tbuckley/cabot-search huggingface dataset:
Intracortical Distribution of Renal Blood Flow in Hemorrhagic Shock in Dogs
Authors: AlexanderLogan, PedroJose, GilbertEisner, LawrenceLilienfield, LawrenceSlotkoff
Journal: Circulation Research (1971)

The effect of acute hypotensive hemorrhage on the intracortical distribution of renal blood flow was studied in anesthetized mongrel dogs with radioactive microspheres. In the early stages of shock, when carotid artery manipulation was avoided, outer cortical blood flow fell drastically and juxtamedullary flow was relatively well preserved. Carotid artery cannulation caused a redistribution of blood flow within the kidney even before hemorrhage, presumably by stimulating the carotid sinus reflex. Subsequently, with hemorrhage there was a parallel reduction in outer cortical and juxtamedullary blood flow. 138Xe washout curves agreed with the microsphere findings. It was concluded that when the carotid artery was not disturbed, juxtamedullary blood flow was selectively preserved in the early stages of acute hypotensive hemorrhage.
Abstract 2006: Tobacco smoke-induced Marcks phosphorylation promotes inflammatory and stemness properties in lung cancer
Authors: David C. Yang, Yichin Wu, Mu-Jen Huang, Kent E. Pinkerton, Reen Wu, Ching-Hsien Chen
Journal: Cancer Research (2018)

Abstract Exposure to tobacco smoke is a major risk factor associated with lung cancer development and progression; however, the mechanisms of how tobacco smoke activates pathways promoting cancer malignancy remain to be established. Previously, phosphorylation of MARCKS at Ser159/163 (phospho-MARCKS) was shown to promote malignancy of neoplastic disease, but it is still unclear how phospho-MARCKS is upregulated in lung cancer. Herein, we investigated if phospho-MARCKS is elevated in response to smoke exposure and plays a key role in smoke-related lung cancer. In a screen of 200 patients with lung cancer, we confirmed that strong phospho-MARCKS staining was observed in lung cancer specimens from smokers and was positively correlated, as compared to non-smokers. In addition, we demonstrated that increased smoking pack-year was noted in lung cancer patients with high phospho-MARCKS. Surprisingly, there is an apparent trend that patients with both tobacco use and high phospho-MARCKS levels had the worst overall survival. MARCKS was found to become activated in airway epithelium and lung cancer in response to smoke both in vitro and in vivo. MARCKS inhibition significantly attenuated smoke-induced oncosphere formation and migratory capability. Mechanistically, upregulation of phospho-MARCKS by smoke occurred in parallel with increased inflammatory cytokine expression (e.g. TNF-α, IL-8) and stemness marker expression (e.g. Oct4, Nanog, CD133, Sox2). Conversely, targeting of MARCKS phosphorylation with the MPS peptide resulted in down-regulation of smoke-induced stemness and cytokine genes. Our data suggests that phospho-MARCKS plays a role in modulating smoke-mediated lung cancer progression and is a potential prognostic biomarker in smoke-related lung cancer. Citation Format: David C. Yang, Yichin Wu, Mu-Jen Huang, Kent E. Pinkerton, Reen Wu, Ching-Hsien Chen. Tobacco smoke-induced Marcks phosphorylation promotes inflammatory and stemness properties in lung 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 2006.
Abstract 278: Inhibition of skin tumor promotion by TPA using a combination of topically applied ursolic acid and curcumin
Authors: Lisa Tremmel, Okkyung Rho, John DiGiovanni
Journal: Cancer Research (2018)

Abstract Despite the many advances that have been made in understanding cancer development and the discovery of new therapies, cancer still remains the second leading cause of death in the US. In addition, approximately two out of five people are expected to be diagnosed with an invasive cancer in their lifetime. Prevention remains an important strategy to reduce the burden of cancer. One approach to prevent cancer is the use of phytochemicals in various combinations as safe and effective cancer preventive agents. The purpose of this study was to examine the effects of the combination of ursolic acid (UA) and curcumin (Curc) for potential synergistic chemopreventive activity to inhibit tumor promotion using the mouse two-stage skin carcinogenesis model. UA and Curc alone have been shown to inhibit tumorigenesis in several mouse models, and both have been shown to inhibit mouse skin tumor promotion by 12-O-tetradecanoylphorbol-13-acetate (TPA). The anti-cancer activity of these phytochemicals is due primarily to their anti-inflammatory, anti-oxidant, and anti-proliferative effects. These effects are accomplished by acting on a broad spectrum of signaling pathways. In initial short-term experiments (mice treated twice weekly for two weeks with TPA), the combination of UA and Curc pretreated topically inhibited TPA-induced activation of epidermal NF-κB, Cox-2, epidermal growth factor receptor (EGFR) and Stat3 to a greater extent than either compound alone. Additionally, these compounds increased levels of programmed cell death protein 4 (Pdcd4). The alterations in these signaling pathways by the combination of UA and Curc were associated with decreased epidermal proliferation and skin inflammation as assessed by measuring BrdU incorporation and inflammatory gene expression, respectively. Furthermore, results from skin tumor experiments (mice initiated with DMBA and promoted twice weekly with TPA) indicate that the combination of UA and Curc given topically significantly inhibited mouse skin tumor promotion by TPA to a greater extent than the individual compounds given alone. The greatest effects were seen on tumor free survival and on tumor size. These results suggests the potential for the combination of UA and Curc to be used topically for chemopreventive strategies in non-melanoma skin cancer. Citation Format: Lisa Tremmel, Okkyung Rho, John DiGiovanni. Inhibition of skin tumor promotion by TPA using a combination of topically applied ursolic acid and curcumin [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 278.
Abstract 244: Pathway analysis of OncoArray data identifies biological pathways involved in lung cancer development
Authors: Zhihui Wang, Ruyang Zhang, Li Su, Rayjean Hung, Christopher Amos, David C. Christiani
Journal: Cancer Research (2018)

Abstract Background:Genome-wide association studies (GWAS) have identified susceptible loci associated with lung cancer development. However, these variants only account for a small proportion of lung cancer heritability. With the aim to identify the missing heritability, we propose to conduct pathway analysis to test the joint effects of rare and common variants using the OncoArray data. By grouping SNPs into genes and pathways, we may shed light into the underlying mechanisms for lung cancer development and identify novel candidate genes and pathways.Methods:We applied sequence kernel association test (SKAT) to the OncoArray data of the Transdisciplinary Research of Cancer in lung of the International Lung Cancer Consortium (TRICL-ILCCO) that includes 34,432 individuals (19,028 cases and 15,404 controls) across over twenty lung cancer studies. A total of 403 KEGG and Biocarta pathways containing 5,555 genes and 58,717 SNPs were included in the study. As a score-based variance-component test, SKAT calculated p values for each pathway set by fitting the null model containing only age, gender, smoking, and first three PCAs. Results:KEGG neuroactive ligand receptor interaction (p=1.18×10-4, FDR=0.0285) and KEGG pancreatic cancer pathways (p=1.41×10-4, FDR=0.0285) were significantly associated with lung cancer. Gene-based analyses found that the most significant genes on the KEGG neuroactive ligand receptor interaction pathway to be CHRNA5 (p=2.33×10-8, FDR=0.0003), CHRNA3 (p=2.85×10-7, FDR=0.0019), and CHRNB4 (p=7.49×10-7, FDR=0.0034), while the most significant genes for KEGG pancreatic cancer pathway to be BRCA2 (p=2.23×10-5, FDR=0.0505). Stratified analyses highlighted five pathways (KEGG intestinal immune network for IGA production, KEGG leishmania infection, KEGG bladder cancer, KEGG pancreatic cancer, and KEGG axon guidance) for squamous cell carcinoma and one pathway (Biocarta ACH pathway) for adenocarcinoma with FWER&amp;lt;0.05. Noteworthy, the most significant gene on ACH pathway for adenocarcinoma was TERT gene, whereas the top two significant pathways for squamous carcinoma shared the most significant HLA-DQA1 gene, along with 11 other HLA genes at 6p21.Conclusion:The results suggest that the underlying pathways differ by cancer cell types and further research should be conducted to investigate the effects of immune pathways and HLA genes on squamous cell carcinoma etiology. Citation Format: Zhihui Wang, Ruyang Zhang, Li Su, Rayjean Hung, Christopher Amos, David C. Christiani. Pathway analysis of OncoArray data identifies biological pathways involved in lung cancer development [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 244.
Abstract LB-015: Differential therapeutic responses of MET oncogenic activations to Met kinase inhibitor and neutralizing antibody
Authors: Jianqun Kou, Ben Staal, Phillip R. Musich, Liang Kang, Yuan Qin, Zhi Q. Yao, Boheng Zhang, Tam Angela, Alan Huang, Huaixiang Hao, George F. Vande Woude, Qian Xie
Journal: Cancer Research (2018)

Abstract Purpose: MET inhibitors are in clinical trials against several cancer types, but the mechanisms toward vulnerability remain elusive. Here we characterized the molecular basis of MET amplification (METamp) and HGF-autocrine driven tumors in response to MET tyrosine kinase inhibitors (TKI) and neutralizing antibodies. Experimental Design: METamp (MKN45 and MHCC97H) and HGF-autocrine activation (JHH5 and U87) cells were treated by the MET kinase inhibitor (INC280) and the anti-MET monoclonal antibody (MetMab) to determine the sensitivity and biological responses in vitro. Tumor inhibition was evaluated in vivo using SCID and SCIDhgf mouse models, respectively. HGF-mediated angiogenesis was measured by using the human endothelial cells (HUVEC) tube formation assay. Results: MKN45 and MHCC97H cells are more sensitive than JHH5 and U87 cells to INC280 treatment but are unresponsive to MetMab. In METamp cells, INC280 induced a DNA damage response with activation of repair through the p53BP1/ATM signaling pathway. Although INC280 and MetMab showed a moderate inhibitory effect on - JHH5 and U87 cells in vitro, both treatments potently suppressed tumor growth in mouse models. We found that HGF stimulation promotes human HUVEC cell tube formation via the Src pathway. INC280 or MetMab inhibited tube formation; thus in HGF-autocrine tumors, the endothelial cells are the secondary targets of tumor-derived HGF and MET inhibition. Conclusion: METamp and HGF-autocrine activation favor different molecular mechanisms, such as a DNA damage response or angiogenesis. Because individual types of MET oncogenic activation may respond to MET inhibitors differently, combination strategies should be developed based upon the molecular subtypes of the tumors. Citation Format: Jianqun Kou, Ben Staal, Phillip R. Musich, Liang Kang, Yuan Qin, Zhi Q. Yao, Boheng Zhang, Tam Angela, Alan Huang, Huaixiang Hao, George F. Vande Woude, Qian Xie. Differential therapeutic responses of MET oncogenic activations to Met kinase inhibitor and neutralizing antibody [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-015.
Intradiscal delivery of celecoxib-loaded microspheres restores intervertebral disc integrity in a preclinical canine model
Authors: A.R. Tellegen, I. Rudnik-Jansen, M. Beukers, A. Miranda-Bedate, F.C. Bach, W. de Jong, N. Woike, G. Mihov, J.C. Thies, B.P. Meij, L.B. Creemers, M.A. Tryfonidou
Journal: Journal of Controlled Release (2018)

Low back pain, related to degeneration of the intervertebral disc (IVD), affects millions of people worldwide. Clinical studies using oral cyclooxygenase-2 (COX-2) inhibitors have shown beneficial effects, although side-effects were reported. Therefore, intradiscal delivery of nonsteroidal anti-inflammatory drugs can be an alternative treatment strategy to halt degeneration and address IVD-related pain. In the present study, the controlled release and biologic potency of celecoxib, a selective COX-2 inhibitor, from polyesteramide microspheres was investigated in vitro. In addition, safety and efficacy of injection of celecoxib-loaded microspheres were evaluated in vivo in a canine IVD degeneration model. In vitro, a sustained release of celecoxib was noted for over 28 days resulting in sustained inhibition of inflammation, as indicated by decreased prostaglandin E2 (PGE2) production, and anti-catabolic effects in nucleus pulposus (NP) cells from degenerated IVDs on qPCR. In vivo, there was no evidence of adverse effects on computed tomography and magnetic resonance imaging or macroscopic evaluation of IVDs. Local and sustained delivery of celecoxib prevented progression of IVD degeneration corroborated by MRI, histology, and measurement of NP proteoglycan content. Furthermore, it seemed to harness inflammation as indicated by decreased PGE2 tissue levels and decreased neuronal growth factor immunopositivity, providing indirect evidence that local delivery of a COX-2 inhibitor could also address pain related to IVD degeneration. In conclusion, intradiscal controlled release of celecoxib from polyesteramide microspheres prevented progression of IVD degeneration both in vitro and in vivo. Follow-up studies are warranted to determine the clinical efficacy of celecoxib-loaded PEAMs in chronic back pain.
Protective Role of Endogenous Erythropoietin System in Nonhematopoietic Cells Against Pressure Overload–Induced Left Ventricular Dysfunction in Mice
Authors: YasuhideAsaumi, YutakaKagaya, MorihikoTakeda, NobuhiroYamaguchi, HirokoTada, KentaIto, JunOhta, TakashiShiroto, KunioShirato, NaokoMinegishi, HiroakiShimokawa
Journal: Circulation (2007)

Background— Erythropoietin (Epo) receptors (EpoRs) are expressed in the heart. We have recently demonstrated that the endogenous Epo-EpoR system plays an important protective role in myocardial ischemia in mice and humans. In the present study, we tested our hypothesis that the endogenous Epo-EpoR system in nonhematopoietic cells also plays a protective role against pressure overload–induced cardiac dysfunction in vivo. Methods and Results— Transgene-rescued EpoR-null mutant mice (EpoR−/−rescued) that express EpoR exclusively in the hematopoietic cells were subjected to transverse aortic constriction (TAC). At 1 week after TAC, left ventricular weight and lung weight were significantly increased in EpoR−/−rescued mice compared with wild-type mice, although the fibrotic area was comparably increased after TAC in the 2 genotypes. In the EpoR−/−rescued mice with TAC, left ventricular end-diastolic diameter was significantly increased, left ventricular fractional shortening was significantly decreased, and su...
Fetuin-A Regulation of Calcified Matrix Metabolism
Authors: WilliJahnen-Dechent, AlexanderHeiss, CoraSchäfer, MarkusKetteler
Journal: Circulation Research (2011)

The final step of biomineralization is a chemical precipitation reaction that occurs spontaneously in supersaturated or metastable salt solutions. Genetic programs direct precursor cells into a mineralization-competent state in physiological bone formation (osteogenesis) and in pathological mineralization (ectopic mineralization or calcification). Therefore, all tissues not meant to mineralize must be actively protected against chance precipitation of mineral. Fetuin-A is a liver-derived blood protein that acts as a potent inhibitor of ectopic mineralization. Monomeric fetuin-A protein binds small clusters of calcium and phosphate. This interaction results in the formation of prenucleation cluster-laden fetuin-A monomers, calciprotein monomers, and considerably larger aggregates of protein and mineral calciprotein particles. Both monomeric and aggregate forms of fetuin-A mineral accrue acidic plasma protein including albumin, thus stabilizing supersaturated and metastable mineral ion solutions as colloids...
Abstract 12622: The Modeling of Werner Syndrome by Induced Pluripotent Stem Cells
Authors: Gakuto Yozu, Shinsuke Yuasa, Chikaaki Motoda, Dai Kusumoto, Akira Kunitomi, Shin Kashimura, Makoto Takei, Masaya Shimojima, Nozomi Hayashiji, Tomohisa Seki, Shugo Tohyama, Koutaro Yokote, Hiroyuki Daita, Keiichi Fukuda
Journal: Circulation (2015)

Backgrounds: Werner syndrome (WS) is a rare autosomal recessive disorder characterized by premature onset of several aging-associated diseases, such as atherosclerosis, diabetes, cancer, and early death. The aging phenotypes of WS is resembling to those of normal aging. To uncover the mechanism of aging, we tried to model WS by patient-specific induced pluripotent stem cells (iPSCs). WS is caused by mutations in WRN gene belonging to the RecQ DNA helicase family which plays a role in genomic stability. But some of WS phenotypes are hardly explained by genomic instability. Thus, we aimed to model WS by patient-specific iPSCs to elucidate the mechanisms. Methods and Results: We sampled T lymphocytes from a patient with WS. Then we transduced with Yamanaka factors (OCT4, SOX2, KLF4, and MYC) by sendai virus, and iPSC colonies were derived. We confirmed that WS-iPSCs expressed pluripotent markers, could differentiate into all three germ-layer derived tissues, and retained a normal karyotype. We could culture WS-iPSCs over 2 years with pluripotent status. Then, we differentiated WS-iPSCs into fibroblasts-like cells. The proliferation rate of WS-iPSC-derived fibroblast-like cells (WS-iPSC-fibroblasts) was significantly decreased. WS-iPSC-fibroblasts showed a vulnerability to cellular stress and resulted in increased cell population which is positive for senescence associated β-galactosidase activity and γ-H2AX foci. Singled WS-iPSC-fibroblasts showed excessive blebbing of plasma membrane and increased apoptosis compared with control-iPSC-fibroblasts. To compare global gene expression profiles, we performed microarray analysis in WS-iPSC-fibroblasts and control-iPSC-fibroblasts. Interestingly, WS-iPSC-fibroblasts reproduced the global gene expression pattern of physiological aging. To confirm whether the phenotypes of WS-iPSCs are induced by WRN mutation, we generated isogenic control of WS-iPSC (corrected-WS-iPSC) by homologous recombination using helper-dependent adenovirus vector. Corrected-WS-iPSCs lost the aging-associated phenotypes but showed the phenotypes resembling to control-iPSCs. Conclusion: We modeled aging phenotypes by WS-specific iPSCs. This model would be utilize for uncovering the aging mechanisms.
Abstract 17826: Frequency and Pattern of Left Ventricular Dysfunction in Potential Heart Transplant Donors
Authors: Burhan Mohamedali, Allan Zelinger
Journal: Circulation (2011)

Cardiac transplantation is a recognized treatment for patients with end stage cardiomyopathy. However, the scarcity of donor hearts remains a limiting factor. In addition, some potential donor hearts may be rejected due to cardiac dysfunction reported on diagnostic imaging by echocardiography or cardiac catheterization. We report a series of 34 consecutive adult organ donors whose hearts were evaluated for LV systolic function. The donors suffered acute, fatal brain injury. 11/34 (32%) had LV systolic dysfunction. Predominate apical, basal, mid-cavity, or global dysfunction patterns were characterized. Serial echocardiograms, when available, were examined. The findings are summarized in the table 1. In our series we noted that serial studies uniformly demonstrated a significant improvement in LV systolic function. Improvement appeared independent of the specific pattern in LV dysfunction or sex. In 27% systolic function completely normalized. No difference between the sex of the donor and the pattern of cardiac dysfunction was seen. In conclusion, our study noted that greater than 30% of screened potential donor hearts have systolic dysfunction. A variable pattern of dysfunction is seen with Global type noted most frequently. Even in hearts with severe initial dysfunction, considerable improvement in EF occurred. Our findings suggest that an initial examination showing LV dysfunction should not exclude a potential heart donor. Reassessment over time and possibly temporizing organ procurement to permit left ventricular function to improve could increase the pool of hearts available for transplantation. Further research into the mechanism underlying transient LV dysfunction in potential heart donor suffering acute, fatal brain injury is warranted.
Heparin Inhibits Ligand Binding to the Leukocyte Integrin Mac-1 (CD11b/CD18)
Authors: KarlheinzPeter, MeikeSchwarz, ChristianConradt, ThomasNordt, MartinMoser, WolfgangKübler, ChristophBode
Journal: Circulation (1999)

Background—The clinical benefits of heparin reach beyond its anticoagulative properties. Recently, it has been described that leukocytes adhere on immobilized heparin mediated by the integrin Mac-1 (CD11b/CD18, αMβ2, or CR3). Because inhibition of this versatile adhesion molecule could explain various aspects of the beneficial clinical effects of heparin, we evaluated whether soluble heparin modulates Mac-1 function in vitro and in vivo. Methods and Results—Binding of unfractionated heparin to Mac-1 on PMA-stimulated monocytes and granulocytes was directly demonstrated in flow cytometry, whereas no binding of heparin was detected on unstimulated leukocytes. Unfractionated heparin inhibited binding of the soluble ligands fibrinogen, factor X, and iC3b to Mac-1. Adhesion of the monocytic cell line THP-1 and of peripheral monocytes and granulocytes to immobilized ICAM-1 was impaired by unfractionated heparin, to the same extent as with inhibition of Mac-1 by monoclonal antibodies such as c7E3. Low-molecular-...