tbuckley/cabot-search huggingface dataset:
Selective gene dependencies in MYCN-amplified neuroblastoma include the core transcriptional regulatory circuitry
Authors: Adam D. Durbin, Mark W. Zimmerman, Neekesh V. Dharia, Brian J. Abraham, Amanda Balboni Iniguez, Nina Weichert-Leahey, Shuning He, John M. Krill-Burger, David E. Root, Francisca Vazquez, Aviad Tsherniak, William C. Hahn, Todd R. Golub, Richard A. Young, A. Thomas Look, Kimberly Stegmaier
Journal: Nature Genetics (2018)
Use of First- and Second-Generation Cyclooxygenase-2–Selective Nonsteroidal Antiinflammatory Drugs and Risk of Acute Myocardial Infarction
Authors: FrankAndersohn, SamySuissa, EdeltrautGarbe
Journal: Circulation (2006)

Background— The cardiovascular safety of cyclooxygenase (COX)-2–selective nonsteroidal antiinflammatory drugs (NSAIDs) has come under scrutiny after the withdrawal of rofecoxib and halting of the Adenoma Prevention with Celecoxib trial. Whether the newer second-generation COX-2 inhibitors (etoricoxib, valdecoxib) also increase the cardiovascular risk is unknown. Methods and Results— We performed a nested case-control study in a cohort of 486 378 persons registered within the United Kingdom General Practice Research Database with at least 1 prescription of an NSAID between June 1, 2000, and October 31, 2004. A total of 3643 cases with acute myocardial infarction (AMI) were matched to 13 918 controls on age, sex, year of cohort entry, and general practice. Rate ratios (RRs) of AMI associated with use of COX-2–selective and –nonselective NSAIDs were calculated. Current use of etoricoxib was associated with a 2.09-fold (95% confidence interval [CI], 1.10 to 3.97) risk of AMI compared with no use of NSAIDs dur...
Abstract 3673: Targeting the epigenome of small cell hypercalcemic carcinoma of the ovary, hypercalcemic type (SCCOHT)
Authors: Yemin Wang, Shary Yu-ting Chen, Shane Colborne, Krystal Orlando, Jessica Lang, Anthony Karnezis, William Hendricks, Gregg Morin, Bernard Weissman, Jeffrey Trent, David Huntsman
Journal: Cancer Research (2018)

Abstract Small cell carcinoma of the ovary hypercalcemic type (SCCOHT) is a rare and poorly differentiated cancer that impacts young women with an average 2-year survival of less than 35%. We and others have discovered the inactivating mutations of SMARCA4 as the only consistent genetic alternation in SCCOHT genomes. SMARCA4 is the ATPase of the SWI/SNF chromatin-remodeling complex, which modulates chromatin accessibility to regulate transcription and plays critical roles in many biologic processes such as cell cycle control, apoptosis, and differentiation. SCCOHT also lacks the expression of SMARCA2, the alternative ATPase in the complex, contrasting the requirement of SMARCA2 for survival of most SMARCA4-deficient cancer cells. This suggest that the complete loss of chromatin-remodeling activity may rewire the epigenome and create opportunities for synthetic lethal targeting. A rational epigenetic drug screen identified EZH2 inhibitors and HDAC inhibitors as promising therapeutic agents in SCCOHT cells. We confirm that catalytic inhibition of EZH2 selectively suppressed the growth of SCCOHT cells in vitro and in xenograft models through activation of apoptosis and differentiation. Pan-HDAC inhibitors also displayed a more robust anticancer effect in SCCOHT cells than other in other ovarian cancer cell lines. Furthermore, combined treatment of EZH2 inhibitors and pan-HDAC inhibitors increased the global acetylation level at histone H3K27 site and synergistically suppressed the growth of SCCOHT cell lines and xenografts through robust induction of apoptosis. Although EZH2 or HDAC inhibitor treatment led to re-expression of SMARCA2, depletion of SMARCA2 had only minimal effect on drug response. Proteomic analysis identified key signaling pathways underlying the efficacy of epigenetic therapy that are under investigation. Therefore, inactivation of SWI/SNF chromatin remodeling complex may drive SCCOHT development through PRC2-dependent rewiring of the epigenome. Targeting these oncogenic events can be the feasible strategies for treatment of SCCOHT that warrant clinical investigation. Citation Format: Yemin Wang, Shary Yu-ting Chen, Shane Colborne, Krystal Orlando, Jessica Lang, Anthony Karnezis, William Hendricks, Gregg Morin, Bernard Weissman, Jeffrey Trent, David Huntsman. Targeting the epigenome of small cell hypercalcemic carcinoma of the ovary, hypercalcemic type (SCCOHT) [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 3673.
Abstract 18048: Dysregulated Microrna-30c and -376c Promotes Functional Disability of Diabetic Cardiac Stem Cells
Authors: Rajesh Katare, Nima Purvis, Sweta Kumari
Journal: Circulation (2016)

Background: Diabetes mellitus leads to a progressive loss in the number and functional efficacy of cardiac stem cells (CSCs) and transplanted CSCs from diabetic heart failed to improve the recovery of damaged heart tissue. However, the underlying mechanism for this functional deficit remains unknown. Our recent study showed marked deregulation of microRNAs (miRs) in diabetic heart. Objective: To investigate if deregulated miRs are the underlying molecular mechanism responsible for functional deterioration of diabetic CSCs. Methods and Results: CSCs were isolated from type-2 diabetic and age-matched non-diabetic mice hearts (n=9 each) using collagenase digestion, followed by purification of the cells using stem cell specific antigen-1 (Sca-1) magnetic labelling. Following one week of culture, total RNA was extracted and miR expression profiles were analysed using an nCounter miR expression assay (Nanostring Technologies). Among 601 miRs evaluated, 14 miRs were significantly altered (12 up-regulated and 2 d...
Isoproterenol Activates Extracellular Signal–Regulated Protein Kinases in Cardiomyocytes Through Calcineurin
Authors: YunzengZou, AtsushiYao, WeidongZhu, SumiyoKudoh, YukioHiroi, MasakiShimoyama, HirokiUozumi, OsamiKohmoto, ToshiyukiTakahashi, FutoshiShibasaki, RyozoNagai, YoshioYazaki, IsseiKomuro
Journal: Circulation (2001)

Background—Extracellular signal–regulated kinases (ERKs) and calcineurin have been reported to play important roles in the development of cardiac hypertrophy. We examined here the relation between calcineurin and ERKs in cardiomyocytes. Methods and Results—Isoproterenol activated ERKs in cultured cardiomyocytes of neonatal rats, and the activation was abolished by chelation of extracellular Ca2+ with EGTA, blockade of L-type Ca2+ channels with nifedipine, or depletion of intracellular Ca2+ stores with thapsigargin. Isoproterenol-induced activation of ERKs was also significantly suppressed by calcineurin inhibitors in cultured cardiomyocytes as well as in the hearts of mice. Isoproterenol failed to activate ERKs in either the cultured cardiomyocytes or the hearts of mice that overexpress the dominant negative mutant of calcineurin. Isoproterenol elevated intracellular Ca2+ levels at both systolic and diastolic phases and dose-dependently activated calcineurin. Inhibition of calcineurin also attenuated isop...
Abstract 5561: High-affinity antisense oligonucleotides targeting Foxp3 inhibit immunosuppressive function of regulatory T-cells and produce antitumor effects in syngeneic tumor models
Authors: Charles Sinclair, Alexey S. Revenko, Alison Peter, Robert B. Johnson, Lisa A. Hettrick, Molly Taylor, Anna Staniszewska, Adina Hughes, Lisa Sandin, Stephanie Klein, Andrew Watt, Simon Barry, Brett T. Monia, Paul Lyne, A Robert Macleod, Mark Edbrooke
Journal: Cancer Research (2018)

Abstract Regulatory T-cells (Treg) contribute to cancer progression by suppressing anti-tumor immuity. Tregs specifically require expression of the lineage defining transcription factor Foxp3 for their development and function, but this protein cannot be targeted with conventional small molecule or biologic drugs. We employed next-generation antisense inhibitors (Gen 2.5 cEt-modified ASOs) in an attempt to selectively inhibit Foxp3 expression in mouse Treg cells, and evaluated consequences of ASO-mediated Foxp3 knock-down in vitro and in vivo. Mouse Foxp3-specific ASOs promoted potent dose-dependent reductions in Foxp3 mRNA and protein in vitro, without the use of transfection reagents. Foxp3 knockdown also resulted in loss of immunosuppressive markers and conferred Tregs with a reduced immunosuppressive capacity. Whilst genetic ablation of FOXP3 leads to manifestation of autoimmunity due to a complete loss of Treg function, we observed that the systemic delivery of unformulated mouse Foxp3 ASOs to WT mice resulted in Foxp3 knockdown in vivo, but spared mice from an autoimmune phenotype. Nevertheless, when syngeneic tumor-bearing mice were treated with mouse Foxp3 ASOs tumor growth was significantly attenuated, with a fraction of animals (25%-50%) achieving complete regressions. Anti-tumor activity of mouse Foxp3 ASOs was associated with immunophenotypic changes consistent with an increased anti-tumor immune response. Overall these data demonstrate the therapeutic capacity of mouse ASO to directly target regulatory T-cells, and suggesting that targeting of Foxp3 represents an attractive opportunity in cancer immunotherapy. Citation Format: Charles Sinclair, Alexey S. Revenko, Alison Peter, Robert B. Johnson, Lisa A. Hettrick, Molly Taylor, Anna Staniszewska, Adina Hughes, Lisa Sandin, Stephanie Klein, Andrew Watt, Simon Barry, Brett T. Monia, Paul Lyne, A Robert Macleod, Mark Edbrooke. High-affinity antisense oligonucleotides targeting Foxp3 inhibit immunosuppressive function of regulatory T-cells and produce antitumor effects in syngeneic tumor models [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 5561.
Continuous Improvements in “Chain of Survival” Increased Survival After Out-of-Hospital Cardiac Arrests
Authors: TakuIwami, GrahamNichol, AtsushiHiraide, YasuyukiHayashi, TatsuyaNishiuchi, KentaroKajino, HiroshiMorita, HidekazuYukioka, HisashiIkeuchi, HisashiSugimoto, HiroshiNonogi, TakashiKawamura
Journal: Circulation (2009)

Background— The impact of ongoing efforts to improve the “chain of survival” for out-of-hospital cardiac arrest (OHCA) is unclear. The objective of this study was to evaluate the incremental effect of changes in prehospital emergency care on survival after OHCA. Methods and Results— This prospective, population-based observational study involved consecutive patients with OHCA from May 1998 through December 2006. The primary outcome measure was 1-month survival with favorable neurological outcome. Multiple logistic regression analysis was used to assess factors that were potentially associated with better neurological outcome. Among 42 873 resuscitation-attempted adult OHCAs, 8782 bystander-witnessed arrests of presumed cardiac origin were analyzed. The median time interval from collapse to call for medical help, first cardiopulmonary resuscitation, and first shock shortened from 4 (interquartile range [IQR] 2 to 11) to 2 (IQR 1 to 5) minutes, from 9 (IQR 5 to 13) to 7 (IQR 3 to 11) minutes, and from 19 (I...
Abstract 1903: Antiproliferative effect of cannabinoid receptor agonists on rectal cancer lines
Authors: Alette Ortega Gómez, Pedro Luna-Merlos, Victor Manuel García Hernández, Abelardo Meneses García, Horacio Astudillo- de la Vega, Eric Alejandro García López, Abel Santamaría Del Angel, Erika Betzabé Ruiz García
Journal: Cancer Research (2018)

Abstract Rectal cancer is considered a major health issue in several countries that present advanced and metastatic stages and a limited response to standard treatments. Though the antineoplasic activity of cannabinoids has been documented in several studies, scarce information is available about the effect of these agents in cell lines of rectal cancer. In this work, we explored the antiproliferative effects of cannabinoid receptor agonists in rectal tumor cells. The effects of the three agonists anandamide, methanandamide and CP55940 were evaluated in the SW837 rectal tumor cell line. The three agents tested showed time and concentration dependent effects on cell viability, induction of cell death and morphological changes. The three agonists were effective to induce late apoptosis and necrosis and internucleosomal DNA fragmentation. In addition, we evaluated for the first time the patterns of CB1 and CB2 cannabinoid receptor expression in SW837. Though some differences in their effects were found, our data support the concept that these agents mostly share common antiproliferative/cell death mechanisms. Our results also confirm the antineoplasic potential of cannabinoids receptor agonists against rectal cancer, and suggest the design of cannabinoid based coadjutant therapies at the clinical level. Citation Format: Alette Ortega Gómez, Pedro Luna-Merlos, Victor Manuel García Hernández, Abelardo Meneses García, Horacio Astudillo- de la Vega, Eric Alejandro García López, Abel Santamaría Del Angel, Erika Betzabé Ruiz García. Antiproliferative effect of cannabinoid receptor agonists on rectal cancer lines [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 1903.
Emergency department closures do not lead to more deaths, study finds
Authors: Jacqui Wise
Journal: BMJ (2018)

Closing emergency departments did not lead to more deaths despite patients having to travel further for lifesaving treatment but neither did it improve patient outcomes, in a study into the impact of closing emergency departments in England.1

Reorganisation of emergency care services is often controversial and tends to provoke strong reactions from local groups. However, little research evidence had been found to support decisions about closing emergency departments.

Jon Nicholl, study coauthor from the School of Health and Related Research at the University of Sheffield, said, “We didn’t find the better outcomes for patients that …
Relationship of Anti-60 kDa Heat Shock Protein and Anti-Cholesterol Antibodies to Cardiovascular Events
Authors: AmarillaVeres, GeorgeFüst, MarekSmieja, MatthewMcQueen, AnnaHorváth, QilongYi, AdriennBíró, JanicePogue, LászlóRomics, IstvánKarádi, MahavirSingh, JudyGnarpe, ZoltánProhászka, SalimYusuf
Journal: Circulation (2002)

Background— Several recent studies have indicated an association between key inflammatory mediators and atherosclerotic diseases. We evaluated whether high levels of antibodies against heat shock proteins and cholesterol (ACHA) predicted cardiovascular (CV) events. Methods and Results— We used blood samples from the Heart Outcomes Prevention Evaluation (HOPE) study to conduct a nested case-control study of 386 cases with CV events and 386 age- and sex-matched HOPE study controls without events. We explored the relationship between anti-hsp antibodies, ACHA, and subsequent outcomes (incident myocardial infarction, stroke, or CV death) during a mean follow-up of 4.5 years using conditional logistic regression. High levels of anti-hsp65 antibodies (≥90th percentile) predicted CV events (OR, 2.1; 95% CI, 1.2 to 3.9, P=0.01). Anti-hsp60 antibodies did not predict any event type, whereas incident stroke developed significantly less frequently in patients with high ACHA levels. Anti-hsp antibodies and ACHA did n...
Abstract 761: The role of PI3 kinase pathway in the the skin of Sezary syndrome
Authors: Cristina Cristofoletti, Antonella Bresin, Mario Picozza, Maria Cristina Picchio, Francesca Passarelli, Francesca Monzo, Mauro Helmer Citterich, Alessandro Monopoli, Roberto Benucci, Maria Cantonetti, Alessandra Frezzolini, Enrico Scala, Elisabetta Caprini, Giandomenico Russo, Maria Grazia Narducci
Journal: Cancer Research (2018)

Abstract Sezary Syndrome (SS) is an aggressive variant of cutaneous T cell lymphoma (CTCL) characterized by an accumulation of malignant T lymphocytes - the Sezary (SS) cells - in the skin, lymph nodes and blood. Until now, most studies on the characterization of this lymphoma have been performed on circulating SS cells because of the easy availability of tumor material from this compartment. For this reason, the role of skin microenvironment has not been characterized although it might play a fundamental role in the pathogenesis and in the disease progression of this neoplasia. According to this view, we recently demonstrated that PTEN downregulation, due to genetic loss and microRNA deregulation, commonly observed in SS patients, mainly activates AKT in skin-resident respect to blood-derived SS cells. This data underline how microenvironment signals amplify genetic abnormalities. Based on these observations, we investigated the effect of the skin microenvironment on SS cells in vivo. Comparing skin and blood-derived SS cells concurrently obtained from SS patients, we demonstrate that skin milieu promotes proliferation and PI3K/AKT/mTORC1 activation, a pathway that we prove to have multiple copy number (CN) alterations in our cohort of forty-three patients, thus indicating these genetic lesions as valid therapeutic targets to treat SS. At the end, we also demonstrate that the progressive increase of these CN alterations is associated to the shortening of overall survival of SS patients. Citation Format: Cristina Cristofoletti, Antonella Bresin, Mario Picozza, Maria Cristina Picchio, Francesca Passarelli, Francesca Monzo, Mauro Helmer Citterich, Alessandro Monopoli, Roberto Benucci, Maria Cantonetti, Alessandra Frezzolini, Enrico Scala, Elisabetta Caprini, Giandomenico Russo, Maria Grazia Narducci. The role of PI3 kinase pathway in the the skin of Sezary syndrome [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 761.
Abstract 4123: Pancreatic cancer imaging and interventional PTT with a human bispecific scfv antibody via click chemistry
Authors: qian wang, dan li, kun wang, chunyan liu, mingyuan gao, xinming zhao, jie tian
Journal: Cancer Research (2018)

Abstract Early diagnosis and therapy intervention remains a meaningful task for prolonging pancreatic cancer lifetime and improving prognosis. Successful development of so many highly specific targets emerge, for accurate diagnosis and precise treatment. Herein, we generated bispecific antibody fragment by connecting anti-EGFR scfv and anti-VEGF scfv, via click ligation of TCO and tetrazine. Firstly, Cellvizo imaging was acquired by AF488/647 labeled anti-EGFR scfv and anti-VEGF scfv, respectively, displayed overexpression and metabolic process in real time. IVIS and 3D MSOT imaging of mice bearing anthropogenic cell line of bxpc3(EGFR+/VEGF+) subcutaneous and orthotopic and tumors with Irdye800 labeled Bs-(scfv)2 revealed a more significantly enhancement and long circulation of tumor uptake and tumor-to-background ratio compared with each special scfv group(T/B ratio of 12.1±3.4 at 4h post-injection, n=5 in IVIS image). Thus, we validated that dual targeting of VEGF and EGFR provides a high affinity and specificity by Irdye800-labeled-Bs-(scfv)2. Finally, we successfully replaced irdye800 with PLA-PEG-NHS@ICG (combined or uncombined GEM) and conjugated Bs-(scfv)2 for interventional PTT, compared with GEM treatment, a 18% higher median survival rate of PTT combined GEM has been achieved. Our finding offer a preclinical proof concept for Bs-(scfv)2 PTT in clinical trial in future, due to effective bio-distribution and high affinity. Citation Format: qian wang, dan li, kun wang, chunyan liu, mingyuan gao, xinming zhao, jie tian. Pancreatic cancer imaging and interventional PTT with a human bispecific scfv antibody via click chemistry [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 4123.
Abstract 1355: Mutation signatures including APOBEC in cancer cell lines
Authors: Reuben S. Harris
Journal: Cancer Research (2018)

Abstract Background: Multiple endogenous and exogenous sources of DNA damage contribute to the overall mutation burden in cancer, with distinct and overlapping combinations contributing to each cancer type. Many mutation sources result in diagnostic mutation signatures, which can be deduced from tumor genomic DNA sequences. Examples include spontaneous hydrolytic deamination of methyl-cytosine bases in CG motifs (AGEING signature) and C-to-T and C-to-G mutations in 5'-TC(A/T) motifs (APOBEC signature). Methods: The deconstructSigs R package was used to analyze single base substitution mutation signatures in over 1000 cancer cell lines. Two additional approaches were used to analyze the APOBEC mutation signature. Results: Most cell lines show evidence for multiple mutation signatures. For instance, the AGEING signature, which is the largest source of mutation in most primary tumors, predominates in the majority of cancer cell lines. The APOBEC mutation signature is enriched in cancer cell lines from breast, lung, head/neck, bladder, and cervical cancers, where this signature also comprises a large fraction of all mutations. Conclusions: The single base substitution mutation signatures of cancer cell lines often reflect those of the original tumors from which they are derived. Cancer cell lines with enrichments for distinct mutation signatures such as APOBEC have the potential to become model systems for fundamental research on the underlying mechanisms and for advancing clinical strategies to target these processes and, ultimately, constrain tumor evolvability. Citation Format: Reuben S. Harris. Mutation signatures including APOBEC in cancer cell lines [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 1355.