tbuckley/cabot-search huggingface dataset:
Abstract 1246: A family history of CRC confers protection against other cancers in a cohort of patients at risk for CRC
Authors: Martin Tobi, Fadi Antaki, MaryAnn Rambus, Michael Lawson, Daniel Ezekwudo
Journal: Cancer Research (2018)

Abstract Risk for colorectal cancer (CRC) confers susceptibility to other cancers such as small bowel, breast, prostate, and female genital. However, these cancer family histories (F/H) have not been studied systematically. Methods: 1,948 patients at increased CRC risk were followed to determine if the biomarker outcome was related to personal cancer prevalence or a cancer F/H by risk questionnaire which categorized patients as: Group 0 (no family history of cancer), Group 1 (F/H of breast cancer), Group 2 (F/H CRC), and Group 3 (P/H uterine/ovarian cancers). Results: Demographics (age, sex, race, obesity) and NSAID use were similar in all groups and 88% were males. The proportion of cancer incidence in Group 1 is statistically greater [RR 1.36 (1.08-1.72) p = 0.014] compared to group 0 (Figure). Conversely, group 2 had statistically less cancer [RR 0.72 [0.52-0.99], p=0.045]. There was no significance difference between Group 0 and Group 3. About half the tumors in this older group of Veterans were prostatic. There was a wide variety of other cancers. In the entire cohort of the 5 tumors the most common tumor was prostate (n=222) followed by lung (n=61); CRC (n=53); bladder (n=23) and breast (n=20). Conclusions: These differences may be explained by the effect of exosomes which play a major role in CRC and other cancers. Exosomes are nano-lipid particles of 30-100 nm released into the extracellular compartment. The ability of exosomes to facilitate cell-cell communication could be used to inhibit tumorigenic pathways. Exosomes may be endogenous in the case of CRC cell release or exogenous, found in breast milk containing microRNA moieties relevant to inhibition of carcinogenesis of cancers. Many of these mutated genes may inhibit tumorigenic process of cancers thus conferring protection against incipient cancers thus explaining our observation in Group 2. A commonality between CRC and endometrial cancer genetics potentially explains the reduced cancer prevalence in Groups 2 &amp; 3. Breast cancer does not share BRCA “founder genes” with CRC and in contrast to CRC, K-ras mutations are not major events and thus F/H does not confer protection. This hypothesis remains to be proven but in the interim, timely screening for common cancers in patients with a family history of breast cancer may be effective. Citation Format: Martin Tobi, Fadi Antaki, MaryAnn Rambus, Michael Lawson, Daniel Ezekwudo. A family history of CRC confers protection against other cancers in a cohort of patients at risk for CRC [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 1246.
Abstract 17979: Global Metabolomic Profiling in Heart Failure With Preserved Ejection Fraction Identifies Markers of Myocardial Dysfunction
Authors: Lydia C Kwee, Wynn G Hunter, Robert W McGarrah, Jacob P Kelly, Damian Craig, Petia Shipkova, Michael Reily, Jian Chen, Scott Chasalow, Serhiy Hnatyshyn, John Thompson, Peter Gargalovic, Adrian F Hernandez, G M Felker, Eric J Velazquez, William E Kraus, Svati H Shah
Journal: Circulation (2016)

Background: Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous disease felt to be distinct from heart failure with reduced ejection fraction (HFrEF). We hypothesized that met...
Abstract 3528: Anti-CD47 immunotherapy regulates T cell metabolism and hypoxia in the tumor microenvironment
Authors: Yismelin R. Feliz-Mosquea, Elizabeth Stirling, Katherine L. Cook, Adam Wilson, Manish Bharadwaj, Anthony J. Molina, Liliya Yamaleyeva, Pierre L. Triozzi, David R. Soto-Pantoja
Journal: Cancer Research (2018)

Abstract Dysfunction of infiltrating CD8+ effector T cells can be induced by hypoxia and aberrant tumor metabolite uptake in the microenvironment causing an “exhausted” T cell phenotype that limits anti-tumor immunosurveilance. Hence- therapeutic strategies aimed at improving T cell bioenergetics have the potential to reinvigorate T cell responses to reduce tumor burden. CD47 is a widely expressed receptor that controls phagocytic activity by engaging its counter receptor, SIRPα, in macrophages. Also autonomously or by binding to its ligand Thrombospondin-1 CD47 activation can control cell fate under stress. Our prior work shows that targeting CD47 on CD8+ T cells enhanced cytotoxicity against cancer cells. Moreover, depletion of CD8+ T cells in murine models reversed the anti-tumor effect of anti-CD47 therapy. Our new data shows that targeting CD47 reduced the growth of B16 melanoma tumors by approximately 50% (1607 ± 213.7, saline vs. 815.1 ± 67.8, CD47 (-) *p&amp;lt;0.02 n=5-6). Further examination of tumors by live photoacoustic imaging showed that tumors of animals treated with anti-CD47 had reduction in oxygen tension and reduced vascularity when compared to control. This suggests that the reduction in tumor hypoxia by CD47 may shift metabolic competition in the microenvironment to increase metabolite availability allowing optimal activation of cytotoxic T cells. Cell respirometry measurements using an Agilent Seahorse bioanalyzer showed increased levels of mitochondrial function and glycolytic flux in CD47 null T cells when compared to WT. Moreover, these cells showed increased mitochondrial density and increased levels of the mitochondrial biogenesis regulator, PGC1-a. Treatment with CD47 antibody enhanced Pmel-1 CD8+ T cell effector function by reducing B16 melanoma target cell viability by over 60%. Anti-CD47 treatment of these T cells also resulted in upregulation of cell bioenergetics, suggesting that targeting CD47 may impact T cell metabolism to enhance cytotoxic activity against cancer cells. Therefore, our studies show a new role of CD47 immunotherapy regulating immunometabolism of T cells to enhance effector function which may lead to improvement of clinical outcomes in melanoma patients. Citation Format: Yismelin R. Feliz-Mosquea, Elizabeth Stirling, Katherine L. Cook, Adam Wilson, Manish Bharadwaj, Anthony J. Molina, Liliya Yamaleyeva, Pierre L. Triozzi, David R. Soto-Pantoja. Anti-CD47 immunotherapy regulates T cell metabolism and hypoxia in the tumor microenvironment [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 3528.
Reflex Cardiovascular Effects of Epicardial Stimulation by Acetylstrophanthidin in Dogs
Authors: PeterSleight, AmritLall, MartinMuers
Journal: Circulation Research (1969)

Application of 25 to 100 µg of acetylstrophanthidin to the epicardium of the left ventricle of anesthetized and unanesthetized dogs caused hypotension and bradycardia without signs of discomfort. The response developed after an average latency of 8 seconds and lasted up to 12 minutes. Cooling the cervical vagi to 8 to 10°C or prior application of 0.1% procaine hydrochloride to the epicardium of the heart blocked the response. The response was, therefore, a reflex; the sensory receptors were located in the surface layers of the left ventricle. Electrophysiological recordings from single and multifiber preparations of the right recurrent cardiac nerve showed that the receptors for this reflex were mechanoreceptors whose fibers belonged to the C group. The sinus bradycardia caused by digitalis glycosides may result partly from excitation of these receptors.
Abstract 5164: Mechanosensor MYL9 regulates cancer cell malignancy in gastrointestinal tumors
Authors: Masamitsu Konno, Kiminori Yanagisawa, Katsunori Matsushita, Ayumu Asai, Jun Koseki, Michiya Matsusaki, Shinji Deguchi, Yuichiro Doki, Masaki Mori, Hideshi Ishii
Journal: Cancer Research (2018)

Abstract Although the stiffness of tissues likely is involved in the malignant behavior of tumors, it remains to be clarified which molecules control the nature, how it is involved in the invasiveness of tumors, or whether any marker is available for the prediction of cancer patient prognosis. In the present study, we studied the role of Myl9, a non-muscle-type, myosin light chain by the experiment in vitro, and assessed the usefulness in the stratification of patients in vivo as the precision medicine. Given that Myl9 is involved in the contraction of cell skeleton, cell hardness, and alterations of cell morphology in various tissues, we first examined whether the expression of the Myl9 is associated with the clinical status of tumors by immunohistochemistry. The results of 45 cases with colon cancer and pancreatic cancer indicated that the increased expression of Myl9 is associated significantly with a reduced provability of overall survival and disease-free survival of those cancers. Moreover, we noted the differential expression of Myl9 in epithelial cancer cells and mesenchymal fibroblasts, i.e., the accumulation of Myl9 staining in cell nuclei of fibroblasts. The experiment of 3-dimensional culture with cancer cells and fibroblasts confirmed the results. Furthermore, we investigated whether Myl9 overexpression is involved in the biologic behavior of gastrointestinal cancer cells. The results showed that the rentiviral-mediated overexpression of Myl9 resulted in an increase of cell proliferation and invasion as well as tumorigenicity in mice. The present study indicates that Myl9 protein can play a fundamental role in the malignant behaviors of gastrointestinal cancer cells. Citation Format: Masamitsu Konno, Kiminori Yanagisawa, Katsunori Matsushita, Ayumu Asai, Jun Koseki, Michiya Matsusaki, Shinji Deguchi, Yuichiro Doki, Masaki Mori, Hideshi Ishii. Mechanosensor MYL9 regulates cancer cell malignancy in gastrointestinal 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 5164.
Role of hypoxia-induced exosomes in tumor biology
Authors: Chuchu Shao, Fengming Yang, Suyu Miao, Weitao Liu, Chaoshan Wang, Yongqian Shu, Hua Shen
Journal: Molecular Cancer (2018)

Hypoxia is a major regulator of angiogenesis and always influences the release of exosomes in various types of tumors. The present review aimed to assess the role of hypoxia-induced exosomes in the tumor biology. The relevant publications were retrieved from PubMed using keywords such as hypoxia, exosome, extracellular vesicles, tumor, cancer, and other similar terms. Recent studies have shown that cancer cells produce more exosomes under hypoxic conditions than do parental cells under normoxic conditions. The secretion and function of exosomes could be influenced by hypoxia in various types of cancer. Hypoxia-induced exosomes play critical roles in tumor angiogenesis, invasion, metastasis, and the immune system. These findings provide new insights into the complex networks underlying cellular and genomic regulation in response to hypoxia and might provide novel and specific targets for future therapies.
Abstract 823: Anti-melanoma effects of novel Cripto-1 CFC small peptide mimetics
Authors: Emanuela Iaccarino, Gustavo Untiveros, Annamaria Sandomenico, Andrea Caporale, Luisa Calvanese, Lucia Falcigno, Gabriella D'Auria, Menotti Ruvo, Luigi Strizzi
Journal: Cancer Research (2018)

Abstract The diagnosis of melanoma is increasing and current therapies for advanced disease remain unsuccessful. Thus, research aimed at developing novel targeting approaches is needed. Cripto-1 (CR-1), an epidermal growth factor (EGF)-like developmental morphogen, functions as a co-receptor for the tumor growth factor (TGF)-beta related molecule, Nodal. CR-1/Nodal signaling pathways can induce cell survival, proliferation and migration of cancer cells. Studies have shown that Nodal is expressed at high levels in advanced melanoma. CR-1 has also been shown to be expressed in melanoma but limited to a small subpopulation of melanoma cells with more stem cell-like characteristics. Recent work has demonstrated that targeting Nodal in melanoma is associated with reduction of a significant population of melanoma cells. However, a residual population continues to persist. We hypothesize that interference with CR-1/Nodal receptor binding dynamics will negatively affect downstream Nodal-dependent signaling events important for cancer growth and further reduce the number of surviving melanoma cells. To test this hypothesis, we have developed small peptides that mimic CR-1 CFC binding domain and prevent CR-1 from binding to the ALK4 receptor necessary for proper CR-1 co-receptor function for Nodal. We show that in vitro treatment of human melanoma cells with our prototype CFC mimetic B3 reduced melanoma cell viability and negatively affected melanoma cell cycle progression. We also show that treatment with B3 resulted in reduction of active Smad2/3 and ERK1/2, known to be involved in downstream Nodal signaling, as a result of B3 interference with CR-1 co-receptor function. These preliminary data provide the scientific rationale for the development of anti-CR-1 and Nodal therapeutics that can synergize with or complement current treatment approaches in melanoma. Citation Format: Emanuela Iaccarino, Gustavo Untiveros, Annamaria Sandomenico, Andrea Caporale, Luisa Calvanese, Lucia Falcigno, Gabriella D'Auria, Menotti Ruvo, Luigi Strizzi. Anti-melanoma effects of novel Cripto-1 CFC small peptide mimetics [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 823.
Abstract 1591: Cell-free DNA quantification reflects survival in non-small cell lung cancer patients with low metabolic tumor burden
Authors: Myung Han Hyun, Eun Sung Lee, Jae Seon Eo, Jae Sook Sung, Eun Joo Kang, Yoon Jee Choi, Kyong Hwa Park, Sang Won Shin, Sung Yong Lee, Yeul Hong Kim
Journal: Cancer Research (2018)

Abstract We aimed to assess the role of tumor biological behavior/aggressiveness measured by cell-free DNA (cfDNA) quantification according to metabolic tumor burden measured by FDG-PET/CT scan to predict survival of advanced non-small cell lung cancer (NSCLC). Newly-diagnosed eighty-two NSCLC patients with baseline cfDNA quantification and positron emission tomography/computed tomography (PET/CT) scan were prospectively enrolled. The cfDNA level was quantified by Agilent High Sensitivity DNA kit. Metabolic tumor burden was measured by metabolic tumor volume (MTV) and total lesion glycolysis (TLG) from PET/CT scan. The optimal cut-off value for cfDNA quantification, MTV, and TLG were found using X-tile analysis. The high-cfDNA quantification is associated with poor overall survival (OS) (hazard ratio=2.71, 95% confidential interval=1.33-5.52; p=0.006) than that of low. After categorized by metabolic tumor burden, however, the patients with high-MTV showed poor prognosis regardless of cfDNA quantification (low-cfDNA quantification vs high-cfDNA quantification, median OS = 3.9 months vs 7.0 months; p value &amp;gt; 0.05). On the other hands, the patients with high-cfDNA quantification showed poor prognosis in patients with low-MTV (low-cfDNA quantification vs high-cfDNA quantification, median OS = 52.8 months vs 22.9 months; p values &amp;lt; 0.001). According to baseline TLG level, the role of cfDNA quantification to predict survival was similar to MTV. Although cfDNA quantification independent prognostic factors for OS, the significance was disappeared when adjusted by MTV or TLG. This finding provides novel insights that the cfDNA quantification reflect survival for selected patients with low metabolic tumor burden in NSCLC. Citation Format: Myung Han Hyun, Eun Sung Lee, Jae Seon Eo, Jae Sook Sung, Eun Joo Kang, Yoon Jee Choi, Kyong Hwa Park, Sang Won Shin, Sung Yong Lee, Yeul Hong Kim. Cell-free DNA quantification reflects survival in non-small cell lung cancer patients with low metabolic tumor burden [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 1591.
Pivotal Role of Rho-Associated Kinase 2 in Generating the Intrinsic Circadian Rhythm of Vascular Contractility
Authors: ToshiroSaito, MayumiHirano, TomomiIde, ToshihiroIchiki, NoriyukiKoibuchi, KenjiSunagawa, KatsuyaHirano
Journal: Circulation (2013)

Background—The circadian variation in the incidence of cardiovascular events may be attributable to the circadian changes in vascular contractility. The circadian rhythm of vascular contractility is determined by the interplay between the central and peripheral clocks. However, the molecular mechanism of the vascular intrinsic clock that generates the circadian rhythm of vascular contractility still remains largely unknown. Methods and Results—The agonist-induced phosphorylation of myosin light chain in cultured smooth muscle cells synchronized by dexamethasone pulse treatment exhibited an apparent circadian oscillation, with a 25.4-hour cycle length. The pharmacological inhibition and knockdown of Rho-associated kinase 2 (ROCK2) abolished the circadian rhythm of myosin light chain phosphorylation. The expression and activity of ROCK2 exhibited a circadian rhythm in phase with that of myosin light chain phosphorylation. A clock gene, RORα, activated the promoter of the ROCK2 gene, whereas its knockdown ab...
Effect of Hematocrit and Colloid-Induced Changes in Blood Viscosity on Renal Hemodynamics and Renin Release in the Dog
Authors: KEITH M. McDONALD
Journal: Circulation Research (1974)

This study compared the effects on the kidney of two major determinants of blood viscosity, the hematocrit and the plasma colloid content. In anesthetized dogs, blood viscosity was raised 30% by increasing hematocrit or infusing isoncotic Dextran 500 while blood volume was kept constant. Neither form of hyperviscosity altered blood pressure, but both forms caused a decrease of about 35% in cardiac output and a comparable rise in total peripheral resistance. Renal blood flow decreased minimally (&lt;10%) in the group of dogs with increased hematocrit but fell more than 30% in the group given Dextran 500. Reciprocal changes occurred in renal vascular resistance. The increase in hematocrit was accompanied by an increase in renin secretion from 146 units/min to 416 units/min ( P &lt;0.001), but Dextran 500 caused a decrease from 167 units/min to 107 units/min ( P &lt;0.025). Sodium and potassium excretion both decreased similarly in the two groups. The data suggest that increased hematocrits are accompanied by renal vasodilatation so that renal vascular resistance rises less than blood viscosity. Dextran hyperviscosity, however, causes no compensatory vasodilatation. This difference in renal vascular response might explain the difference in renin secretion; afferent arteriolar dilatation might stimulate renin release during a rise in hematocrit, and the absence of vasodilatation in colloid hyperviscosity might explain its failure to stimulate renin.
Abstract 14331: Role for HDAC6 in Pulmonary Arterial Hypertension
Authors: Sophie Chabot, Grégoire Ruffenach, Sandra Breuils-Bonnet, Eve Tremblay, Olivier Boucherat, Sébastien Bonnet, Steeve Provencher
Journal: Circulation (2015)

Background: Pulmonary arterial smooth muscle cells (PASMCs) from pulmonary arterial hypertension (PAH) patients exhibit a pro-proliferative, pro-migratory and anti-apoptotic phenotype mediated, at least in part, by survivin overexpression, leading to the development of progressive pulmonary artery (PA) remodeling. This results in right ventricle (RV) hypertrophy and failure. For many years, the cytoplasmic class IIb histone deacetylase 6 (HDAC6), which mainly functions as a α-tubulin deacetylase has been understudied. Several cancer studies have demonstrated that HDAC6 cooperates with the Heat Shock Protein 90 (HSP90) and regulates many signaling pathways involved in cancer and PAH development. In the cardiovascular field, HDAC6 upregulation has been associated with heart failure. We hypothesized that specific HDAC6 inhibition corrects the abnormal phenotype of PAH-PASMCs and improves RV function. Method/Results: Using a multidisciplinary and translational approach, we demonstrated that both HDAC6 and HSP90 are upregulated (Wb; p&lt;0.01) in the lungs, distal PAs, and PASMCs from PAH patients (n=5) compared to controls (n=5). HDAC6 inhibition using Tubastatin A dose-dependently increased α-tubulin acetylation and decreased PAH-PASMC migration (scratch test; p&lt;0.05), apoptosis resistance (Annexin-V; p&lt;0.05) and proliferation (Ki67; p&lt;0.01). Tubastatin A also reduced the expression of survivin in PAH-PASMCs (Wb). Similar effects were observed after HSP90 inhibition with AT13387, which also reduced HDAC6 expression in PAH-PASMCs (Wb) suggesting that a HSP90-dependent mechanism may account for HDAC6 upregulation. Within the heart, HDAC6 was exclusively expressed in human decompensated RV from PAH patients (n=5) and not in control RV (Wb, p&lt;0.01). Conclusion: We provide evidence that HSP90 and HDAC6 are upregulated in human PAH and contribute to the proliferative, migratory and anti-apoptotic phenotype of PAH-PASMCs. Moreover, HDAC6 is specifically increased in the RV of PAH patients, suggesting that specific HDAC6 inhibition may represent a novel and attractive target in PAH for the treatment of both PA remodeling and RV failure. The therapeutic potential of HDAC6 inhibition in a PAH rat model is currently under investigation.
Morning Hypercoagulability and Hypofibrinolysis
Authors: StylianosKapiotis, BerndJilma, PeterQuehenberger, KatharinaRuzicka, SylviaHandler, WolfgangSpeiser
Journal: Circulation (1997)

Background Diurnal fluctuations of blood coagulation and fibrinolysis activity are thought to play a role in the observed circadian variation in the frequency of onset of acute cardiovascular events. In the present study, the diurnal variations in blood coagulation and fibrinolysis activity were investigated in 10 young, healthy control subjects by use of specific molecular activation markers. Methods and Results The plasma levels of activated factor FVII (FVIIa), the active portion of the main coagulation activator, decreased during the day (8 am: 2.03 ng/mL, CI 1.16 to 2.88 ng/mL; 8 pm: 1.16 ng/mL, CI 0.81 to 1.5 ng/mL; P=.005), whereas FVII antigen did not change significantly. In parallel with the diurnal variations of FVIIa, we found a decrease of prothrombin fragment F1+2 (8 am: 0.97 nmol/L, CI 0.79 to 1.15 nmol/L; 8 pm: 0.78 nmol/L, CI 0.64 to 0.93 nmol/L; P=.005), a molecular marker of intravasal thrombin generation. Evidence for a possible functional relevance of circulating FVIIa was found becau...