tbuckley/cabot-search huggingface dataset:
Abstract 3471: Expression of the DEK oncogene in breast cancer cells promotes M2 polarization of tumor associated macrophages
Authors: Miranda S. Shephard, Nicholas A. Pease, Jon Cheek, Lisa M. Privette Vinnedge
Journal: Cancer Research (2018)

Abstract Breast cancer is the most common cancer and the second leading cause of cancer deaths among women. DEK is a known oncoprotein found to be highly expressed in more than 60% breast cancers and is found to be an independent marker of poor prognosis. However, the molecular mechanisms by which DEK promotes tumor progression are poorly understood. To elucidate the oncogenic functions of DEK, we performed RNA-seq analysis on isogenic Dek-knockout and complemented murine breast cancer cells, which indicated dysregulation of immune signaling. Among the target genes identified and confirmed was an upregulation of thymic stromal lymphopoietin (TSLP) in Dek expressing breast cancer cells. TSLP was previously shown by Han et al to amplify the alternative (M2) activation of macrophages. M2-like macrophages are tumor promoting, they recycle iron for cell growth and encourage tissue remodeling and repair activities like angiogenesis. Classically (M1) activated macrophages are tumor suppressing and are typically associated with response to infection. To test the immune modulating functions of Dek-expressing breast cancer cells, we treated bone marrow derived macrophages (BMDM) with tumor cell conditioned media. We found that in vitro, Dek expressing cancer cells induced an M2-like polarization of macrophages, as determined by the expression of M2-associated genes, enhanced migration, and iron recycling phenotypes, which was accompanied by inhibited ERK1/2 sighnaling. We found this phenotypic trend to be true in vivo, as well. In sectioned mammary tumors from MMTV-RontgDek+/+ and MMTV-RontgDek-/- mice, we see lower levels of iron staining in Dek+/+ tumors than in Dek-/- tumors using Prussian blue staining that co-localized with F4/80 macrophage marker staining. This suggested that Dek expression in the tumors induced an iron recycling, M2-like phenotype in tumor associated macrophages. These findings suggest that tumor Dek expression may promote breast cancer progression by inducing M2-like macrophage polarization in a murine breast cancer model. Citation Format: Miranda S. Shephard, Nicholas A. Pease, Jon Cheek, Lisa M. Privette Vinnedge. Expression of the DEK oncogene in breast cancer cells promotes M2 polarization of tumor associated macrophages [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 3471.
Abstract 2609: Overexpression of YAP1 of EGFR-mutant lung adenocarcinoma before tyrosine kinase inhibitor is associated with poor survival
Authors: Soon Auck Hong, Jin-Hyoung Kang, Sook Hee Hong
Journal: Cancer Research (2018)

Abstract Purpose: EGFR tyrosine kinase inhibitor (EGFR TKI) was approved as a first line treatment for EGFR mutant lung adenocarcinoma (LADC) with advanced stage. YAP1 (Yes-associated protein 1) is a main effector of hippo pathway, related with adverse prognosis and EGFR TKI modulation of non-small cell lung cancer. This study aimed to clarify a prognostic role of YAP1 in EGFR mutant LADC and efficacy for EGFR TKI through the course of EGFR TKI. Materials and Methods: 41 patients with paired lung cancer specimen before and after EGFR TKI were enrolled in this study. The expression of YAP1 protein was evaluated by immunohistochemistry. Results: 15 cases (36.6%) with high YAP1 expression was found in pre-EGFR TKI LADC, while high YAP1 expression in 21 cases (52.5%) was detected after EGFR-TKI. The transitional level of YAP1 between pre- and post-EGFR TKI was significantly upregulated (P=0.002). High YAP1 before EGFR TKI was related with shorter OS (P=0.023) and PFS (P=0.041). In addition, high YAP1 before EGFR TKI in T790M mutant LADC was related with poor OS (P&amp;lt;0.001). Conclusion: YAP1 burden before EGFR TKI was crucial role in prognosis of EGFR mutant LADC treated by EGFR TKI. Citation Format: Soon Auck Hong, Jin-Hyoung Kang, Sook Hee Hong. Overexpression of YAP1 of EGFR-mutant lung adenocarcinoma before tyrosine kinase inhibitor is associated with poor survival [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 2609.
Bio‐Orthogonally Crosslinked, In Situ Forming Corneal Stromal Tissue Substitute
Authors: Hyun Jong Lee, Gabriella M. Fernandes‐Cunha, Kyung‐Sun Na, Sarah M. Hull, David Myung
Journal: Advanced Healthcare Materials (2018)

In this study, an in situ forming corneal stromal substitute based on collagen type I crosslinked by bio-orthogonal strain-promoted azide-alkyne cycloaddition (SPAAC) is presented. The crosslinked collagen gel has greater transparency compared to non-crosslinked collagen gels. The mechanical properties of the gels are controlled by changing functional group ratios and conjugated collagen concentrations. Higher concentrations of conjugated collagen yield enhances mechanical properties, where the storage modulus increases from 42.39 ± 8.95 to 112.03 ± 3.94 Pa after SPAAC crosslinking. Encapsulated corneal keratocytes grow within the SPAAC-crosslinked gels and corneal keratinocytes are supported on top of the gel surfaces. SPAAC-crosslinked gels support more favorable and stable keratinocyte morphology on their surface compared to non-crosslinked gels likely as a result of more optimal substrate stiffness, gel integrity, and resistance to degradation. SPAAC-crosslinked collagen gels with and without encapsulated keratocytes applied to rabbit corneas in an organ culture model after keratectomy exhibit surface epithelialization with multilayered morphology. The novel in situ forming gel is a promising candidate for lamellar and defect reconstruction of corneal stromal tissue.
Abstract 3298: High-content phenotyping of somatic cancer mutations by functional variomics
Authors: Nidhi Sahni, Patrick Kwok-Shing Ng, Kang Jin Jeong, Gordon B. Mills
Journal: Cancer Research (2018)

Abstract Cancer genomes are highly complex with numerous somatic mutations identified across patient populations. Previous studies on genomic mutations have shed light on new means for cancer therapeutic interventions. With rapid advances in next-generation sequencing, accumulating genotypic information in the absence of efficient and systematic functional analyses of genomic aberrations will create a bottleneck in understanding genotype-phenotype relationships in cancer. To address these challenges, here we report a systems-level functional variomics approach integrating high-throughput phenotyping with robust computational analyses to investigate mutation-specific effects. This systematic functional platform consists of massively parallel mutagenesis, sensitive survival assays using growth factor-dependent cell models, and functional network perturbation profiling of mutations on signaling effects. We profile several thousands of genomic aberrations, including point mutations, gene fusions and indels, and significantly expand the repertoire of characterized actionable mutations. This study represents a valuable resource and provides insights in prioritizing cancer-causing mutations, and uncovering patient-specific disease mechanisms at a high resolution, a critical step towards personalized precision medicine. Citation Format: Nidhi Sahni, Patrick Kwok-Shing Ng, Kang Jin Jeong, Gordon B. Mills. High-content phenotyping of somatic cancer mutations by functional variomics [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 3298.
Brentuximab vedotin with gemcitabine for paediatric and young adult patients with relapsed or refractory Hodgkin's lymphoma (AHOD1221): a Children's Oncology Group, multicentre single-arm, phase 1–2 trial
Authors: Peter D Cole, Kathleen M McCarten, Qinglin Pei, Menachem Spira, Monika L Metzger, Richard A Drachtman, Terzah M Horton, Rizvan Bush, Susan M Blaney, Brenda J Weigel, Kara M Kelly
Journal: The Lancet Oncology (2018)
Abstract 17173: Reversal of Vascular Macrophage Accumulation and Hypertension by a Chemokine C-C motif Receptor 2 Antagonist in Deoxycorticosterone/Salt-Treated Mice
Authors: Christopher T Chan, Jeffrey P Moore, Klaudia Budzyn, Elizabeth Guida, Antony Vinh, Emma S Jones, Samy Sakkal, Sharon D Ricardo, Christopher G Sobey, Grant R Drummond
Journal: Circulation (2012)

Macrophage infiltration into the artery wall plays a pathophysiological role in hypertension by promoting vascular inflammation and endothelial dysfunction. Chemokines are chemoattractant cytokines...
Abstract 416: Impact of virus integration into the genomes of hepatocellular carcinoma patients with prior hepatitis B virus infection
Authors: Yutaka Midorikawa, Kenji Tatsuno, Shogo Yamamoto, Genta Nagae, Kazuhiko Koike, Mitsuhiko Moriyama, Tadatoshi Takayama, Kyoji Moriya, Hiroyuki Aburatani
Journal: Cancer Research (2018)

Abstract It has been elucidated that hepatitis B virus (HBV) DNA is frequently integrated to some cancer related genes such as TERT or KMT2B in patients with chronic HBV infection. On the other hand, it has not yet become clear of the integration of HBV to the genome of patients with prior infection with HBV. To identify the integration sites of HBV, we performed next generation of target capture technology for hepatocellular carcinoma samples obtained from 73 HBc antibody positive patients but negative for HBs antigen nor hepatitis C antibody (HCV) (Group 1; prior infection), 78 HBs antigen positive patients (Group 2; positive control), and 33 patients without any antigens nor antibodies for HBV (Group 3; negative control). Among these patients, overall HBV integration in Group 2 (54 patients, 69.2%) was significantly frequent compared with that in Group 1 (12, 16.4%) (P &amp;lt; 0.001), and was not detected in any patients of Group 3. On the other hand, HBV integration occurred in the known driver genes; TERT in seven (9.5%) and 12 (15.3%) patients (P = 0.332), MLL4 in two (3.5%) and four (5.1%) patients (P = 682), and CCNE1 in 0 and one (1.2%) patient (P = 1.000) in Group 1 and 2, respectively. Notably, integration of any driver genes was not observed in 56 patients with prior infection with HBV who were positive for HCV infection.Taken together, despite the disappearance of HBV, the frequency of driver events by HBV integration in patients with prior HBV infection is similar to those with chronic HBV infection, and patients with prior HBV infection are still at the risk of hepatocellular carcinoma. Citation Format: Yutaka Midorikawa, Kenji Tatsuno, Shogo Yamamoto, Genta Nagae, Kazuhiko Koike, Mitsuhiko Moriyama, Tadatoshi Takayama, Kyoji Moriya, Hiroyuki Aburatani. Impact of virus integration into the genomes of hepatocellular carcinoma patients with prior hepatitis B virus infection [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 416.
The Phenotypic Spectrum of Nephropathies Associated with Mutations in Diacylglycerol Kinase epsilon (vol 28, pg 3066, 2017)
Authors: Karolis Azukaitis, Eva Simkova, Mohammad Abdul Majid, Matthias Galiano, Kerstin Benz, Kerstin Amann, Clemens Bockmeyer, Radha Gajjar, Kevin E. Meyers, Hae Il Cheong, Bärbel Lange-Sperandio, Therese Jungraithmayr, Veronique Fremeaux-Bacchi, Carsten Bergmann, Csaba Bereczki, Monika Miklaszewska, Dorottya Csuka, Zoltan Prohaszka, Paul Killen, Patrick Gipson, Matthew G. Sampson, Mathieu Lemaire, Franz Schäfer
Journal: Journal of the American Society of Nephrology (2017)
Surgical Treatment of Aortic Regurgitation due to Takayasu Arteritis
Authors: KaoruMatsuura, HitoshiOgino, JunjiroKobayashi, HatsueIshibashi-Ueda, HitoshiMatsuda, KenjiMinatoya, HiroakiSasaki, KoBando, KazuoNiwaya, OsamuTagusari, HiroyukiNakajima, ToshikatsuYagihara, SoichiroKitamura
Journal: Circulation (2005)

Background— The goal of this retrospective study was to determine the late outcome of surgical treatment for aortic valve regurgitation due to Takayasu arteritis and correlate it with evidence of inflammation on pathological examination. Methods and Results— Ninety consecutive patients who underwent surgery for aortic valve regurgitation due to Takayasu arteritis between 1979 and 2003 were studied. Intraoperative pathological specimens of the aortic wall from 69 patients were retrospectively examined for inflammation. Aortic valve replacement was performed in 63 patients (group A) and composite graft repair in 27 patients (group B). The aortic root diameter was 39.9±9.5 mm in group A and 54.4±13.6 mm in group B (P<0.0001). Preoperative steroid therapy was performed in 40 patients (44.4%). Hospital mortality was 4.8% (3/63) in group A and 7.4% (2/27) in group B. The overall 15-year survival rate was 76.1%. Detachment of the valve or graft occurred in 11.1% (7/63) of group A and in 3.7% (1/27) of group B pa...
Abstract 345: Characterizing and therapeutically targeting G-quadruplex DNA in <i>ATRX</i>-mutant glioma
Authors: Yuxiang Wang, Carla Danussi, Kasthuri Kannan, Timothy A. Chan, Jason T. Huse
Journal: Cancer Research (2018)

Abstract Inactivating ATRX mutations are defining molecular alterations in several cancer variants, including large subsets of malignant glioma. ATRX encodes a chromatin binding protein widely implicated in epigenetic and transcriptional regulation. However, ATRX is also thought to guard against genomic instability, in part by mitigating the formation of deleterious G-quadruplex (G4) DNA secondary structures. G4s have been shown to stall DNA replication leading to single-strand breaks and, potentially, DNA damage and genomic instability. To study this biology in a glioma-relevant context, we generated an isogenic astrocyte model featuring intact or deficient ATRX. While ATRX deficiency had no effect on baseline proliferation, cell cycle progression, and apoptosis, it led to markedly increased G4 formation, DNA damage, and replication stress signaling. These effects were reversed by ATRX re-expression. Moreover, ATRX-deficient astrocytes acquired copy number alterations over time, unlike ATRX-intact counterparts. Given these findings, we hypothesized that therapeutically targeting G4s might serve to exploit the inherent genomic vulnerabilities of ATRX-deficient cancer. Remarkably, treatment with a G4 stabilizing compound (CX3543) selectively inhibited growth and colony formation in ATRX-deficient astrocytes at nanomolar concentrations, and synergistically potentiated the effects of ionizing radiation and hydroxyurea. Finally, CX3543 significantly inhibited the growth of patient-derived, ATRX-deficient glioma xenografts in mice, with only minimal effects on ATRX-intact glioma xenografts. These results confirm and characterize a novel functionality for ATRX in the mitigation of genomic instability and point towards a viable strategy for therapeutically targeting ATRX deficiency in cancer. Citation Format: Yuxiang Wang, Carla Danussi, Kasthuri Kannan, Timothy A. Chan, Jason T. Huse. Characterizing and therapeutically targeting G-quadruplex DNA in ATRX-mutant glioma [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 345.
Abstract 14738: Inflammasome Activation by Mitochondrial Oxidative Stress in Macrophages Leads to the Development of Angiotensin II-induced Aortic Aneurysm
Authors: MasafumiTakahashi, FumitakeUsui, AkiraKawashima, TadayoshiKarasawa, HiroakiKimura
Journal: Circulation (2014)

Introduction: Abdominal aortic aneurysm (AAA) is considered a chronic inflammatory disease; however, the molecular basis underlying the sterile inflammatory response involved in the process of AAA formation remains unclear. The NLRP3 inflammasome is a multiprotein complex consisting of NLRP3, ASC, and caspase-1, and regulates caspase-1-dependent maturation of interleukin-1β (IL-1β). We previously showed that the NLRP3 inflammasome mediates the sterile cardiovascular inflammatory responses in vascular injury and myocardial ischemia-reperfusion injury. Hypothesis: We hypothesized that the NLRP3 inflammasome is a key mediator of initial inflammation in AAA formation. Methods: ASC is highly expressed in adventitial macrophages in human and murine AAA tissues. Using an established mouse model of AAA induced by continuous infusion of angiotensin II (AII) for 28 days in Apoe-/- mice, NLRP3, ASC, and caspase-1 deficiency in Apoe-/- mice was shown to significantly decrease the incidence, maximal diameter, and seve...
Abstract 264: Vaccination against neoantigens induced in future tumors in the setting of recurrence and premalignancy
Authors: Greta Garrido Hidalgo, Brett Schrand, Ailem Rabasa, Agata Levay, Alexey Berezhnoy, Shrey Modi, Giri Bhuwan Bhuwan, Vikas Dudeja, Elien Doorduijn, Thorbald van Hall, Eli Gilboa
Journal: Cancer Research (2018)

Abstract Development of therapeutic strategies to prevent recurrence in cancer patients, or tumor progression in at risk individuals has been challenging given the long and often unpredictable time to the emergence of the malignant tumors. Neoantigens represent the most potent antigens to induce antitumor immunity, yet the ability to predict which neoantigens will be expressed in future tumors is at present not an option. We have developed a simple and broadly applicable approach to induce neoantigens in tumor cells in situ by reducing the expression of antigen processing mediators like TAP, ERAAP, or invariant chain (Ii), using siRNAs that were targeted to tumor cells by conjugation to a nucleolin-binding aptamer. Exploiting the ability to induce neoantigens in situ, we describe a novel vaccination strategy targeting potent neoantigens to control the growth of the future tumors whereby patients in remission or individuals at risk are first vaccinated against the antigen processing downregulation-induced neoantigens and when or if tumor develops the same antigens are induced in the tumor, termed prorapeutic vaccination (prophylactic + therapeutic). Mice were vaccinated against the TAP downregulation-induced neoantigens by targeting the corresponding siRNAs to dendritic cells (DC) in situ via conjugation to a short CpG oligonucleotide (ODN); the CpG ODN also activated the targeted DC to avoid induction of tolerance against the neoantigens. Vaccination with CpG ODN-TAP siRNA conjugates inhibited subsequently implanted or autochthonous tumors in several tumor models, provided the said neoantigens were also induced in the tumor by nucleolin aptamer-targeted siRNA inhibition of TAP. The CpG-siRNA and nucleolin aptamer-siRNA conjugates are simple, chemically- synthesized, off-the-shelf, and broadly applicable reagents to vaccinate against neoantigens and control the growth of future tumors irrespective of their origin. Citation Format: Greta Garrido Hidalgo, Brett Schrand, Ailem Rabasa, Agata Levay, Alexey Berezhnoy, Shrey Modi, Giri Bhuwan Bhuwan, Vikas Dudeja, Elien Doorduijn, Thorbald van Hall, Eli Gilboa. Vaccination against neoantigens induced in future tumors in the setting of recurrence and premalignancy [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 264.
Association of Type 2 Diabetes With Cyclooxygenase-Mediated Inflammation and Oxidative Stress in an Elderly Population
Authors: JohannaHelmersson, BengtVessby, AndersLarsson, SamarBasu
Journal: Circulation (2004)

Background— Involvement of cyclooxygenase (COX)-mediated inflammation in type 2 diabetes has not been studied, and the association between cytokine-mediated inflammation and diabetes is not fully clarified. Methods and Results— 15-Keto-dihydro-prostaglandin F2α (a metabolite of prostaglandin F2α and an indicator of COX-mediated inflammation), high-sensitivity C-reactive protein (CRP), serum amyloid protein A (SAA), 8-iso-PGF2α (a nonenzymatic, free radical product of arachidonic acid and an indicator of oxidative stress), and α-tocopherol were measured in a population-based sample of 77-year-old men (n=765), in which 112 men had type 2 diabetes. The inflammatory indicators were increased in men with diabetes (urinary 15-keto-dihydro-PGF2α, P<0.001, CRP and SAA, P<0.05). However, when adjusted for body mass index, waist circumference, or fasting insulin, no association was found between diabetes and CRP or SAA. The oxidative stress indicator 8-iso-PGF2α in urine was increased (P<0.01) in men with diabetes....
New Nonprofit Biotech From Bill and Melinda Gates
Authors: Jennifer Abbasi
Journal: JAMA (2018)

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Electrophysiological Delineation of the Tachycardia Circuit in Atrioventricular Nodal Reentrant Tachycardia
Authors: HiroshigeYamabe, IkuoMisumi, HironobuFukushima, KazuhiroUeno, YoshihiroKimura, YouichiHokamura
Journal: Circulation (1999)

Background—The exact boundaries of the reentry circuit in atrioventricular nodal reentrant tachycardia (AVNRT) have not been convincingly defined. Methods and Results—To define the tachycardia circuit, single extrastimuli were delivered during AVNRT to 8 sites of the right intra-atrial septum: 3 arbitrarily divided sites of the AV junction extending from the His bundle (HB) site to the coronary sinus ostium (CSOS) (sites S, M, and I) and the superior (S-CSOS), inferior (I-CSOS), posterior (P-CSOS), and posteroinferior (PI-CSOS) portions of the CSOS and the CSOS in 18 patients. The mean tachycardia cycle length (TCL) was 368±52 ms. Retrograde earliest atrial activation was observed at the HB site in all patients. The longest coupling intervals of single extrastimuli that reset AVNRT at sites S, M, I, I-CSOS, CSOS, S-CSOS, P-CSOS, and PI-CSOS were 356±51, 356±51, 355±52, 357±51, 318±47, 305±53, 311±56, and 312±56 ms, respectively, and the following return cycles at these sites were 368±52, 368±53, 367±53, 3...