal transition (EMT). Expression of miR-21 in stromal fibroblastic cells in colorectal cancers is well documented (1,2), whereas miR-21 expression in budding cells is poorly described. In order to characterize miR-21 positive budding cells, we first developed a multiplex fluorescence staining method by combining miR-21 in situ hybridization with immunohistochemical staining for cytokeratin and budding cell marker laminin-γ2, and stained 16 colon cancer cases (stage II, n=5, stage III, n=11). We then employed a confocal scanning microscope to obtain 15-55 GB digital images covering areas of 10-40 mm2 of the invasive front. The high resolution of the confocal digital images allowed detailed examination of the 4-fluorophore-stained slides using extended focus and z-stack images, e.g. in the discrimination of epithelial cells from adjacent stromal cells. All cytokeratin-positive budding cells were evaluated for the presence of miR-21 and laminin-γ2. Five out of the 16 cases had more than 10% miR-21 positive budding cells, a few of which were also laminin-γ2 positive. All five cases were stage III cancers. The presence of miR-21 in the budding cancer cells was not associated with the level of tumor budding. These observations suggest that the miR-21 expression in tumor budding cells increases with the progression of the cancer and is independent of laminin-γ2. References: 1. Nielsen BS et al, Clin Exp Mets 2011, 28:27-38. 2. Kjaer-Frifeldt S et al, Br J Cancer 2012, 107:1169-1174. Citation Format: Boye Schnack Nielsen, Kirsten Nguyen Knudsen, Jan Lindebjerg, Alexandra Kalmár, Béla Molnár, Flemming Sorensen, Torben Hansen. Characterization of miR-21 expression in budding colon cancer cells using digital images of multiplex fluorescence stained slides obtained by confocal scanning microscopy [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 475.
T Cell Tumor Immunotherapy: Oncolysis Beats Lymphodepletion
Authors: John Barrett
Journal: Molecular Therapy (2018)

Much progress has been made in the immunotherapy of melanoma with the isolation and expansion of tumor-specific cytotoxic T cells (TSTs). To enhance tumor killing, investigators have used intensive chemotherapy and radiotherapy to deplete the lymphocyte compartment prior to infusion of TSTs. In clinical trials, some spectacular tumor responses have been achieved, but at the expense of toxicity from the lymphodepleting regimen. In this issue of Molecular Therapy, Santos and colleagues1 describe a strategy to enhance the therapeutic efficacy of TSTs that achieves tumor lysis without the need for toxic lymphodepletion.
Surgery trainees start enhanced training as part of pilot scheme
Authors: Abi Rimmer
Journal: BMJ (2018)

Trainee surgeons at 30 trusts and health boards in England, Scotland, and Wales have joined a pilot scheme designed to improve their training.

The scheme, developed by the Royal College of Surgeons and Health Education England, includes 48 general surgery trainees in England and 31 core surgical trainees in Scotland, who take up their posts on 1 August.

The Improving Surgical Training pilot aims to improve the …