tbuckley/cabot-search huggingface dataset:
Abstract 2739: The ketone body β-hydroxybutyrate alters expression of PD-L1 on malignant glioma cells but does not directly affect T cells <i>in vitro</i>
Authors: Eric C. Woolf, Kavita R. Manhas, Deborah R. Healey, Joseph N. Blattman, Adrienne C. Scheck
Journal: Cancer Research (2018)

Abstract Patients with newly diagnosed glioblastoma multiforme (GBM), the most aggressive grade of glioma, have an average life expectancy of ~15 months, and less than 6% survive five years, despite the current standard of care, which consists of aggressive surgery followed by radiation and chemotherapy. Advances in the survival of GBM patients require the design of new therapeutic approaches. One novel strategy being explored in our laboratory and others involves using ketogenic therapy (KT). This approach involves shifting the body's metabolic physiology by increasing the production of ketone bodies such as β-hydroxybutyrate (BHB) and decreasing blood glucose. We have demonstrated that nutritionally-induced KT enhances survival and potentiates standard therapy in a mouse model of malignant glioma. Our previous study shows that KT works in part as an immune adjuvant, boosting tumor-reactive immune responses in the microenvironment by alleviating immune suppression in vivo. In particular we found that KT reduced expression of programmed cell death-1 (PD-1) on tumor-infiltrating T cells and its ligand PD-L1 on tumor cells. The PD-1/PD-L1 axis represents a crucial mechanism of glioma-mediated immunosuppression and is a major focus of immunotherapy in GBM and other cancers. The current study aims to determine the role of BHB in the anti-tumor and immune-enhancing effects of KT. We show that in vitro treatment with BHB induces a variety of molecular changes in glioma cells including reduced protein expression of PD-L1. Given that our in vivo data suggests that KT enhances T cell function against tumors we also sought to determine the impact of BHB on T cell function in vitro. Activated CD8+ and CD4+ T cells were cultured with varying doses of BHB prior to flow cytometric analysis. There were no significant changes in expression of immune checkpoint receptors (PD-1, CTLA-4 and LAG-3), production of anti-tumor promoting cytokines (IFN-y, TNF, IL-2) or viability in either T cell population following treatment with any dose of BHB. This suggests that BHB and KT may indirectly impact T cell function by influencing the way tumor cells manipulate the microenvironment. Taken together this data helps us better understand the anti-tumor mechanisms underlying KT and warrants further exploration of combinational treatment strategies using this approach and immunotherapies for GBM. Citation Format: Eric C. Woolf, Kavita R. Manhas, Deborah R. Healey, Joseph N. Blattman, Adrienne C. Scheck. The ketone body β-hydroxybutyrate alters expression of PD-L1 on malignant glioma cells but does not directly affect T cells in vitro [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 2739.
Role of Exosomes in Myocardial Remodeling
Authors: AndersWaldenström, GunnarRonquist
Journal: Circulation Research (2014)

Exosomes are nanovesicles released from cells through exocytosis and are known to be mediators of proximal as well as distant cell-to-cell signaling. They are surrounded by a classical bilayered membrane with an exceptionally high cholesterol/phospholipid ratio. Exosomes were first described in 1977, then named prostasomes, and in 1987 the name exosome was coined. Exosomes contain surface proteins, some of which can act as labels in order to find their target cells. Exosomes also contain messages in the form of proteins and nucleic acids (RNA and DNA) that are transferable to target cells. Little is known and written about cardiac exosomes, although Gupta and Knowlton described exosomes containing HSP60 in 2007. It is now known that exosomes from cardiomyocytes can transfect other cells and that the metabolic milieu of the parental cell decides the quality of exosomes released such that they induce differential gene expression in transfected cells. Future clinical use of exosomes in diagnosis, monitoring ...
Cellular Mechanisms of Atrial Contractile Dysfunction Caused by Sustained Atrial Tachycardia
Authors: HuiSun, RaniaGaspo, NormandLeblanc, StanleyNattel
Journal: Circulation (1998)

Background—Transient atrial contractile dysfunction (“atrial stunning”) follows conversion of atrial fibrillation (AF) to sinus rhythm and has significant clinical implications; however, the underlying mechanisms are poorly understood. We investigated the hypothesis that rapid atrial activation (as during AF) impairs cellular contractility and affects cellular Ca2+ handling. Methods and Results—Edge detection and indo 1 fluorescence techniques were used to measure unloaded cell shortening and intracellular Ca2+ transients in atrial myocytes from control (Ctl) dogs and dogs subjected to atrial pacing at 400 bpm for 7 (P7) or 42 (P42) days. Atrial tachycardia reduced fractional cell shortening (0.1 Hz) from 7.3±0.4% (Ctl) to 4.3±0.3% and 2.0±0.3% in P7 and P42 dogs, respectively (P<0.01 for each). Resting [Ca2+]i was not altered in paced dogs, but the systolic Ca2+ transient was significantly reduced. Furthermore, cells from paced dogs showed slowed relaxation and use-dependent decreases of Ca2+ transients ...
Abstract LB-195: Identifying cooperative effects of tumor suppressor gene mutations in lung adenocarcinoma using paired CRISPR-Cas9
Authors: Mabel G. Perez-Oquendo, David M. Feldser, David Walter
Journal: Cancer Research (2018)

Abstract Cancer is a heterogeneous disease that arises from the accumulation of genetic mutations that lead to a loss of tumor suppressor genes and activation of oncogenes. Mutational inactivation of genes that regulate epigenetic mechanisms, such as post translational modifications to DNA and histones, also contribute to cancer progression but the mechanisms are poorly understood. Trimethylation on histone 3 lysine 36 (H3K36me3) is encoded by the histone lysine methyltransferase (SETD2). SETD2 is recurrently inactivated by missense and frameshift mutations in multiple tumor types. Previously, we identified that Setd2 loss has potent tumor promoting activities in a mouse model of oncogenic Kras-induced lung adenocarcinoma. However, whether Setd2 loss has cooperating effects with other tumor suppressor gene mutations remains unstudied. To simultaneously inactivate distinct tumor suppressor genes, we use a lentiviral-based CRISPR/Cas gene editing approach to express a combination of specific gRNA-pairs along with Cas9 and Cre recombinase. Inhalation of these lentiviral particles leads activation of an oncogenic KrasLSL-G12D allele and simultaneously inactivation two gRNA-targeted genes. We hypothesize that SETD2 will collaborate with other tumor suppressor gene mutations in lung adenocarcinoma. To clone lentivirus vectors that have two different gRNA we use oligonucleotides encoding gRNAs targeting Setd2 and either Lkb1, Apc, or Rb1 to PCR amplify the 3' region of the murine U6 (mU6) promoter and the 5' region of the gRNA scaffold. Overlapping sequences in the 148-bp PCR amplicon, facilitate recombination with a 415-bp donor fragment derived from BbsI-digested pDonor plasmid using the Gibson cloning method. The newly circularized fragment is then re-linearized via BbsI digestion and cloned into LentiCRISPRv2Cre vector through the Golden Gate method using BsmBI type IIs restriction endonuclease and T4 DNA ligase. Our data demonstrate the development and presence of dual gRNA nucleotides through NotI/EcoRI restriction enzymes digestion and DNA Sequencing. Moreover, to study the cooperative effects of these mutations in mice, we created viruses and corroborated through Flow cytometry and Fluorescence microscopy. In conclusion, we generate lentiviral particles expressing pairs of gRNAs targeting distinct tumor suppressor genes, to identify cooperative effects of their mutation in lung adenocarcinoma models. Citation Format: Mabel G. Perez-Oquendo, David M. Feldser, David Walter. Identifying cooperative effects of tumor suppressor gene mutations in lung adenocarcinoma using paired CRISPR-Cas9 [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-195.
Effectiveness of β-Blockade in Experimental Chronic Aortic Regurgitation
Authors: EricPlante, DominicLachance, MartinGaudreau, Marie-ClaudeDrolet, ÉliseRoussel, MarieArsenault, JacquesCouet
Journal: Circulation (2004)

Background— Past studies have suggested that the adrenergic system becomes abnormally activated in chronic volume overload, such as in severe aortic valve regurgitation (AR). However, the effectiveness of agents directed against this adrenergic activation has never been adequately tested in chronic AR. We therefore tested the effects of metoprolol treatment on the left ventricular (LV) function and remodeling in severe chronic AR in rats. Methods and Results— Severe AR was created in adult male Wistar rats by retrograde puncture of the aortic leaflets under echocardiographic guidance. Two weeks later, some animals received metoprolol treatment (25 mg/kg) orally for 24 weeks, and some were left untreated. LV dimensions, ejection fraction, and filling parameters were evaluated by echocardiography. Hearts were harvested at 1, 2, 14, and 180 days for the evaluation of hypertrophy, β-adrenergic receptor status, and extracellular matrix remodeling. We found that metoprolol treatment prevented LV dilatation and ...
Ozone Air Pollution Is Associated With Acute Myocardial Infarction
Authors: Jean-BernardRuidavets, MaximeCournot, SylvieCassadou, MichelGiroux, MariamMeybeck, JeanFerrières
Journal: Circulation (2005)

Background— Despite the diversity of the studied health outcomes, types and levels of pollution, and various environmental settings, there is substantial evidence for a positive link between urban air pollution and cardiovascular diseases. The objective of this study was to test the associations between air pollutants and the occurrence of acute myocardial infarction (AMI). Methods and Results— Pollutant concentrations (SO2, NO2, and O3) were measured hourly as part of the automated air quality network. Since 1985, an AMI registry (the Toulouse MONICA Project) has been collecting data in the southwest of France. All cases of AMI and sudden and probable cardiac deaths are recorded for subjects 35 to 64 years of age. We studied the short-term exposure effect of pollution on the risk of AMI (from January 1, 1997, to June 30, 1999) using a case-crossover design method. We performed a conditional logistic regression analysis to calculate relative risks (RRs) and their 95% CIs. After adjustment for temperature,...
Empirical Types of Medical Psychiatry Units
Authors: Maarten A. van Schijndel, Luc A.W. Jansen, Joris J. van de Klundert
Journal: Psychotherapy and Psychosomatics (2018)

Background  

Medical psychiatry units (MPU) provide integrated care for hospital patients with medical and psychiatric comorbidity. Lack of an empirically validated MPU typology hampers comparison of their (cost-)effectiveness.  

Methods  
A recent database on the organization of Dutch MPUs was used to empirically validate the MPU typology of Kathol (Model 1), develop types on the basis of the medical and psychiatric capabilities underlying this typology (Model 2), and to develop types from the data using k-means clustering (Model 3).   

Results  
Dutch MPUs are most alike the type III/IV MPUs described by Kathol. However, these types appear hardly distinctive for the Dutch context. The more generic approach of Model 2 provides comparable results. Both models show that the majority of Dutch MPUs handle moderate to high level medical and psychiatric acuity and can be classified as Complexity Intervention Units (CIUs). Model 3 yields three clusters to best characterize the Dutch field: CIUs with coercive admission facilities and 24/7 availability of ECT, CIUs without these facilities but with grossly comparable medical capabilities, and a smaller group of low acuity MPUs.   

Conclusions  
Kathol distinguished two types of CIUs (types III and IV MPUs) on the basis of medical acuity capabilities. This study reveals that psychiatric capabilities are most distinctive for the two high acuity MPU-types encountered in The Netherlands. In addition, a modest number of low acuity MPUs was found. Repeating our analysis in other countries is called for, as well as using the newly identified types for (cost)-effectiveness analysis in the Dutch context.
Ultrasoundcardiographic Studies of the Mitral Valve Region in Young Infants with Mitral Atresia, Mitral Stenosis, Hypoplasia of the Left Ventricle, and Cor Triatriatum
Authors: Nils-Runelundström
Journal: Circulation (1972)

Reflected ultrasound has been used for investigation of the mitral valve region in early infancy. The material consists of two patients with mitral atresia, three patients with mitral stenosis and aortic valvular atresia, five patients with mitral and aortic valvular stenosis, one patient with cor triatriatum, and one patient with severe degree of aortic valvular stenosis with a normal mitral valve. The results are compared with ultrasoundcardiographic findings in ten infants without heart disease. A specific abnormal echo was obtained in cases with mitral atresia and cor triatriatum. The patients with a combination of mitral and aortic valvular lesions could be separated into two groups by means of ultrasoundcardiography. This separation reflected the functional state of the left ventricle based on the degree of mitral stenosis and hypoplasia of the left ventricle. This noninvasive technic has been found useful as a complementary method for the investigation of the mitral valve region. It can even be per...
Heat Shock Protein 90α–Dependent Translocation of Annexin II to the Surface of Endothelial Cells Modulates Plasmin Activity in the Diabetic Rat Aorta
Authors: HetianLei, GiulioRomeo, AndriusKazlauskas
Journal: Circulation Research (2004)

The goals of this article were (1) to identify cell surface proteins whose expression was regulated by diabetes and (2) to assess their contribution to diabetic complications. We purified heat shock protein 90α (Hsp90α) from the membrane fraction of high glucose–treated endothelial cells (ECs) as a binding partner for a diabetes-specific phage. Further investigation revealed that high glucose elevated cell surface Hsp90α in cultured cells, and that diabetes increased the amount of Hsp90α on the luminal surface of the aorta. We also found that high glucose or diabetes promoted the association of Hsp90α with annexin II and increased the expression of annexin II on the surface of aortic ECs. Finally, plasmin activity was increased by high glucose or diabetes, and this change was partially reversed with an annexin II antibody. These findings reveal a novel glucose-regulated interaction between Hsp90α and annexin II, and raise the possibility that increased expression of annexin II, which promotes the generati...
Abstract 535: The impact on transcriptome diversity after oncogenic transformation of human mammary epithelial cells
Authors: Anthony Tran
Journal: Cancer Research (2018)

Abstract Breast cancer is a leading cause of cancer-related morbidity and mortality worldwide. In the USA, one out of eight women will be diagnosed with breast cancer over the course of their lifetime. A major obstacle hindering the treatment of breast cancers is intratumor heterogeneity since cytotoxic drug sensitivities among different clonal populations may vary. Previously, we have shown that cancer cells display an increased repertoire and abundance of all transcripts within a cell (termed transcriptome diversity) compared to normal cells. The driving mechanism(s) of cellular intratumor heterogeneity has yet to be fully elucidated. In this study, we utilize immortalized human mammary epithelial cells (MCF10A) transformed with an array of doxycycline-inducible lentiviral vectors encoding known genetic drivers of breast tumorigenesis (TP53 mutant, BRCA1 mutant, PIK3CA mutant, shPTEN and c-MYC) alone and in combination to determine their impact on transcriptome diversity based on RNA-seq. Our strategy enables strict temporal control and reversibility of gene expression alterations via the doxycycline-inducible promoter. Transcriptome diversity will also be interrogated using single-cell RNA sequencing to determine how individual cellular transcriptional profiles contribute to the overall population-based transcriptional landscape. These results will be compared to patient tumor samples' transcriptome diversity and correlated with their respective clinicopathologic characteristics. Advancing our understanding of cellular transcriptome diversity will enable new avenues of treatment for breast cancers resistant to current clinical interventions such as metastatic and triple negative breast cancers, both of which are characterized by high transcriptome diversity. Citation Format: Anthony Tran. The impact on transcriptome diversity after oncogenic transformation of human mammary epithelial cells [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 535.
Abstract 2746: Synergistic immunotherapeutic effects of TLR7/8 agonist on low-dose cyclophosphamide-treated C26 model
Authors: Jing Yang, Patrick Z. Li, Xiangyun Yin, Xiaohua Nie, Jingshu Wang, Walter Lau, Liguo Zhang, Lixin Li
Journal: Cancer Research (2018)

Abstract In recent years, low dose cyclophosphamide has been used clinically either as a single agent or as combination therapy to treat lymphomas, and breast and ovarian cancers. The efficacy of low dose cyclophosphamide is primarily due to its ability to immune-modulate in addition to its direct anti-tumor effects. This ability highlights the potential for synergism between conventional chemotherapy and novel immunotherapy. Toll-like receptors (TLRs) are a crucial part of the innate immunity and present the first line of defense against pathogens. Resiquimod is the ligand for TLR7 and 8 and directly activate innate immune cells, including myeloid dendritic cells, plasmacytoid dendritic cells, and monocytes/macrophages. This activation may result in activation of co-stimulatory molecules, production of antiviral cytokines, and stimulation of cell-mediated NK and T cell immune responses. The aim of this study was to analyze whether immunopotentiating TLR7/8 agonist might synergize with low doses of cyclophosphamide in the treatment of colorectal carcinoma. The effect of combining a weekly dosing of cyclophosphamide intraperitoneally with systemic administration of Resiquimod was evaluated in an in vivo murine C26 synergistic model. Systemic administration of Resiquimod in mice induced significant systemic immune responses as evidenced by upregulating IFNα inducible gene clusters. The combined therapy with Resiquimod and cyclophosphamide was superior to each single treatment and increased efficacy of tumor inhibition and prolonged their survival significantly. Importantly, the combined treatment generated a significant numbers of tumor-specific T cell infiltration in tumor microenvironment. Our data suggest that systemic administration of TLR7/8 agonist enhances anti-tumor effect of low dose of cyclophosphamide. The data supports the use of a combination of TLR7/8 agonist and cyclophosphamide as a novel therapeutic strategy against colorectal carcinoma. Citation Format: Jing Yang, Patrick Z. Li, Xiangyun Yin, Xiaohua Nie, Jingshu Wang, Walter Lau, Liguo Zhang, Lixin Li. Synergistic immunotherapeutic effects of TLR7/8 agonist on low-dose cyclophosphamide-treated C26 model [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 2746.
Biobrane™ for burns of the pubic region: minimizing dressing changes
Authors: Jia-Jun Feng, Jia Le See, Abby Choke, Adrian Ooi, Si Jack Chong
Journal: Military Medical Research (2018)

The pubic region is often involved in accidental hot water or soup-spill burns. Most of these wounds are superficial partial thickness burns. Due to their proximity to the urinary system, as well as vaginal and anal openings, these burns are easily contaminated. Daily dressings are routinely prescribed as the sole treatment. The cumbersome dressing process is uncomfortable and embarrassing for patients. Biobrane™ is a bilayered biosynthetic dressing. Its coverage of superficial partial thickness burns promotes wound healing and allows one-time application.We report two patients who suffered superficial dermal burns over their pubic region. One patient had 23% total body surface area (TBSA) burns over her lower abdomen, both thighs and pubic region. The second patient had 10% TBSA burns that involved her perineum and the medial sides of both thighs and buttocks. Both were managed with the standard resuscitation protocol in the initial phase. Their burn injuries were managed by shaving, Foley catheterization and Biobrane™ coverage. Their wounds healed uneventfully without complications. Full epithelization was achieved by post-operative day seven. Both patients consented to medical photography and academic publication.Shaving and catheterization improved the hygiene of the burns of the pubic area. The Biobrane™ method circumvents the need of regular dressing changes, eliminating the pain due to dressing changes and preserving patient dignity.
The Calcium Paradoxon of Renin Release
Authors: ChristianGrünberger, BirgitObermayer, JürgenKlar, ArminKurtz, FrankSchweda
Journal: Circulation Research (2006)

An increase in the free intracellular calcium concentration promotes exocytosis in most secretory cells. In contrast, renin release from juxtaglomerular (JG) cells is suppressed by calcium. The further downstream signaling cascades of this so called “calcium paradoxon” of renin secretion have been incompletely defined. Because cAMP is the main intracellular stimulator of renin release, we hypothesized that calcium might exert its suppressive effects on renin secretion via the inhibition of the calcium-regulated adenylate cyclases AC5 and AC6. In primary cultures of JG cells, calcium-dependent inhibitors of renin release (angiotensin II, endothelin-1, thapsigargin) suppressed renin secretion, which was paralleled by decreases in intracellular cAMP levels [cAMP]. When [cAMP] was clamped by membrane permeable cAMP derivates, renin release was not suppressed by any of the calcium liberators. Additionally, both endothelin and thapsigargin suppressed cAMP levels and renin release in isoproterenol or forskolin-p...