tbuckley/cabot-search huggingface dataset:
Experimental Graft Coronary Artery Disease in a Murine Heterotopic Cardiac Transplant Model
Authors: ToshiroHirozane, AkiraMatsumori, YutakaFurukawa, ShigetakeSasayama
Journal: Circulation (1995)

Background The development of immunosuppressive therapy has brought about a remarkable decrease in the risk of acute cardiac allograft rejection; however, the major cause of patient death or retransplantation after the first postoperative year is coronary artery disease (CAD) in the graft. The pathogenesis and management of CAD are still not clearly established. Methods and Results To make an animal model of CAD, we performed primary vascularized heterotopic cardiac transplantation using mice. Inbred strains, sharing major histocompatibility antigens but differing in minor antigens, were selected. DBA/2 mice (H-2d) served as donors and B10.D2 mice (H-2d) as recipients. Viability of the cardiac grafts was assessed by abdominal palpation. Eight of twelve cardiac allografts (67%) survived for 10 weeks after operation without any immunosuppressive therapy. Allografts rejected within 4 weeks showed acute rejection histologically, whereas allografts surviving more than 4 weeks displayed intimal hyperplasia in t...
Abstract 3682: Expression levels of genes in primary melanoma associated with clinically meaningful characteristics
Authors: Marianne Berwick, Ivan P. Gorlov, Irene Orlow, Carol Ringelberg, Marc Ernstoff, Joel Parker, Meg Gerstenblith, Cheryl Thompson, Eva Hernando, Klaus Busam, Cecilia Lezcano, Sergio Corrales, Siok Leong, Nancy E. Thomas, Christopher I. Amos
Journal: Cancer Research (2018)

Abstract Melanoma survival appears to be improving; however, between 13-68% of individuals with melanoma diagnosed with Stages II-III ultimately die from their melanoma. Factors influencing melanoma survival include sex, age, clinical stage, lymph node involvement and several primary tumor characteristics, such as Breslow thickness, presence of infiltrating lymphocytes (TILs), mitotic rate and ulceration. Identification of genes whose expression in primary tumors is associated with these key tumor/patient characteristics can shed light on molecular mechanisms of melanoma survival. Here we show results from a gene expression analysis of 32 formalin-fixed, paraffin embedded (FFPE) primary melanomas with extensive clinical annotation. We extracted RNA, and measured the expression of 760 genes selected based on published evidence of association with melanoma initiation or outcome using NanoString. The Cancer Genome Atlas (TCGA) data on primary melanomas was used for validation of nominally significant associations. We identified 5 genes that were significantly associated with the presence of TILs in the combined analysis of both datasets after adjustment for multiple testing using the Benjamini-Hochberg false discovery rate method: IL1R2, PPL, PLA2G3, RASAL1, and SGK2. We also identified two genes significantly associated with lymph node status (PIK3CG and IL2RA), and two genes significantly associated with sex (KDM5C and KDM6A). We found that LEF1 was significantly associated with Breslow thickness and CCNA2 with mitosis. These results demonstrate that genetic expression in primary tumors is associated with clinically meaningful characteristics of cutaneous melanoma. Citation Format: Marianne Berwick, Ivan P. Gorlov, Irene Orlow, Carol Ringelberg, Marc Ernstoff, Joel Parker, Meg Gerstenblith, Cheryl Thompson, Eva Hernando, Klaus Busam, Cecilia Lezcano, Sergio Corrales, Siok Leong, Nancy E. Thomas, Christopher I. Amos. Expression levels of genes in primary melanoma associated with clinically meaningful characteristics [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 3682.
Phase I Study of the Investigational Aurora A Kinase Inhibitor Alisertib plus Rituximab or Rituximab/Vincristine in Relapsed/Refractory Aggressive B-cell Lymphoma
Authors: Kevin R. Kelly, Jonathan W. Friedberg, Steven I. Park, Kevin McDonagh, John Hayslip, Daniel Persky, Jia Ruan, Soham Puvvada, Peter Rosen, Swaminathan Padmanabhan Iyer, Alexandra Stefanovic, Steven H. Bernstein, Steven Weitman, Anand Karnad, Gregory Monohan, Ari VanderWalde, Raul Mena, Monika Schmelz, Catherine Spier, Susan Groshen, Karthik Venkatakrishnan, Xiaofei Zhou, Emily Sheldon-Waniga, E. Jane Leonard, Daruka Mahadevan
Journal: Clinical Cancer Research (2018)

The aurora A kinase inhibitor alisertib demonstrated single-agent clinical activity and preclinical synergy with vincristine/rituximab in B-cell non-Hodgkin lymphoma (B-NHL). This phase I study aimed to determine the safety and recommended phase II dose (RP2D) of alisertib in combination with rituximab ± vincristine in patients with relapsed/refractory aggressive B-NHL.Patients with relapsed/refractory, diffuse, large, or other aggressive B-NHL received oral alisertib 50 mg b.i.d. days 1 to 7, plus i.v. rituximab 375 mg/m2 on day 1, for up to eight 21-day cycles (MR). Patients in subsequent cohorts (3 + 3 design) received increasing doses of alisertib (30 mg starting dose; 10 mg increments) b.i.d. days 1 to 7 plus rituximab and vincristine [1.4 mg/m2 (maximum 2 mg) days 1, 8] for 8 cycles (MRV). Patients benefiting could continue single-agent alisertib beyond 8 cycles. Cell-of-origin and MYC/BCL2 IHC was performed on available archival tissue.Forty-five patients participated. The alisertib RP2D for MR was 50 mg b.i.d. For MRV (n = 32), the RP2D was determined as 40 mg b.i.d. [1 dose-limiting toxicity (DLT) at 40 mg; 2 DLTs at 50 mg]. Drug-related adverse events were reported in 89% of patients, the most common was neutropenia (47%). Seven patients had complete responses (CR), 7 had partial responses (PRs); 9 of 20 (45%) patients at the MRV RP2D responded (4 CRs, 5 PRs), all with non-germinal center B-cell (GCB) diffuse large B-cell lymphoma (DLBCL).The combination of alisertib 50 mg b.i.d. plus rituximab or alisertib 40 mg b.i.d. plus rituximab and vincristine was well tolerated and demonstrated activity in non-GCB DLBCL.
Structural Changes of Atrial Myocardium due to Sustained Atrial Fibrillation in the Goat
Authors: JannieAusma, MauritsWijffels, FredThoné, LucWouters, MauritsAllessie, MarcelBorgers
Journal: Circulation (1997)

Background After cardioversion of sustained atrial fibrillation (AF), the electrical and contractile functions of the atria are impaired, and recurrences of AF frequently occur. Whether remodeling of the structure of atrial myocardium is the basis for this problem is not known. Methods and Results Sustained AF was induced by electrical pacing in 13 goats instrumented long-term. The goats were killed after 9 to 23 weeks, and the atrial myocardium was examined by light and electron microscopy. The changes were quantified in left and right atrial free walls, appendages, trabeculae, the interatrial septum, and the bundle of Bachmann. A substantial proportion of the atrial myocytes (up to 92%) revealed marked changes in their cellular substructures, such as loss of myofibrils, accumulation of glycogen, changes in mitochondrial shape and size, fragmentation of sarcoplasmic reticulum, and dispersion of nuclear chromatin. These changes were accompanied by an increase in size of the myocytes (up to 195%). There we...
Abstract 2094: Pathology beyond 2D: Imaging and analysis of cells and the tumor microenvironment in three dimensions
Authors: James R. Mansfield, James Wainright, Christopher Bagnall, Geraint Wilde, Meredith Price, Benjamin E. Willcox, Mark Browne
Journal: Cancer Research (2018)

Abstract The success of cancer immunotherapy treatments and the development of immuno-oncology into the “fifth pillar” of cancer treatment has fueled a rapid growth in interest into methodologies that investigate immune cells in the context of the tumor microenvironment. However, nearly all technologies that investigate the immune contexture of tumors either rely on homogenization or disaggregation of the sample and the concomitant loss of spatial relationships, or rely on a thin section (5 um or less), two-dimensional sample of a biopsy, which is a poor representation of an inherently three-dimensional structure. An image of a thin section will tend to over-estimate the numbers of proximal cells and underestimate the numbers of more distant cells due to sampling error. To address this, we have implemented an imaging system capable of 3D confocal and super-resolution imaging, tiling of large sample areas and imaging samples over time along with software for the visualization and analysis of the datasets. We present here a series of examples showing the utility of 3D fluorescence imaging of labeled cells in thick (ca. 50 micron) FFPE tissue sections. By using a multimarker immunostaining scheme, this enables the phenotyping of cells within the tumor microenvironment and the calculation of distance metrics between cells in three dimensions. This methodology is an inherently better means of assessing cellular distributions in the tumor microenvironment and can give a much better representation of the complicated 3D structure of a tumor than imaging of thin sections. Citation Format: James R. Mansfield, James Wainright, Christopher Bagnall, Geraint Wilde, Meredith Price, Benjamin E. Willcox, Mark Browne. Pathology beyond 2D: Imaging and analysis of cells and the tumor microenvironment in three dimensions [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 2094.
Extrinsic Compression of the Left Anterior Descending Coronary Artery by Rib in a Patient With Progressive Left Ventricular Remodeling
Authors: Jin-SunPark, Hyoung-MoYang, Seung-JeaTahk, Dai-YeolJoe, Xiong JieJin, Hong-SeokLim, Byoung-JooChoi, So-YeonChoi, Myeong-HoYoon, Gyo-SeungHwang, Joon-HanShin
Journal: Circulation (2012)
Atrial Fibrillation Begets Heart Failure and Vice Versa
Authors: Rajalakshmi Santhanakrishnan, Na Wang, Martin G. Larson, Jared W. Magnani, David D. McManus, Steven A. Lubitz, Patrick T. Ellinor, Susan Cheng, Ramachandran S. Vasan, Douglas S. Lee, Thomas J. Wang, Daniel Levy, Emelia J. Benjamin, Jennifer E. Ho
Journal: Circulation (2016)

Atrial fibrillation (AF) and heart failure (HF) frequently coexist and together confer an adverse prognosis. The association of AF with HF subtypes has not been well described. We sought to examine differences in the temporal association of AF and HF with preserved versus reduced ejection fraction.We studied Framingham Heart Study participants with new-onset AF or HF between 1980 and 2012. Among 1737 individuals with new AF (mean age, 75±12 years; 48% women), more than one third (37%) had HF. Conversely, among 1166 individuals with new HF (mean age, 79±11 years; 53% women), more than half (57%) had AF. Prevalent AF was more strongly associated with incident HF with preserved ejection fraction (multivariable-adjusted hazard ratio [HR], 2.34; 95% confidence interval [CI], 1.48-3.70; no AF as referent) versus HF with reduced ejection fraction (HR, 1.32; 95% CI, 0.83-2.10), with a trend toward difference between HF subtypes (P for difference=0.06). Prevalent HF was associated with incident AF (HR, 2.18; 95% CI, 1.26-3.76; no HF as referent). The presence of both AF and HF portended greater mortality risk compared with neither condition, particularly among individuals with new HF with reduced ejection fraction and prevalent AF (HR, 2.72; 95% CI, 2.12-3.48) compared with new HF with preserved ejection fraction and prevalent AF (HR, 1.83; 95% CI, 1.41-2.37; P for difference=0.02).AF occurs in more than half of individuals with HF, and HF occurs in more than one third of individuals with AF. AF precedes and follows HF with both preserved and reduced ejection fraction, with some differences in temporal association and prognosis. Future studies focused on underlying mechanisms of these dual conditions are warranted.
The Significance of the Intensity and Time of Appearance of the Korotkoff Sounds in Auricular Fibrillation
Authors: Simonrodbard, Jackmargolis
Journal: Circulation (1956)

Aside from their value in the indirect determination of the blood pressure the sounds at the brachial artery provide other valuable clinical information. Their value in blood pressure determination in auricular fibrillation generally has been found to be limited. By using a simple technic involving the counting of the brachial-artery-sound deficit, a satisfactory, repeatable method of blood pressure estimation is achieved in such patients with marked pulse rate irregularities. Other information, including a rough estimation of left ventricular stroke output, pulse wave force and velocity, are also appraised by analysis of these bruits.
Demonstration of the Exact Anatomic Tachycardia Circuit in the Fast-Slow Form of Atrioventricular Nodal Reentrant Tachycardia
Authors: HiroshigeYamabe, YukioShimasaki, OsamuHonda, YoshihiroKimura, YouichiHokamura
Journal: Circulation (2001)

Background The tachycardia circuit in the fast-slow form of atrioventricular nodal reentrant tachycardia (FS-AVNRT) has not been convincingly defined. Methods and Results To define the tachycardia circuit, single extrastimuli were delivered during FS-AVNRT to 9 intra-atrial sites in 12 patients: the His bundle (HB) site; the superior portion of the HB site (S-HB); 3 arbitrarily divided sites on the AV junction extending from the HB site to the coronary sinus ostium (CSOS) (sites S, M, and I); the superior, posterior, and posteroinferior portions of the CSOS (S-CSOS, P-CSOS, and PI-CSOS, respectively); and the CSOS. The inferior portion of coronary sinus ostium (I-CSOS), at which the earliest retrograde activation was observed, was excluded. At each site, the longest coupling interval of the single extrastimulus that reset the tachycardia and the subsequent return cycle was measured. The mean tachycardia cycle length was 370±55 ms. The longest coupling intervals at sites S-HB, HB, S, M, I, CSOS, S-CSOS, P-...
177Lu-DOTATATE Therapy in Radioiodine-refractory Differentiated Thyroid Cancer
Authors: Wolfgang Roll, Burkhard Riemann, Michael Schäfers, Lars Stegger, Alexis Vrachimis
Journal: Clinical Nuclear Medicine (2018)

Patients with radioiodine-refractory differentiated thyroid cancer (RrDTC) have a rather poor prognosis and are in need of novel treatments. As RrDTCs can in some cases express somatostatin receptors (SSRT), targeting of these receptors by Ga/Lu-DOTATATE could evolve as a novel theranostic option.Five RrDTC patients with limited further therapeutic options and documented expression of SSRT using Ga-DOTATATE-PET/CT received 2 to 4 cycles of PRRT with Lu-DOTATATE. Response to therapy was assessed by thyroglobulin (Tg) and morphological and metabolic criteria based on interim and follow-up Ga-DOTATATE-PET/CTs. Analysis was performed on a per-patient basis.In the post-therapy evaluation, only one out of five patients showed a partial response, whereas three patients had a progressive disease. One patient had discordant findings between stable imaging results albeit rising Tg levels.In this case study of five patients, Lu-DOTATATE therapy showed only heterogeneous response and efficacy in RrDTC patients despite good lesional uptake in pre-therapeutic PET.
Elevated 68Ga-DOTATATE Activity in IgG4-Related Lymphadenopathy
Authors: Zhaoting Cheng, Shuang Song, Yunfeng Han, Sijuan Zou, Xiaohua Zhu
Journal: Clinical Nuclear Medicine (2018)

Ga-DOTATATE PET/CT was performed in a 60-year-old man to detect culprit tumor responsible for tumor-induced osteomalacia (TIO). The images revealed multiple foci of abnormal activity in soft tissue lesion, which were not typical of tumor causing TIO in Ga-DOTATATE PET/CT. Considering other neoplastic processes, FDG PET/CT were subsequently performed, which showed all same lesions, although the lesions with highest activity were different between the scans. Pathological examination demonstrated that the patient experienced TIO caused by 1 lesion, but other lesions were due to IgG4-related lymphadenopathy.
Oral Administration of Tetrahydrobiopterin Prevents Endothelial Dysfunction and Vascular Oxidative Stress in the Aortas of Insulin-Resistant Rats
Authors: KazuyaShinozaki, YoshihikoNishio, TomioOkamura, YuichiYoshida, HiroshiMaegawa, HidetoKojima, MasahiroMasada, NoboruToda, RyuichiKikkawa, AtsunoriKashiwagi
Journal: Circulation Research (2000)

Abstract—We have reported that a deficiency of tetrahydrobiopterin (BH4), an active cofactor of endothelial NO synthase (eNOS), contributes to the endothelial dysfunction through reduced eNOS activity and increased superoxide anion (O2−) generation in the insulin-resistant state. To further confirm this hypothesis, we investigated the effects of dietary treatment with BH4 on endothelium-dependent arterial relaxation and vascular oxidative stress in the aortas of insulin-resistant rats. Oral supplementation of BH4 (10 mg · kg−1 · d−1) for 8 weeks significantly increased the BH4 content in cardiovascular tissues of rats fed high levels of fructose (fructose-fed rats). Impairment of endothelium-dependent arterial relaxation in the aortic strips of the fructose-fed rats was reversed with BH4 treatment. The BH4 treatment was associated with a 2-fold increase in eNOS activity as well as a 70% reduction in endothelial O2− production compared with those in fructose-fed rats. The BH4 treatment also partially impro...
Abstract 1909: NR4A2 role in head and neck cancer: Mechanistic and functional analysis
Authors: Sanjib Chaudhary, Ramesh Pothuraju, Pranita Atri, Satyanarayana Rachagani, Surinder K. Batra, Muzafar A. Macha
Journal: Cancer Research (2018)

Abstract Background: Nuclear receptor related 1 protein (NURR1/NR4A2) is a transcription factor that mediates numerous functions in differentiation/development, maintenance and metabolism. In cancer cells, NR4A2 promotes proliferation, migration, transformation and chemo-resistance in many cancers. Here, we explore the role of NR4A2 in head and neck squamous cell cancers (HNC) tumorigenesis and define its target genes. Methods: NR4A2 expression was determined by immunohistochemistry (IHC) and in publically available databases (Oncomine, TCGA). NR4A2 was knockedout/knockdown by CRISPR or shRNA. Coimmunoprepitation and reverse chromatin immunoprecipitation were done to study the interaction between EGFR/STAT3. ChIPSeq analysis was done by using Illumina NextSeq 500 Genome Analyzer and integrated with microarray (HPV+/- patients) to identify the true target genes of NR4A2 using BETA Software and validated by PCR/qPCR. Results: IHC and database analysis demonstrated overexpression of NR4A2 in HNC patients. NR4A2 was significantly overexpressed in HPV+ HNC patients, SCC47 and SCC104 cell lines. Functionally, CRISPR/shRNA knockout/knockdown of NR4A2 in cell lines significantly decreased colonogenicity, proliferation and migration. Expression of NR4A2 was positively correlated with EGFR expression (R2=0.92), and EGF treatment (100ng/ml; 24-48h) induced NR4A2 (~2 fold) expression coupled with epithelial to mesenchymal transition in SCC1 and SCC10B cells (HPV-). We also observed EGF mediated NR4A2 induction was abrogated by panEGFR inhibitor (afatinib) with concomitant decrease in STAT3 expression. Physical interaction between EGFR and STAT3 with EGF treatment regulated NR4A2 expression. Whole genome integration of ChIPseq and microarray demonstrates 9% (2015) and 23% (3002) of the enriched up and down-regulated target genes, respectively were canonically regulated in HPV+ HNC. ChIP PCR validation indicates enrichment of NR4A2 in some of the target genes, wnt10, p53, cxcl13, cln10 and hoxb8 in HPV+ cells. Conclusions: Our data indicate overexpression of NR4A2 in HNC, and its positive correlation with EGFR expression. We also noted the physical interaction between EGFR and STAT3 which functionally attribute the NR4A2 expression. Integration and validation data showed the differential enrichment of NR4A2 target genes in HPV+/- cell lines which suggest its possible discriminatory role in HNC pathogenesis which needs to be confirmed. Citation Format: Sanjib Chaudhary, Ramesh Pothuraju, Pranita Atri, Satyanarayana Rachagani, Surinder K. Batra, Muzafar A. Macha. NR4A2 role in head and neck cancer: Mechanistic and functional analysis [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 1909.
Long-Term Treatment With a Rho-Kinase Inhibitor Improves Monocrotaline-Induced Fatal Pulmonary Hypertension in Rats
Authors: KohtaroAbe, HiroakiShimokawa, KeikoMorikawa, ToyokazuUwatoku, KeijiOi, YasuharuMatsumoto, TsuyoshiHattori, YutakaNakashima, KozoKaibuchi, KatsuoSueishi, AkiraTakeshit
Journal: Circulation Research (2004)

Primary pulmonary hypertension is a fatal disease characterized by endothelial dysfunction, hypercontraction and proliferation of vascular smooth muscle cells (VSMCs), and migration of inflammatory cells, for which no satisfactory treatment has yet been developed. We have recently demonstrated that intracellular signaling pathway mediated by Rho-kinase, an effector of the small GTPase Rho, is involved in the pathogenesis of arteriosclerosis. In the present study, we examined whether the Rho-kinase–mediated pathway is also involved in the pathogenesis of fatal pulmonary hypertension in rats. Animals received a subcutaneous injection of monocrotaline, which resulted in the development of severe pulmonary hypertension, right ventricular hypertrophy, and pulmonary vascular lesions in 3 weeks associated with subsequent high mortality rate. The long-term blockade of Rho-kinase with fasudil, which is metabolized to a specific Rho-kinase inhibitor hydroxyfasudil after oral administration, markedly improved surviv...