tbuckley/cabot-search huggingface dataset:
Perceived Level of Life Enjoyment and Risks of Cardiovascular Disease Incidence and Mortality
Authors: KokoroShirai, HiroyasuIso, TetsuyaOhira, AiIkeda, HiroyukiNoda, KaoriHonjo, ManamiInoue, ShoichiroTsugane
Journal: Circulation (2009)

Background— Perceived level of life enjoyment, a positive psychological condition that reflects the ability to engage pleasurably with the environment, may relate to risks of cardiovascular disease. This prospective cohort study attempted to examine the effects of perceived level of life enjoyment on cardiovascular disease incidence and mortality among Japanese community residents. Methods and Results— Subjects were 88 175 Japanese men and women 40 to 69 years of age who were free of cardiovascular disease at baseline and followed up for a median of 12.0 years and were included in the Japan Public Health Center–Based (JPHC) Study Cohort. Data about psychological conditions and other confounding variables were obtained through self-administered questionnaires. Information on incidence and mortality for cardiovascular disease was collected through registered hospitals and public health centers. The multivariable hazard ratios of cardiovascular disease incidence for men in the high versus low perceived level...
Abstract 19843: Myocardial Microcirculation Induces Anisotropic Diffusion-like Magnetic Resonance Contrast
Authors: Osama Abdullah, Arnold David Gomez, Samer Merchant, Michael Heidinger, Steven Poelzing, Edward Hsu
Journal: Circulation (2015)

Introduction: The magnetic resonance (MR) signal in the presence of a magnetic field gradient is highly sensitive to the aggregate translational molecular motion of water. In highly vascularized tissues, diffusion-like contrast induced by microcirculation has been used to characterize blood flow in heart. The effect in tissues with random capillary orientations has been modeled as intravoxel incoherent motion (IVIM), but is not completely understood in organized tissues. Hypothesis: We hypothesize that blood flow in organized tissues will manifest as speed- and orientation- dependent “pseudo” diffusion coefficient D*. Methods: For Gaussian-distributed flow with mean speed vm in parallel capillaries as a function of the relative encoding angle θ, it can be shown that D* is proportional to the square power of both vm and cos(θ), which is then incorporated into a generalized formulation of anisotropic tissue diffusion and flow with a tensor entity D* to characterize the flow pseudo diffusivity in 3D space using the familiar diffusion tensor imaging (DTI) notation. Validation experiments were conducted on isolated, perfused, guinea pig hearts (n=7) in a Langendorff setup and imaged with Bruker (7T) MRI scanner under normal and low flow conditions. Statistical analyses were conducted via 1-way ANOVA with Bonferroni post-hoc multiple-comparison correction (P&lt;0.05 considered statistically significant). Results: Figure 1A-C show representative diffusion-weighted MR images encoded at perpendicular directions, and Fig 1D shows the flow-speed and angular dependence (or anisotropy) of the fitted D* component at high flow and low flow. D* significantly decreased by 63% only in the parallel direction to myocytes (or capillaries) (P&lt;0.05). Conclusions: These findings suggest that the DTI formalism of anisotropic spin motion can be incorporated into the classical IVIM theory to describe the MR signal arising from diffusion and microcirculation in organized tissues.
Abstract 2783: Empowering therapeutic monoclonal antibodies with IFN-alpha for cancer immunotherapy
Authors: Jun Guo, Yu Xiao, Ramesh B. Lyer, Marc R. Lake, Uri S. Ladror, Xin Lu, Bill Pappano, John E. Harlan, Medha J. Tomlinson, Gail T. Bukofzer, Cherrie K. Donawho, Alexander R. Shoemaker, Tzu-Hsuan Huang
Journal: Cancer Research (2018)

Abstract Type 1 IFNs stimulates secretion of IP-10 (CXCL10) which is a critical chemokine to recruit effector T cells to the tumor microenvironment and IP-10 knockout mice exhibit a phenotype with compromised effector T cell generation and trafficking. Type 1 IFNs also induces MHC class 1 upregulation on tumor cells which can enhance anti-tumor CD8 T cell effector response in the tumor microenvironment. Although type 1 IFNs show great promise in potentiating anti-tumor immune response, systemic delivery of type 1 IFNs is associated with toxicity thereby limiting clinical application. In this study, we fused tumor targeting antibodies with IFN-alpha and showed that the fusion proteins can be produced with high yields and purity. IFN fusions selectively induced IP-10 secretion from antigen positive tumor cells, which was critical in recruiting the effector T cells to the tumor microenvironment. Further, we establish a real time in vitro antigen specific CTL killing assay using IncuCyte Zoom and tested the anti-tumor efficacy of anti-PDL1-IFN-alpha fusion using this system. We found anti-PDL1-IFN-alpha as low as 10 pM exhibits potent activity in potentiating OT1 CD8 T cells killing against OVA expressing tumor cells, while control IFN fusion did not exhibit any activity in the same experiment. Furthermore, IFN-alpha fusion antibody was well tolerated in vivo and demonstrated anti-tumor efficacy in an anti-PD-L1 resistant syngeneic mouse tumor model. Our data supports the hypothesis of targeting type 1 IFN to the tumor microenvironment may enhance effector T cell responses in non-inflamed tumors. Citation Format: Jun Guo, Yu Xiao, Ramesh B. Lyer, Marc R. Lake, Uri S. Ladror, Xin Lu, Bill Pappano, John E. Harlan, Medha J. Tomlinson, Gail T. Bukofzer, Cherrie K. Donawho, Alexander R. Shoemaker, Tzu-Hsuan Huang. Empowering therapeutic monoclonal antibodies with IFN-alpha for cancer immunotherapy [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 2783.
Angiogenic Gene Therapy for Experimental Critical Limb Ischemia
Authors: IchiroMasaki, YoshikazuYonemitsu, AkihisaYamashita, ShihokoSata, MitsuguTanii, KimihiroKomori, KazunoriNakagawa, XiaogangHou, YoshiyukiNagai, MamoruHasegawa, KeizoSugimachi, KatsuoSueishi
Journal: Circulation Research (2002)

Recent studies suggest the possible therapeutic effect of intramuscular vascular endothelial growth factor (VEGF) gene transfer in individuals with critical limb ischemia. Little information, however, is available regarding (1) the required expression level of VEGF for therapeutic effect, (2) the related expression of endogenous angiogenic factors, including fibroblast growth factor-2 (FGF-2), and (3) the related adverse effects due to overexpression of VEGF. To address these issues, we tested effects of overexpression of VEGF165 using recombinant Sendai virus (SeV), as directly compared with FGF-2 gene transfer. Intramuscular injection of SeV strongly boosted FGF-2, resulting in significant therapeutic effects for limb salvage with increased blood perfusion associated with enhanced endogenous VEGF expression in murine models of critical limb ischemia. In contrast, VEGF165 overexpression, 5-times higher than that of baseline on day 1, also strongly evoked endogenous VEGF in muscles, resulting in an accele...
Polymerase-mediated ultramutagenesis in mice produces diverse cancers with high mutational load
Authors: Hao-Dong Li, Ileana Cuevas, Musi Zhang, Changzheng Lu, Md Maksudul Alam, Yang-Xin Fu, M. James You, Esra A. Akbay, He Zhang, Diego H. Castrillon
Journal: Journal of Clinical Investigation (2018)

Mutations underlie all cancers, and their identification and study are the foundation of cancer biology. We describe what we believe to be a novel approach to mutagenesis and cancer studies based on the DNA polymerase ε (POLE) ultramutator phenotype recently described in human cancers, in which a single amino acid substitution (most commonly P286R) in the proofreading domain results in error-prone DNA replication. We engineered a conditional PoleP286R allele in mice. PoleP286R/+ embryonic fibroblasts exhibited a striking mutator phenotype and immortalized more efficiently. PoleP286R/+ mice were born at Mendelian ratios but rapidly developed lethal cancers of diverse lineages, yielding the most cancer-prone monoallelic model described to date, to our knowledge. Comprehensive whole-genome sequencing analyses showed that the cancers were driven by high base substitution rates in the range of human cancers, overcoming a major limitation of previous murine cancer models. These data establish polymerase-mediated ultramutagenesis as an efficient in vivo approach for the generation of diverse animal cancer models that recapitulate the high mutational loads inherent to human cancers.
Abstract 4279: The genomic profile investigation of metastatic triple-negative breast cancer for precision medicine achievement
Authors: Wooyeong Jang, Jihyun Kim, Hanna Yang, Youngmee Kwon, Keun Seok Lee, Sung Hoon Sim, Sun-Young Kong, Kyounghee An, In Hae Park, Charny Park
Journal: Cancer Research (2018)

Abstract Objective: The molecular profile of primary breast cancer has been studied associated with drug responses. Metastatic triple-negative breast cancer (mTNBC) is heterogeneous disease and there is no effective therapeutic target. We investigated the genomic profiles of mTNBC to find potential drug targets. Methods: Metastatic breast cancer samples were collected for genomic analysis (fresh tissue, n=17; FFPE, n=28). We conducted both whole-exome sequencing and RNA-seq for these samples and validated genomic variants by Sanger sequencing. We built up pipelines for somatic mutation, copy number alteration, mRNA expression, and fusion gene analysis. Precise somatic mutations were additionally filtered out for FFPE without matched normal. In addition, we investigated the differences of genomic profiles of mTNBC with those of primary breast cancer from TCGA data. Results: Most of somatic mutation profiles of mTNBC were similar with those of primary cancer. However, there were some specific alterations that were not found in primary tumor. TP53 (&amp;gt;40 %) was concordantly discovered with primary TNBC, but KDM6A (&amp;gt;20 %) was highly recurrent than other breast datasets. We ascertained the diversity of immune cell activity from mRNA expression analysis, and additional pathways also represented the variance within our mTNBC population, which was differentiated from those of primary breast cancer. In addition, we found two novel FGFR1/2 fusion in two cases and validated it by RT-PCR and Western blot. Conclusion: We found specific genomic profiles of mTNBC that were distinct from those of primary tumor. Novel structural variants discovered in our dataset could be potential therapeutic targets for mTNBC patients. Citation Format: Wooyeong Jang, Jihyun Kim, Hanna Yang, Youngmee Kwon, Keun Seok Lee, Sung Hoon Sim, Sun-Young Kong, Kyounghee An, In Hae Park, Charny Park. The genomic profile investigation of metastatic triple-negative breast cancer for precision medicine achievement [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 4279.
Abstract 18446: Identification of a Novel Cellular Actor Participating in Vascular Remodeling During Pulmonary Arterial Hypertension : the PW1+ Progenitor Cells
Authors: France Dierick
Journal: Circulation (2014)

AIM: PW1+ progenitors were identified in various adult tissues and can differentiate in smooth muscle cells (SMC) in vitro. Our hypothesis is that PW1+ progenitors are recruited to participate in the vascular remodeling during pulmonary arterial hypertension (PAH). METHODS: PW1IRESnLacZ+/- mice express the β-galactosidase as a reporter gene for PW1 expression allowing to follow the lineage of PW1+ cells during a few days. These mice were exposed to chronic hypoxia (CH) to induce PAH, lung vessels neomuscularisation and SMC proliferation. PW1+ and β-Gal+ cells were studied by FACS and by immunofluorescence. RESULTS: PW1+ cells are localized in the lung parenchyma and in the perivascular zone in rodent and human lung. Two PW1+ populations were identified by flow cytometry in the mouse lung 1/ a Sca-1high/CD34high/PDGFR-α+ population which differentiates into calponin+ or α-SMA+ SMC and into vWF+ endothelial cell and 2/ a CD34-/CD146+ population expressing pericyte markers. After 2-4 days of CH, the number of lung PW1+ cells is increased (x3.5, p&lt;0.01) and, in small pulmonary vessels media, the proportion of β-Gal+ SMC derived from PW1+ cells is increased (64±6% vs 35±3%, p&lt;0.05) suggesting a recruitment and differentiation of PW1+ cells into lung vascular SMC. Moreover WT mice irradiated and engrafted with GFP+/β-Gal+ bone marrow cells do not show any increase in GFP+ SMC in lung vessels and do not show any β-Gal+ cells in the lung indicating that the lung PW1+ progenitors are not derived from bone marrow . Moreover, in the human PAH lung, PW1+ cells were observed in remodeled vascular structures: in the media of remodeled vessel and in plexiform lesions. CONCLUSION: These results suggest that lung resident PW1+ progenitors are recruited to participate in the vascular remodeling of small pulmonary vessels in experimental and human PAH. These progenitors show characteristics of pericytes and of vascular progenitors.
Abstract LB-298: MEDI7247: A first in class antibody drug conjugate targeting ASCT2 in a range of solid tumors
Authors: Kevin P. Schifferli, Noel R. Monks, Ravinder Tammali, M Jack Borrok, Matthew G. Flynn, Elaine M. Hurt, Steven R. Coats, Ronald Herbst, David A. Tice, Nabendu Pore
Journal: Cancer Research (2018)

Abstract MEDI7247 is a first in class ADC consisting of a human anti-ASCT2 monoclonal antibody, site specifically conjugated to highly cytotoxic DNA cross-linking pyrrolobenzodiazepine (PBD) dimers (DAR of 2) via a protease-cleavable linker. ASCT2 (SLC1A5) is a multi-pass, Na+-dependent, neutral amino acid transporter that mediates the uptake of amino acids required for tumor growth and progression. ASCT2 over-expression has been identified on numerous solid tumor indications including pancreatic (94% Positive), small cell (SCLC) and non-small cell (NSCLC) lung cancer (65% positive), colorectal (73% positive), squamous cell carcinoma of the head and neck (SCCHN - 94% positive) and prostate (65% positive). MEDI7247 binds to ASCT2 facilitating internalization and ultimately cell death. We have evaluated the in vivo anti-tumor activity of MEDI7247 in both cell line-derived xenografts (CDX) and patient-derived xenografts (PDX). Cell line-derived xenografts were utilized to examine the anti-tumor activity in colorectal (WiDR), small cell lung cancer (H69) and squamous head and neck (FADU) tumors. Expression of ASCT2 was determined to be high in WiDR and low in both H69 and FADU. Regardless of ASCT2 expression level MEDI7247 controlled tumor growth in each of these models. MEDI7247 was further examined in numerous PDX models of pancreatic, NSCLC and colorectal tumors. Activity was observed across all the PDX models tested. Two pancreatic cancer PDX with both low and high ASCT2 expression levels showed anti-tumor responses to MEDI7247 at all dose levels tested (0.1, 0.2, 0.3 and 0.4 mg/kg). In both models, tumor regressions were observed with durable responses observed beyond 100 days. Flow cytometry analyses reveal high ASCT2 expression of cancer stem cells (CSCs) in Patient Derived Xenografts(PDX). Additionally, MEDI7247 ablates CSCs in vivo in PDX tumors, which may yield opportunity for more durable clinical responses. In summary, preclinical in vivo evaluation of MEDI7247 demonstrates target dependent anti-tumor activity across all the solid tumor indications evaluated and may be important in tumor initiating cell populations. MEDI7247 is currently in Phase I clinical trials. Citation Format: Kevin P. Schifferli, Noel R. Monks, Ravinder Tammali, M Jack Borrok, Matthew G. Flynn, Elaine M. Hurt, Steven R. Coats, Ronald Herbst, David A. Tice, Nabendu Pore. MEDI7247: A first in class antibody drug conjugate targeting ASCT2 in a range of solid tumors [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-298.
Protective Effects of Endogenous Adrenomedullin on Cardiac Hypertrophy, Fibrosis, and Renal Damage
Authors: PeiNiu, TakayukiShindo, HiroshiIwata, SatoshiIimuro, NorifumiTakeda, YuelanZhang, AyaEbihara, YoshihiroSuematsu, KenjiKangawa, YasunobuHirata, RyozoNagai
Journal: Circulation (2004)

Background— Adrenomedullin (AM) is a novel vasodilating peptide thought to have important effects on cardiovascular function. The aim of this study was to assess the activity of endogenous AM in the cardiovascular system using AM knockout mice. Methods and Results— Mice heterozygous for an AM-null mutation (AM+/−) and their wild-type littermates were subjected to aortic constriction or angiotensin II (Ang II) infusion. The resultant cardiovascular stress led to increases in heart weight/body weight ratios, left ventricular wall thickness, and perivascular fibrosis, as well as expression of genes encoding angiotensinogen, ACE, transforming growth factor-β, collagen type I, brain natriuretic peptide, and c-fos. In addition, renal damage characterized by decreased creatinine clearance with glomerular sclerosis was noted. In all cases, the effects were significantly more pronounced in AM+/− mice. Hearts from adult mice subjected to aortic constriction showed enhanced extracellular signal-regulated kinase (ERK...
Abstract 3118: Oncogenesis modeling in malignant pleural mesothelioma
Authors: Nathanael D. Pruett, Anand Singh, Nisan Bhattacharyya, Chuong D. Hoang
Journal: Cancer Research (2018)

Abstract Malignant pleural mesothelioma (MPM) is causally associated with exposure to asbestos and accounts for roughly 75% of mesothelioma cancers. It is an aggressive tumor with a median survival time of approximately 12 months. Treatment options are limited, largely palliative, and still based on cisplatin and pemetrexed, a regimen that remains unchanged since 2003. Despite widespread study, the complexities of MPM biology remain poorly described, especially at the point of tumor initiation where development of novel clinical interventional strategies would be expected to yield the most effect. The extended latency period in humans consisting of decades (over 20-30 years) remains a prohibitive barrier to gain accurate, in vivo insights about MPM oncogenic processes. As such, all in vitro MPM models, which are designed to accelerate tumor development as a practical endpoint of study, to date have not yielded clinically translatable molecular targets. Here, we present a novel in vitro model system for exploring the earliest molecular mechanisms contributing to the development of MPM using normal, human mesothelial cell lines (MeT-5a and LP9-hTERT) engineered to harbor constitutively enhanced NFkB signaling activity. Both 3D-sphere and soft agar assays were used to assess cellular transformation status in these induced cells compared to their wild-type counterparts. Heterotopic xenograft implantation studies were performed in NOD scid-gamma (NSG) immunocompromised mice (sub-cutaneous dorsal flank injection) for tumorigenic potential. In all cases, these induced cells (despite the complete absence of asbestos exposure) exhibited a significant malignant-like phenotype. Tumor growth in mouse xenograft models occurred very rapidly, and was marked by extensive vascular recruitment with invasion into surrounding tissues. In addition, these transformed cells expressed typical mesothelioma markers such as Wilms tumor protein (WT1 gene product) as revealed by immunohistofluorescence. This new MPM model system could represent a powerful construct to explore the early molecular events involved in transformation of normal mesothelial cells leading to malignancy. Citation Format: Nathanael D. Pruett, Anand Singh, Nisan Bhattacharyya, Chuong D. Hoang. Oncogenesis modeling in malignant pleural mesothelioma [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 3118.
Abstract 2687: Cypripedin inhibits non-small cell lung cancer migration through suppression of epithelial-to-mesenchymal transition
Authors: Surassawadee Treesuwan, Varisa Pongrakhananon
Journal: Cancer Research (2018)

Abstract Lung cancer is one of the most common cause of cancer-related death worldwide because of high metastasis rate. Cancer migration is a prerequisite event among multi-complex processes of metastasis, being one of the interested target for cancer therapy. Accumulative evidence emphasizes that epithelial-to-mesenchymal transition (EMT) plays an important behavior exerting cell motility and survival, and relevant to cancer metastasize. Even the therapeutic approaches have been developed, lung cancer metastasize remains challenge for drug discovery and development. Recent studies highlight the potent anticancer properties of the compounds derived from Orchid. However, the underlying mechanism was unrevealed. This study demonstrated that cypripedin, a phenanthrenequinone extracted from Dendrobium densiflorum, possess an ability to inhibit in vitro cell migration in non-small cell lung cancer H460 and H23 cells. The number of motile cells, examined by transwell migration and wound healing assay, were gradually reduced in a dose-dependent concentration of cypripedin, along with the reduction of colony number and size formed under an anchorage-independent growth. Mechanistic investigation shows that the mesenchymal markers including N-Cadherin, Vimentin and Slug were significantly down-regulated following cypripedin treatment. Our finding suggests that cypripedin potentiates anti-migrative activity in non-small cell lung cancer through the attenuation of EMT process, which support further extensive studies against lung cancer. Citation Format: Surassawadee Treesuwan, Varisa Pongrakhananon. Cypripedin inhibits non-small cell lung cancer migration through suppression of epithelial-to-mesenchymal transition [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 2687.
Response to Letters Regarding Article, “Mild Retinopathy Is a Risk Factor for Cardiovascular Mortality in Japanese With and Without Hypertension: The Ibaraki Prefectural Health Study”
Authors: ToshimiSairenchi, TakashiMuto, HiroyasuIso, KazumasaYamagishi, FujikoIrie, YoshiroOkubo, HitoshiOta, JunkoGunji
Journal: Circulation (2012)