tbuckley/cabot-search huggingface dataset:
Visit-to-Visit Blood Pressure Variability, Carotid Atherosclerosis, and Cardiovascular Events in the European Lacidipine Study on Atherosclerosis
Authors: GiuseppeMancia, RitaFacchetti, GianfrancoParati, AlbertoZanchetti
Journal: Circulation (2012)

Background—In high-cardiovascular-risk treated hypertensive patients, the incidence of cardiovascular events has been reported to relate to visit-to-visit blood pressure (BP) variability. We investigated whether visit-to-visit BP variability is prognostically important in treated mildly to moderately hypertensive patients in whom treatment aims at avoiding events but also at preventing or delaying progression of organ damage. Methods and Results—We analyzed the pooled data from the European Lacidipine Study on Atherosclerosis (ELSA), a randomized, double-blind 4-year trial of the effect of lacidipine or atenolol on echographic carotid intima-media thickness. Visit-to-visit BP variability was assessed by the coefficient of variation or the SD of the mean on-treatment systolic BP (SBP) obtained at 6- (clinic BP) and 12- (24 hours BP) month intervals, respectively (1521 and 1264 patients, respectively). In a multivariable linear regression model, mean on-treatment clinic or 24-hour SBP, but not SBP coefficie...
Interferon‐γ–Mediated Immunopathology Potentiated by Toll‐Like Receptor 9 Activation in a Murine Model of Macrophage Activation Syndrome
Authors: Lehn K. Weaver, Niansheng Chu, Edward M. Behrens
Journal: Arthritis & Rheumatology (2018)

Objective Macrophage activation syndrome (MAS) is a life‐threatening cytokine storm syndrome that occurs in patients with underlying rheumatic diseases. Preclinical and clinical data suggest that interferon‐γ (IFNγ) is pathogenic in MAS, but how IFNγ may be linked to disease pathogenesis remains unknown. This study was undertaken to determine whether IFNγ signals synergize with systemic innate immune responses to drive the cytokine storm in a murine model of MAS. Methods IFNγ‐deficient mice were treated with 5 doses of the Toll‐like receptor 9 (TLR‐9) agonist CpG 1826, IFNγ, or a combination of the 2 stimuli over the course of 10 days. Immunopathologic features of MAS, including cytopenias, hepatitis, hepatosplenomegaly, and induction of inflammatory myelopoiesis, were assessed. Mixed bone marrow chimeras were created to determine whether TLR‐9– and IFNγ receptor 1 (IFNγR1)–dependent signals induce enhanced myelopoiesis in a cell‐intrinsic or cell‐extrinsic manner. Results IFNγ‐deficient mice did not develop features of MAS when treated with repeated doses of either the TLR‐9 agonist or IFNγ alone. In contrast, IFNγ‐deficient mice treated with both the TLR‐9 agonist and IFNγ developed cytopenias, hepatitis, and hepatosplenomegaly, reproducing major clinical features of MAS. TLR‐9– and IFNγR1‐dependent signals synergized to enhance myeloid progenitor cell function and induce myelopoiesis in vivo, which occurred through cell‐extrinsic mechanisms and correlated with the induction of disease. Conclusion These findings demonstrate that TLR‐9–driven signals potentiate the effects of IFNγ to initiate murine MAS, and provide evidence that induction of inflammatory myelopoiesis is a common TLR‐9– and IFNγ‐dependent pathway that may contribute to the pathogenesis of MAS.
Influence of Pituitary, Thyroid, and Adrenal Hormones on Norepinephrine Turnover and Metabolismin the Rat Heart
Authors: Lewislandsberg, Juliusaxelrod
Journal: Circulation Research (1968)

Norepinephrine turnover was estimated in the rat heart from the rate of release of tracer 3H-norepinephrine and the depletion of endogenous norepinephrine after inhibition of synthesis. Cardiac norepinephrine turnover was markedly increased in chronically hypophysectomized rats. Thyroidectomy and adrenalectomy were also associated with increased cardiac norepinephrine turnover, whereas ovariectomy was not. Chronic treatment of hypophysectomized rats with thyroxine and ACTH restored the turnover to normal, the replacement of thyroxine being quantitatively more significant. Cardiac atrophy and decreased blood pressure occurred concomitantly with increased norepinephrine turnover in the hypophysectomized rat and were restored to normal with thyroid treatment. Ganglionic blockade of the hypophysectomized rat also restored the turnover toward normal. The metabolites of 3H-norepinephrine were shifted with a decrease in O-methylated metabolites and an increase in deaminated products. This evidence suggests that ...
Abstract 4503: The paracrine role of p53 in skin
Authors: Tamara Terzian, Nema Sobhani, Rohan Mylavarapu, Manale El Kharbili, Andrew Parker, Colleen Little, Ethan Krauspe, Neil Box
Journal: Cancer Research (2018)

Abstract Exposure to ultraviolet radiation (UVR) in sunlight activates both defensive and repair pathways in the skin. As the major cell type affected by UVR, keratinocytes coordinate critical aspects of the skin response. Molecularly, the transcription factor p53 is induced by UVR in keratinocytes leading to their cell death by apoptosis (peeling). p53 also stimulates the expression of paracrine melanocyte growth factors involved in tanning defined as increase in melanocyte proliferation and melanin synthesis. Here, we investigate the less defined role of p53 in tanning. For this, we use a mouse model that has high p53 levels in keratinocytes and presents with elevated melanocyte number and melanin production. Interestingly, loss of p53 in keratinocytes completely abrogates the hyperpigmentation phenotype. These data demonstrate in a powerful way the paracrine role of p53 expressed in keratinocytes on melanocyte behavior and function. Moreover, it provides an excellent tool to examine molecular and cellular changes that accompany the melanocyte response to sunburn. Sunburn increases melanoma risk in epidemiological studies. To elucidate the role of the p53 response in melanoma, we treated mice with “sunburning” doses of UVB and followed melanocyte proliferation and the expression of keratinocyte-induced melanocyte growth factors. We present our latest findings reinforcing the signs of cross-talk between keratinocytes and melanocytes which support a paracrine role for p53 expressed in keratinocyte on promoting melanocyte proliferation through the release of paracrine factors. Citation Format: Tamara Terzian, Nema Sobhani, Rohan Mylavarapu, Manale El Kharbili, Andrew Parker, Colleen Little, Ethan Krauspe, Neil Box. The paracrine role of p53 in skin [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 4503.
The Origin of an Immediate Diastolic Murmur in Atrioventricular Defects
Authors: Janesomerville, Leonresnekov
Journal: Circulation (1965)

The origin of an audible immediate diastolic murmur in 10 of 22 patients with atrioventricular defects was investigated by intracardiac phonocardiography. It was shown to arise at the site of the atrial septal defect, and all other possible causes of such a murmur were excluded. The production of the murmur depended on the combination of mitral regurgitation and an atrial septal defect of such a size as to permit an interatrial pressure gradient in early diastole.
Takayasu's Arteritis
Authors: Kikunakao, Masaoikeda, Shin-Ichikimata, Hirokazuniitani, Mitsuomiyahara, Zen-Ichiishimi, Kunitakehashiba, Yoshiyukitakeda, Toshioozawa, Satorumatsushita, Moriokuramochi
Journal: Circulation (1967)

The manifestations of Takayasu's arteritis of the aorta were studied in 84 patients. The extent of the involvement of the aorta was classified on aortographic examination in 54 patients and from the clinical manifestations in 30. Involvement of the aorta was classified as: (1) arch type in 47 cases; (2) extensive type (whole aorta and its branches involved) in 27 cases; and (3) descending thoracic and abdominal type (only descending thoracic and abdominal aortas involved) in 10 cases. The three types resembled one another in clinical manifestations and laboratory findings except for ischemic signs which varied with the type of lesion and a slight difference in the ratio of male to female patients. Generalized, cardiac and pulmonary symptoms were noted by about two thirds of the patients in the early stage. About one third complained of local pain. The erythrocyte sedimentation rate and C-reactive protein were high values during the active stage of this disease. The hemagglutination test using tannic acid-...
Brugada Syndrome Behind Complete Right Bundle-Branch Block
Authors: YoshiyasuAizawa, SeijiTakatsuki, MotoakiSano, TakehiroKimura, NobuhiroNishiyama, KotaroFukumoto, YokoTanimoto, KojiroTanimoto, MitsushigeMurata, TakashiKomatsu, HideoMitamura, SatoshiOgawa, ToshikazuFunazaki, MasahitoSato, YoshifusaAizawa, KeiichiFukuda
Journal: Circulation (2013)

Background—The characteristic ECG of Brugada syndrome (BS) can be masked by complete right bundle-branch block (CRBBB) and exposed by resolution of the block or pharmacological or pacing maneuvers. Methods and Results—The study consisted of 11 patients who had BS and CRBBB. BS was diagnosed before the development of CRBBB, on the resolution of CRBBB, or from new characteristic ST-segment changes that could be attributable to BS. Structural heart diseases were excluded, and coronary spasm was excluded on the basis of a provocation test at catheterization. In 7 patients, BS was diagnosed before the development of CRBBB. BS was diagnosed when CRBBB resolved spontaneously (n=1) or by right ventricular pacing (n=3). The precipitating cause for the spontaneous resolution of CRBBB, however, was not apparent. On repeated ECGs, new additional upward-convex ST-segment elevation was found in V2 or V3 in 3 patients. In 2 patients, new ST-segment elevation was induced by class IC drugs. The QRS duration was more prolo...
Abstract LB-353: Spatiotemporal quantification of tumor-associated tertiary lymphoid structures in murine lung adenocarcinoma
Authors: Mursal Nader, Nikhil S. Joshi
Journal: Cancer Research (2018)

Abstract In many human cancer types (i.e., lung, breast, melanoma), infiltrating immune cells are found in complex, lymph node (LN)-like structures known as the tumor-associated tertiary lymphoid structures (TA-TLSs). TA-TLSs are associated with longer patient survival and perform critical functions of LNs such as facilitating recruitment of T cells into the tumor microenvironment, mediating interactions between T cells and tumor-antigen presenting dendritic cells (DCs), and enabling local activation of T cells. Furthermore, using a genetically engineered mouse model (GEMM) of lung adenocarcinoma, we have previously shown that TA-TLSs form as tumors develop and that therapeutically depleting regulatory T cells (Tregs) from TA-TLSs elicits the anti-tumor immune response and results in tumor destruction. Hence, a powerful anti-tumor immune response can be both stimulated and suppressed in TA-TLSs, suggesting that therapeutically targeting the formation and maintenance of TA-TLSs would result in strong anti-tumor outcomes. Understanding how TLS formation is altered by experimental manipulation requires quantitative spatial and temporal analysis of the location, number, and size of TLSs in the tumor-bearing lung. Visualizing the presence of TA-TLSs throughout a tumor-bearing lung lobe presents several technical challenges, thus we have developed a high throughput immunofluorescence (IF) analysis pipeline for visualization and quantification of TA-TLSs in our model. This streamlined process requires 1-2 weeks per lung lobe. We are analyzing tertiary lymphoid structures in influenza-infected mice as a comparison to tumor-associated TLSs. Here, we hypothesize that there are key differences in the location and composition of influenza associated TLSs and TA-TLSs, which will provide substantial mechanistic insight into the biology and formation of TLSs. Using this spatiotemporal quantification technique, detailed interrogation of TLSs in lung adenocarcinoma will provide cellular and molecular targets for therapeutic modulation of TA-TLSs. Furthermore, this method can be expanded and adapted for the study of TA-TLSs in other disease models. Citation Format: Mursal Nader, Nikhil S. Joshi. Spatiotemporal quantification of tumor-associated tertiary lymphoid structures in murine lung adenocarcinoma [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-353.
Abstract 48: Acid ceramidase inhibition: A targeted therapy for acute myeloid leukemia
Authors: Jennifer M. Pearson, Su-Fern Tan, Arati Sharma, Todd E. Fox, Jose Luis Abad, Gemma Fabrias, David F. Claxton, David J. Feith, Mark Kester, Thomas P. Loughran
Journal: Clinical Cancer Research (2017)

Abstract Acute myeloid leukemia (AML) is a disease characterized by uncontrolled proliferation of immature myeloid cells in the blood and bone marrow. Patient 5-year survival rate is only 26%, and there have been no significant treatment advances for decades. Therefore, there is an urgent need to identify novel therapeutic targets. We have previously shown that acid ceramidase (AC) is upregulated in AML and high AC activity correlates with poor patient survival. We continue to validate AC as a potential therapeutic target in AML through inhibitor screening and characterization. We utilize viability assays, enzyme activity assays, Western blotting, qPCR, lipidomics, and flow cytometry to examine the effects of inhibitors on AML cell lines, patient samples, and normal controls. We have found that a newly developed selective AC inhibitor, SACLAC, significantly reduces viability of AML cells with an EC50 of approximately 3 μM, with limited effect on normal cells at an EC50 of approximately 13 μM. Treatment of AML cell lines with SACLAC effectively blocks AC activity, induces a drastic decrease of sphingosine 1-phosphate, and a 2.5-fold increase in total ceramide levels. Ongoing studies continue to explore the mechanistic basis for the loss of viability. These data support the investigation of AC as a therapeutic target in AML and define SACLAC as a potent and selective inhibitor that presents promise for preclinical studies and future clinical development. Citation Format: Jennifer M. Pearson, Su-Fern Tan, Arati Sharma, Todd E. Fox, Jose Luis Abad, Gemma Fabrias, David F. Claxton, David J. Feith, Mark Kester, Thomas P. Loughran, Jr.. Acid ceramidase inhibition: A targeted therapy for acute myeloid leukemia [abstract]. In: Proceedings of the Second AACR Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; May 6-9, 2017; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(24_Suppl):Abstract nr 48.
Identification of Functional Variants in the <i>FAM13A</i> Chronic Obstructive Pulmonary Disease Genome-Wide Association Study Locus by Massively Parallel Reporter Assays
Authors: Peter J. Castaldi, Feng Guo, Dandi Qiao, Fei Du, Zun Zar Chi Naing, Yan Li, Betty Pham, Tarjei S. Mikkelsen, Michael H. Cho, Edwin K. Silverman, Xiaobo Zhou
Journal: American Journal of Respiratory and Critical Care Medicine (2018)

The identification of causal variants responsible for disease associations from genome-wide association studies (GWASs) facilitates functional understanding of the biological mechanisms by which those genetic variants influence disease susceptibility.
Abstract PR14: Immune cell transcript levels, metastatic progression, and survival in osteosarcoma: A comparative transcriptome analysis
Authors: Milcah Scott, Nuri Temiz, Anne Sarver, Rebecca LaRue, Susan Rathe, Jyotika Varshney, Natalie Wolf, Branden Moriarity, Timothy Obrien, Logan Spector, David Largaespada, Jaime Modiano, Subbaya Subramanian, Aaron Sarver
Journal: Clinical Cancer Research (2018)

Abstract Background: Human osteosarcoma (OS) is a rare bone disease primarily affecting children and adolescents that has proven challenging to study, due both to its rarity and its genetic heterogeneity. OS is very common in large-breed dogs and can be genetically induced in mice, making the disease ideal for comparative genomic analyses across species. The overall survival rate of patients with OS is ~60% in patients under 30 years old and only ~30% for patients aged 50 years or older---rates that have not significantly improved over the past two decades. Understanding how intertumor transcriptional variation is conserved across species and associated with progression to metastasis resulting in patient death will enable us to more efficiently develop effective strategies to manage OS and improve therapy. Methods and Findings: Transcriptional profiles of OS tumors and cell lines derived from humans (n=49), mice (n=103), and dogs (n=34) were generated using RNA sequencing. We identified conserved intertumor transcriptional variation present in tumor sets from all 3 species, comprising gene clusters associated with cell cycle/mitosis and with the presence/absence of immune cells. Further, we developed a novel Gene Cluster Expression Summary Score (GCESS) technique to quantify intertumor transcriptional variation and demonstrate that these GCESS values are associated with patient outcome. Specifically, we show that human OS tumors with GCESS values indicative of decreased immune cell presence are associated with metastasis and poor survival. These results were validated in an independent human OS tumor cohort and in 15 different tumor data sets obtained from The Cancer Genome Atlas (TCGA). Conclusions: Utilizing GCESS-based analyses of primary OS tumors to characterize the extent to which immune cells are absent and the tumor cells are undergoing mitosis may provide key information to identify novel drug targets, better inform therapeutic decisions, and improve overall survival for OS patients. This abstract is also being presented as Poster A07. Citation Format: Milcah Scott, Nuri Temiz, Anne Sarver, Rebecca LaRue, Susan Rathe, Jyotika Varshney, Natalie Wolf, Branden Moriarity, Timothy Obrien, Logan Spector, David Largaespada, Jaime Modiano, Subbaya Subramanian, Aaron Sarver. Immune cell transcript levels, metastatic progression, and survival in osteosarcoma: A comparative transcriptome analysis [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr PR14.
Relating tissue selenium to anthropometric and receptor status in Nigerian patients with breast cancer.
Authors: Olusegun Isaac Alatise, Ganiyat Oluwatoyin Omoniyi-Esan, Olukayode O Lawal, Abdulrusheed Kayode Adesunkanmi, Augustine Agbakwuru
Journal: Journal of Clinical Oncology (2012)

e12022 Background: The aim of this study was to identify the relationship of tissue selenium to anthropometric data and receptors status among Nigerian women with breast cancer. Methods: Consecutive consenting patients who had histologically confirmed breast cancer and fibroadenoma at Obafemi Awolowo University Teaching Hospital Complex, Ile-Ife, were recruited for the study. One gram of disease breast tissue was taken for selenium analysis from the subjects. The specimens were analyzed using graphite furnace atomic absorption spectrometer. Subjects’ demographics, anthropometric and breast cancer receptor status were recorded on a standard proforma. Results: There were 127 female subjects in the 2 groups. There were 95 (74.8%) cases of fibroadenoma and 32 (25.2%) of breast cancer. While the median tissue level of selenium in patients with fibroadenoma was 0.0272mg/g with a range of 0.0124 to 0.0576mg/g. The median tissue level of selenium in patients with breast cancer was 0.0178mg/g with a range 0.0072 to 0.0436mg/g. This was statistically significant (r=-0.613; p=0.0001). The anthropometric data of the patients such as weight, height, body mass index (BMI), body surface area, mid upper arm circumference and waist over hip ratio were correlated with tissue level of selenium and only waist over hip ratio and mid upper arm circumference were statistically significant (p&lt;0.0001, 0.049 respectively). When association of the breast cancer receptor status was tested against the tissue level of selenium, while the ER and PR receptors were significantly related to tissue level of selenium (F= 41.765, p= &lt;0.0001; F= 3.904, p=0.021), the HER receptor status was not (F= 1.100, p= 0.467).There was negative correlation between the tissue selenium and waist over hip ratio as well as tissue estrogen receptors status. Conclusions: Tissue selenium in patients with breast cancer was significantly low than that of fibroadenoma group. Similarly, tissue selenium is inversely related to waist over hip ratio and estrogen receptor status in subjects with breast cancer. It therefore implies that low tissue selenium may be an underlying factor in the occurrence of breast cancer in Nigeria.
Measurement and Significance of Cancellation Potentials on the Human Subject
Authors: Ernestfrank
Journal: Circulation (1955)

A versatile four-electrode single-channel system is described which is useful for precise research measurements of mirror patterns on the intact human subject, and the theoretic significance of results obtained on normal subjects for the QRS complex is presented in detail. It is concluded that the QRS complex at all points on the body of normal human subjects, including the precordium, can be considered to arise from a fixed-location equivalent heart dipole to an average accuracy of 5 per cent. Therefore, the proximity potential concept is untenable for the normal QRS complex.