tbuckley/cabot-search huggingface dataset:
The Regulation of Cerebral Blood Circulation in Subclavian Steal Syndrome
Authors: Ferencsolti, Miklósiskum, Sándorpapp, Eszterturbók, Julianagy
Journal: Circulation (1970)

Blood flow to the brain was studied in 11 patients suffering from subclavian steal syndrome. The venous isotope-dilution method was used to measure total blood flow to the brain and the dye-dilution method with intravenous administration of 50 mg of Evans blue was used to determine cardiac output. Cerebral blood flow was significantly lower in the 11 patients with subclavian steal syndrome than in the control group, and the O2 consumption of the brain was low, cerebral resistance was elevated, and the cerebral fraction of the cardiac output was decreased in comparison with the controls. The effect of occlusion of the ipsilateral brachial artery was studied in 10 of the patients with subclavian steal syndrome. The cerebral blood flow and the cerebral fraction of the cardiac output increased significantly as a result of the occlusion in these patients. Studies on three patients after surgical correction of the lesion in the subclavian artery showed significant improvement in the cerebral circulation.
Abstract SY37-03: Mitochondrial genetic contributions to metastatic efficiency
Authors: Danny R. Welch
Journal: Cancer Research (2018)

Abstract Complex phenotypes, like tumorigenicity or metastasis, require coordinated expression of multiple genes. Additionally, the contributions of some of those genes can be affected by polymorphisms in the protein coding or regulatory sequences (PMID: 22257951). The pathobiology of metastasis remains poorly understood because both intrinsic (i.e., genetic) and extrinsic (i.e., tumor-microenvironment interactions) are involved. A growing body of data indicates demonstrate that there are underlying genetic components that govern the processes involved in cancer spread and colonization. To assess the contributions of mitochondrial genetics in metastasis, we created Mitochondrial Nuclear Exchange (MNX) mice by transferring an oocyte nucleus from strainx into an enucleated oocyte from strainy, and showed that mammary tumor formation and metastasis are regulated by inherited mitochondrial polymorphisms in an oncogenic driver-dependent manner (PMID: 26471915; PMID: 29070615). Since stromal compartments also possess changed mitochondria in the MNX mice, we hypothesized that mitochondrial polymorphisms in non-cancer cell compartments could exert effects on tumor formation and/or metastasis in addition to genetic (cell autonomous) changes. Syngeneic tumor cells were injected into MNX mice with the same nuclear, and therefore same MHC, background. Experimental metastasis was compared between wild-type and MNX mice (i.e., with same or different mtDNA backgrounds, respectively). E0771 mammary carcinoma and B16-F10 melanoma cells (both syngeneic to C57BL/6J), formed significantly (P&amp;lt;0.01) more lung metastases in C57BL/6J-mtMNX(C3H/HeN). K1735-M2 melanoma cells (syngeneic to C3H/HeN) formed significantly (P&amp;lt;0.05) fewer lung metastases in C3H/HeNmtMNXC57BL/6J. These results have been replicated ≥3 times using &amp;gt;10 mice per experiment. C57BL/6J mitochondria confer resistance to metastasis in both cell autonomous and non-cell autonomous experiments. Basal metabolic and ROS differences comparing mouse embryonic fibroblasts isolated from wild-type and MNX mice are among mechanisms being explored. Differential gene expression occurred in tissues isolated from wild-type and MNX mice (PMID: 28663334). Additionally, altered immune and microbiota profiles have been observed. Together, our findings highlight striking influences that mitochondrial haplotypes can exert on tumorigenicity and metastasis via both intrinsic and extrinsic mechanisms. Support: Susan G. Komen for the Cure (SAC11037), Natl Fndn Cancer Res. and CA168524. Citation Format: Danny R. Welch. Mitochondrial genetic contributions to metastatic efficiency [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 SY37-03.
Abstract LB-303: Novel peptide is synergistic with checkpoint inhibitor antiCTLA4
Authors: Carola Leuschner, Clifford H. Kern
Journal: Cancer Research (2018)

Abstract Specific peptides are known to modulate cellular immune responses. Isolates of leukocytes containing tyrosine and glycine peptide sequences have been previously tested in HIV-positive, colon cancer, and other patients, where they were found to be safe and to demonstrate pleiotropic effects on CD4+ T cells, CD8+ T cells, and natural killer cells, as well as increased production of interferon gamma and other cytokines. We hypothesized, therefore, that Tyr-Gly peptides may enhance anti-tumor responses in combination with checkpoint inhibitors through stimulation of the immune system. INT-151 (synthetic Tyr-Gly), originally identified as the active component of a leukocyte isolate, was tested alone and in combination with the checkpoint inhibitor anti-CTLA4 in a murine syngeneic lymphoma model (E.G7-OVA) for anti-tumor effect and survival. Immune profiles in control and treatment groups were assessed for tumors and blood using FACs analysis to detect CD8+ T cells, CD4+ T cells, regulatory T cells (Treg), macrophages, and myeloid derived suppressor cells (MDSC). E.G7-OVA tumor bearing mice with an average tumor volume of 43 mm3, were treated 3x weekly for 17 days with INT-151 or anti-CTLA4 alone or in combination. The treatment group receiving INT-151 plus anti-CTLA4 had the lowest tumor volume (351 ± 38.9 mm3, N=6) compared with those treated with vehicle (876.7 ± 142.9 mm3, p &amp;lt; 0.04, N=6), INT-151 alone (821 ± 52.2 mm3, p = 0.8, N=6), and anti-CTLA4 alone (616 ± 117.4 mm3, p = 0.1, N=6). Tumor growth inhibition was highest in the combination group (60 %) compared to single agents anti-CTLA4 (30 %) and INT-151 (7 %). Immune cell populations increased in tumors were CD8+ T cells, CD4+ T cells and M1 macrophages in the combination group. Regulatory T cells, mMDSC or gMDSC remained unchanged in any of the treatment groups compared to controls. The highest ratio of CD8+T/Treg cells of 8.5±2.1 was found in the combination group (INT-151+anti-CTLA4, p&amp;lt;0.001) compared to 4.4±0.9 for anti-CTLA4 and 2.5±0.5 for vehicle and INT-151 (3.2±1.05). The E.G7-OVA mouse model also demonstrated increased survival on day 40 in groups treated with INT-151 plus anti-CTLA4 (55%, N=9) compared to single agent INT-151 (30 %, N=10), anti-CTLA4 (0%, N=8) and vehicle (0 %, N=10). These data demonstrate synergistic activity of INT-151 in a syngeneic murine lymphoma model. Combining a checkpoint inhibitor with INT-151 could be a safe and promising therapeutic strategy for lymphoma and other malignancies. Citation Format: Carola Leuschner, Clifford H. Kern. Novel peptide is synergistic with checkpoint inhibitor antiCTLA4 [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-303.
Abstract 16487: Crucial Role of Proteinase-Activated Receptor 1 in the Development of Monocrotaline Induced Pulmonary Arterial Hypertension in Rats
Authors: Yukimitsu Kuwabara, Kohtaro Abe, Mayumi Hirano, Yoshitaka Hirooka, Kenji Sunagawa, Katsuya Hirano
Journal: Circulation (2013)

Introduction: Pulmonary arterial hypertension (PAH) is a disease with poor prognosis, as characterized by a progressive elevation of pulmonary artery resistance and pressure. PAH is frequently asso...
Abstract 19686: Identification and Putative Function of Fibroblast Activation Protein and Relevance to Post-Myocardial Infarction Remodeling
Authors: Edie C Goldsmith, Heather Doviak, Paige E Perreault, Kaitlyn R Swimmer, Kia N Zellars, Shayne Barlow, Francis G Spinale
Journal: Circulation (2016)

Background: While changes in extracellular matrix (ECM) structure and function contribute to adverse ventricular (LV) remodeling with myocardial infarction (MI), the integration of cellular (fibrob...
Multiple Heterotopic Ossification of the Intestine Detected by 99mTc-MDP Bone Scan in a Patient With Primary Peritoneal Cancer
Authors: Ruiguo Zhang, Feng Dong, Zhaowei Meng, Jian Tan
Journal: Clinical Nuclear Medicine (2018)

Abstract Heterotopic ossification is a rare phenomenon that refers to formation of bone outside the skeletal system. We present a 61-year-old woman who suffered from peritoneal cancer surgery 2 years ago, referred for 99m Tc-MDP bone scan because of higher serum CA-125 level, which showed multiple intense tracer activities in her abdominal and pelvic region without other abnormalities. SPECT/CT revealed the activities were loaded in the intestine but not in the bone. A wait-and-see policy was adopted because of no abdominal discomfort. After 1-year follow-up, another bone scintigraphy showed the tracer uptake was significantly decreased.
Abstract 339: Heterozygous germline mutation in ABRAXAS causes BRCA1 mislocalization and DNA damage response defects
Authors: Robert Winqvist, Muthiah Bose, Juliane Sachsenweger, Niina Laurila, Ann Christin Parplys, Jonas Willmann, Leila Eshraghi, Thomas W. Dunlop, Marco Groth, Katrin Rapakko, Pentti Nieminen, Thomas W. Friedl, Lisa Heiserich, Felix Meyer, Hanna Tuppurainen, Ganapathy Raman Devarajan, Hellevi Peltoketo, Heli Nevanlinna, Katri Pylkäs, Kerstin Borgmann, Lisa Wiesmuller, Helmut Pospiech
Journal: Cancer Research (2018)

Abstract Whilst heterozygous germline mutations in the ABRAXAS gene have been associated with hereditary breast cancer predisposition, their initial effect on promoting tumorigenesis at the cellular level has not been explored. Here, we demonstrate in patient-derived cells that the Finnish ABRAXAS founder mutation (c.1082G&amp;gt;A, Arg361Gln), even in the heterozygous state leads to decreased BRCA1 protein levels as well as reduced nuclear localization and foci formation of BRCA1 and CtIP. This causes disturbances in basal BRCA1-A complex localization, which is reflected by a restraint in error-prone DNA double-strand break (DSB) repair pathway usage, attenuated DNA damage response, deregulated G2-M checkpoint control and apoptosis. Most importantly, mutation carrier cells display a change in their transcriptional profile, which we attribute to the reduced nuclear levels of BRCA1. The current study clearly demonstrates how the Finnish ABRAXAS founder mutation acts in a dominant-negative manner on BRCA1 to promote genome destabilisation in heterozygous carrier cells. Citation Format: Robert Winqvist, Muthiah Bose, Juliane Sachsenweger, Niina Laurila, Ann Christin Parplys, Jonas Willmann, Leila Eshraghi, Thomas W. Dunlop, Marco Groth, Katrin Rapakko, Pentti Nieminen, Thomas W. Friedl, Lisa Heiserich, Felix Meyer, Hanna Tuppurainen, Ganapathy Raman Devarajan, Hellevi Peltoketo, Heli Nevanlinna, Katri Pylkäs, Kerstin Borgmann, Lisa Wiesmuller, Helmut Pospiech. Heterozygous germline mutation in ABRAXAS causes BRCA1 mislocalization and DNA damage response defects [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 339.
Abstract 1289: Crosstalk between methylation and alternative splicing in cancer
Authors: Dongwook Kim, Seonggyun Han, Younghee Lee
Journal: Cancer Research (2018)

Abstract Background: DNA methylation in promoter regions leads to transcriptional silencing, such as of tumor suppressor genes in cancer. However, the functions of DNA methylation in the gene body (intragenic, i.e., exons and introns) have not yet been completely elucidated. Recently, hyper-methylation has been implicated in enhancing exon recognition by recruiting methyl-CpG-binding protein (MECP2) to hyper-methylated sites. In this study, we examined intragenic methylation in splicing regulatory elements (SREs: exonic splicing enhancer (ESE), exon splicing silencer (ESS), intronic splicing enhancer (ISE)) as a mechanism to understand how epigenetic factors contribute to alternative splicing events in cancer. Hypothesis: Methylation patterns of SREs are involved in directing alternative splicing events in cancer. Methods: We developed a splicing decision model to identify actionable methylation loci potentially affecting splicing events (i.e., exon skipping) among CpG sites in putative intragenic SRE regions. We used DNA methylation and RNA-Seq data for breast and lung cancer samples and normal cases from The Cancer Genome Atlas (TCGA). We additionally used hyper- and hypo-methylation data published in Selamat et al. (2013) as an independent lung cancer dataset. To identify regions hyper- and hypo-methylated in cancer, we performed an unpaired t-test for normally distributed data and a Mann-Whitney-Wilcox test for non-normally distributed data for differential methylation status (beta value) between cancer and normal cases. Multiple testing was accounted for by controlling the false discovery rate (p&amp;lt; 0.05 with FDR&amp;lt; 0.1). Results: We investigated whether specific patterns of methylation were enriched in SRE regions affecting exon skipping. We found that for breast cancer samples, differential methylation status was enriched in SRE regions but not in non-SRE regions. Particularly, hypo-methylation in cancer showed a greater enrichment in ESE regions with putative exon skipping events. Similar results were observed in the both the TCGA lung cancer cases and an independent lung cancer dataset. We calculated GC contents and the methylation frequencies at each position of the hexameric sequence of SREs and further investigated whether certain SREs are prevalent to be with methylation or not. These data suggest that hypo-methylation in SRE regions may cause failure to recruit MECP2, therefore leading to exon skipping. Conclusion: Our study suggests that intragenic methylation status is important for splicing regulation and may improve our understanding of how intragenic epigenetic markers play a role in gene regulation by affecting alternative splicing. Citation Format: Dongwook Kim, Seonggyun Han, Younghee Lee. Crosstalk between methylation and alternative splicing in 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 1289.
Enhanced Therapeutic Angiogenesis by Cotransfection of Prostacyclin Synthase Gene or Optimization of Intramuscular Injection of Naked Plasmid DNA
Authors: KazuyaHiraoka, HiromiKoike, SeijiYamamoto, NaruyaTomita, ChiekoYokoyama, TadashiTanabe, TakashiAikou, ToshioOgihara, YasufumiKaneda, RyuichiMorishita
Journal: Circulation (2003)

Background— Although clinical trials of therapeutic angiogenesis by angiogenic growth factors with intramuscular injection of naked plasmid DNA have been successful, there are still unresolved problems such as low transfection efficiency. From this viewpoint, we performed the following modifications: (1) combination with vasodilation using prostacyclin and (2) changing the agents or volume of naked plasmid DNA in vivo. Methods and Results— First, we examined cotransfection of the VEGF gene with the prostacyclin synthase gene in a mouse hindlimb ischemia model. Cotransfection of the VEGF gene with the prostacyclin synthase gene resulted in a further increase in blood flow and capillary density compared with single VEGF gene. Similar results were obtained with other angiogenic growth factors, such as hepatocyte growth factor (HGF). Alternatively, we changed the injection volume of the solution of plasmid DNA. Luciferase activity was increased in a volume-dependent manner. An increase in injection volume at ...
Diagnosis and management of venous leg ulcers
Authors: Chung Sim Lim, Moushumi Baruah, Sandeep S Bahia
Journal: BMJ (2018)

### What you need to know

Venous leg ulcers are the most common type of leg ulcer, with an estimated prevalence of 0.1 and 0.3% in the UK.1 The lifetime risk of developing a venous leg ulcer is 1%.23 A recent retrospective cohort study using THIN (The Health Improvement Network) data reported that in the UK 53% of all venous leg ulcers healed within 12 months, with a mean healing time of three months.4 Service provision in the UK for venous leg ulcers can be poor, with around half of patients receiving inadequate care, minimal specialist involvement, and lack of evidence-based treatment according to GP records.45 Similar significant evidence-practice gap has been reported around the world including in several developed countries.678 This clinical update, aimed at non-specialists, provides information on the diagnosis and management of venous leg ulcers, and offers multidisciplinary team support.

### Sources and selection criteria

We searched PubMed using the terms “venous ulcer” and “compression therapy,” giving particular attention to meta-analyses and systematic reviews, including those from the Cochrane database, and guidelines from major international and national organisations and societies with an interest in venous ulcers. We also looked for publications in nursing journals to explore the up-to-date holistic approach in the diagnosis and management of venous …
Abstract 15692: Resting Heart Rate and Chronotropic Response to Exercise: Prognostic Implications in Heart Failure
Authors: Mario Santos, Erin West, Hicham Skali, Wilson N Junior, Daniel E Forman, Amil M Shah
Journal: Circulation (2015)

Background: Higher resting heart rate (HR) and impaired chronotropic response to exercise are both prognostic of adverse outcomes in heart failure (HF). We aimed to study how resting HR and chronotropic response to exercise relate to each other, and to examine their prognostic value in HF patients across the LVEF spectrum. Methods: We studied 892 HF outpatients (mean age 55 years, 68% male, 33% with atrial fibrillation) who underwent maximal cardiopulmonary exercise testing. Chronotropic index (CIx) was calculated as (peak HR – resting HR)/(age-predicted maximal HR – resting HR). Cox proportional hazards models were fit to study the relationship between CIx and resting HR with the composite outcome of LVAD implantation, transplantation, or death (243 events during 4.2±1.9 yr of follow-up). Multivariate models adjusted for age, sex, symptomatic status, cardiomyopathy etiology, COPD, diabetes, atrial fibrillation, LVEF, eGFR, beta-blocker use, and peak VO 2 . Results: Resting HR was 72±14 bpm and CIx was 0.55±0.28. The average LVEF was 33±15%, with 28% with an LVEF ≥45%. 85% of patients were on beta-blockers. Both higher resting HR and lower CIx were associated with higher NYHA class and lower peak VO 2 , but resting HR poorly correlated with CIx (r=0.07; p=0.04). Both higher resting HR (per SD change: adjusted HR 1.26; 95%CI: 1.09-1.46; p=0.002) and CIx (per SD change: adjusted HR 0.63; 95%CI: 0.63-0.89; p=0.001) were independent prognostic markers in adjusted analyses including both measures. Similar findings were noted in analyses restricted to patients with an LVEF ≥45% or with atrial fibrillation. Conclusion: Higher resting HR and lower CIx are both associated with more severe HF, but correlate poorly with each other. Both are predictive of adverse outcomes suggesting that these two HR-related measures provide independent prognostic information.
Abrupt Shift of the Pattern of Diurnal Variation in Stroke Onset With Daylight Saving Time Transitions
Authors: ChristianFoerch, Horst-WernerKorf, HelmuthSteinmetz, MatthiasSitzer
Journal: Circulation (2008)

Background— Stroke onset shows a pattern of diurnal variation, with a peak in morning hours. Rhythmic changes in blood pressure, hormones, and other parameters have been suggested as underlying mechanisms, but exogenous factors such as increasing physical activity after awakening may also be of relevance. To characterize the impact of external clock changes on the rhythmic variation in stroke onset, this parameter was recorded in patients during transition periods into and out of Daylight Saving Time (DST). Methods and Results— The present study was based on a prospective stroke registry in Germany that contains time points of stroke onset from 44 251 patients admitted between 2000 and 2005. To achieve a uniform timeline, time points of stroke onset were set back from Central European Summer Time (CEST) to Central European Time (CET) for patients admitted during DST periods. Compared with the last week before the clock change, transition to or from DST resulted in an immediate shift of stroke onset time p...
Abstract 371: Utilizing metabolic pathways to improve diagnosis and risk stratification of prostate cancer
Authors: Aymen Alqazzaz, Dexue Fu, Arman Karimi, Gustavo Ferreira, Mary McKenna, Mohummad M. Siddiqui
Journal: Cancer Research (2018)

Abstract Prostate cancer has well-characterized changes that take place metabolically in the citric acid cycle (CAC) such as increased lactate formation, reversal of physiologic buildup of citrate and breakdown into downstream CAC products. Metabolic MR spectroscopy utilizing 13C-labeled pyruvate now allows for clinical characterization of metabolic pathways in tissue. However, the traditionally utilized substrate of [1-13C]pyruvate has limitations because as the pyruvate is broken down, the labeled carbon does not enter the CAC and instead is lost as CO2. We propose that [2-13C]pyruvate, is better to characterize changes in the CAC. Specifically, [2-13]C-pyruvate can be converted to 13C-labeled acetyl CoA and subsequently metabolized in the CAC as 13C-labeled intermediate compounds (such as glutamate which rapidly pools alpha-ketogluterate). Alternatively in altered bioenergetic states, [2-13C]pyruvate is reduced to 13C-labeled lactate (Warburg effect) or transaminated to 13C-labeled alanine. By exposing prostate cancer cells to [2-13C]pyruvate and determining the relative labeling of lactate, glutamate, and alanine, we can elucidate which metabolic pathways (CAC, Warburg, transamination) are utilized in prostate cancer metabolism. The aim of this study was to determine how the metabolism of [2-13C]pyruvate via the CAC, reduction to lactate, and transamination differed in high and low malignancy prostate cancer cells.Methods: Tumorigenic prostate cells LNCaP and PC3 were exposed a medium containing [2-13C]pyruvate for 4 hours. PCA extraction was then performed to obtain the metabolites. 13C labeled compounds formed intracellularly and those released into the medium were analyzed using NMR chemical shifts with focus on peaks associated with pyruvate, lactate, alanine, glutamate, and other compounds related to the CAC. Dioxane was used as an internal standard for NMR characterization. Results: The labeled carbon from the [2-13C]pyruvate can be identified in the downstream metabolites of the citric acid cycle, after reduction to lactate, and/or transamination by determining labeled metabolites by 13C-NMR analysis. This allows for the ability to calculate the relative metabolism of pyruvate via the three pathways; transamination (74%), lactate formation (16%), and CAC (10%). Conclusions: [2-13C]pyruvate can be successfully utilized as a tool to explore the alterations in pathways of metabolism, including the citric acid cycle, in prostate cancer cells. Citation Format: Aymen Alqazzaz, Dexue Fu, Arman Karimi, Gustavo Ferreira, Mary McKenna, Mohummad M. Siddiqui. Utilizing metabolic pathways to improve diagnosis and risk stratification of prostate 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 371.