tbuckley/cabot-search huggingface dataset:
Abstract 461: Sodium Influx Modulates the Modality of Cardiac Relaxation
Authors: Daniel O Cervantes, Alejandro Andrade-Vicenty, Chaoyu Sun, Saketh Anand, Jillian Pope, Jessica R Dorilio, Dong Sun, Antonio Cannata, Eleonora Cianflone, Govindaiah Vinukonda, Thomas H Hintze, Heather O’Malley, Lori L Isom, Jason T Jacobson, Marcello Rota
Journal: Circulation Research (2019)

Aging in experimental animals is coupled with protracted electrical recovery of the heart and increased late Na + current (I NaL ) in cardiomyocytes. These electrophysiological alterations are coupled with impaired cardiac relaxation, raising the possibility of a causative link between enhanced I NaL and diastolic dysfunction. To test this hypothesis, genetic and pharmacological interventions were introduced to assess the consequences of enhanced Na + influx in myocytes on diastolic properties of the mouse heart, together with effects on mechanical properties of isolated cells. Using Langendorff preparations, acute enhancement of I NaL with anemone toxin II increased diastolic and systolic pressure in the mouse heart. Importantly, a shift of the diastolic pressure-volume relationship toward higher pressure values was observed with activation of I NaL . To test the in vivo effects of increased Na + influx, mice with inducible, cardiac restricted deletion of the beta1 subunit of the Na + channel (Scn1b-KO) were employed. Scn1b-KO male mice presented protracted electrical recovery with respect to control (Ctrl) animals, a condition that was reversed by administration of a specific I NaL inhibitor (GS967, 0.5 mg/kg body weight). By invasive hemodynamics, left ventricular (LV) developed pressure was preserved in Scn1b-KO mice, but maximal velocities of pressure development and decay were attenuated by 16% and 25%, respectively. By echocardiography, LV end-diastolic volume and ejection fraction (EF) were preserved in Scn1b-KO. In contrast, using Doppler modality, LV filling pattern was altered and isovolumic relaxation time was prolonged by ~30%. I NaL inhibition (GS967) in Scn1b-KO mice ameliorated LV filling and normalized isovolumic relaxation time, without effects on EF. Using isolated cardiomyocyte preparations, Scn1b deletion had no consequences on fractional cell shortening, but led to a ~5% prolongation of kinetics of contraction and relaxation. Inhibition of I NaL (300 nM GS697) in Scn1b-KO myocytes accelerated contraction and relaxation kinetics and attenuated fractional shortening. In conclusion the late Na + current modulates the modality of myocyte contraction and relaxation with important effects on diastolic function of the heart.
Abstract 281: Single Cell Analysis of Postnatal Heart Development and Disease
Authors: Juanjuan Zhao, Katherine Lupino, Liming Pei
Journal: Circulation Research (2019)

A fundamental challenge in understanding cardiac biology and disease is that the remarkable heterogeneity in cell-type composition and functional states have not been well characterized at single-cell resolution in maturing and diseased mammalian hearts. Massively parallel single-nucleus RNA sequencing (snRNA-Seq) has emerged as a powerful tool to address these questions by interrogating the transcriptome of tens of thousands of nuclei isolated from fresh or frozen tissues. snRNA-Seq overcomes the technical challenge of isolating intact single cell from complex tissues including the maturing mammalian hearts, reduces biased recovery of easily dissociated cell types and minimizes aberrant gene expression during the whole-cell dissociation. We have recently applied sNucDrop-Seq, a droplet microfluidics-based massively parallel snRNA-Seq method, to investigate the transcriptional landscape of postnatal mouse hearts in both healthy and mitochondrial disease states. By profiling the transcriptome of nearly 20,000 nuclei, we identified major and rare cardiac cell types and revealed significant cellular heterogeneity in the postnatal developing heart. When applied to a mouse model of mitochondrial cardiomyopathy, we uncovered profound cell type-specific modifications of the cardiac transcriptional landscape at single-nucleus resolution. Here, we expanded these earlier studies and used our dataset to further decipher the cardiac cell type-specific gene regulatory networks. Our analysis reveals novels insights into the key nodes of gene networks that control the postnatal development and disease-associated changes of different cardiac cell types. Our ongoing work is using genetic mouse models to validate these findings from single cell analysis.
Determining Late Engraftment Following Single Cord, Unrelated Transplantation: An Analysis of the Eurocord Registry
Authors: Riccardo Saccardi, Myriam Labopin, Annalisa Ruggeri, Chantal Kenzey, Wagnara Chaves, Renato Cunha, Eliane Gluckman, Vanderson Rocha
Journal: Blood (2011)
Dysregulation of 5-hydroxytryptamine 6 receptor accelerates maturation of bone-resorbing osteoclasts and induces bone loss
Authors: Kyung-Ran Park, Eun-Cheol Kim, Jin Tae Hong, Hyung-Mun Yun
Journal: Theranostics (2018)

Rationale: Characterizing the regulation of bone-resorbing osteoclasts is central to the understanding of the pathogenesis and treatment of bone diseases, such as osteoporosis and periodontitis.5-hydroxytryptamine (5-HT) has drawn considerable attention for its role in bone; however, it remains unknown whether the intracellular signaling of 5-HT receptors (5-HTRs) is linked to any of the regulatory mechanisms in osteoclasts.Herein, we report 5-HT6R to be a key regulatory receptor for osteoclastogenesis.Methods: In order to explore the critical role of 5-HT6R in bone-resorbing osteoclasts, in vitro experiments were performed using mouse whole bone marrow cells isolated from femora and tibiae and In vivo animal experiments were performed using 5-HT6R-deficient (5-HT6R KO-/-) mice, bone resorption mice model, and osteoporosis mice model.Results: Compared to other 5HTRs, activation of 5-HT6R relatively increased TRAP (tartrate-resistant acid phosphatase) activity during osteoclastogenesis.5-HT6R KO(-/-) mice and 5-HT6R KO(-/-) osteoclast lineages presented with an abnormal phenotype and impaired osteoclastogenesis and impaired osteoclastogenesis.Activation of 5-HT6R increased the number of TRAP-positive multinuclear osteoclasts, actin ring formation, and expression of early osteoclast markers with osteoclast lineage commitment.Intracellular 5-HT6R signaling was found to be linked to RhoA GTPase activation and was involved in the maturation of osteoclasts.This signaling pathway also showed enhanced bone destruction after lipopolysaccharide (LPS) administration in mice.Furthermore, inhibition of 5-HT6R-mediated RhoA GTPase signaling protected against ovariectomy(OVX)-induced bone loss in mice.Conclusion: Taken together, our findings place the 5-HT6R system in a new context of osteoclast lineages in both an in vitro and in vivo system, and also it may offer a novel molecular target for the treatment of bone diseases.
Abstract 781: Doxorubicin-Induced Cardiotoxicity and Novel GATA4-Targeted Compounds
Authors: Tuuli Karhu, Sini Kinnunen, Virpi Talman, Heikki Ruskoaho
Journal: Circulation Research (2019)

Doxorubicin (DOX) is a widely used anticancer drug which, unfortunately, induces dose-related cardiotoxicity. A deep understanding of DOX’s toxicity is still unclear, partly because most in vitro studies have evaluated the effects of short-term high-dose DOX treatments. Thus, a more precise model of DOX cardiotoxicity is needed to more accurately simulate clinical scenario. The first aim of this study was to establish an in vitro model of long-term low-dose administration of DOX utilizing human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). The second aim was to investigate if novel GATA4-targeted compounds can protect CMs from DOX toxicity. Acute toxicity was studied in both primary neonatal rat ventricular cardiomyocytes (NRVCs) and hiPSC-CMs. The cells were exposed to 0.1-3 μM DOX for 48 h, after which the lactate dehydrogenase and the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays were carried out. To study long-term toxicity, hiPSC-CMs were exposed to 100 nM DOX for up to 14 days. MTT assay and high-content analysis were carried out after 4, 7 and 14-day exposures. The effect of the test compound was studied by exposing the cells simultaneously to DOX and the compound. A 48-hour exposure to DOX at 1 and 3 μM concentrations induced more than 62% reductions in both NRVC and hiPSC-CM viability, whereas a 14-day exposure to 100 nM DOX induced a 26% reduction in hiPSC-CM viability. A 4-day exposure to 100 nM DOX induced a 3.1-fold increase in the percentage of cells positive for pro-B-type natriuretic peptide (proBNP) compared to control. When the cells were exposed simultaneously to 100 nM DOX and the test compound (10 μM), the percentage of proBNP+ cells increased only 1.4-fold compared to control. However, over 14-day exposure the compound at 10 μM concentration reduced hiPSC-CM viability 50% compared to control. A long-term exposure of hiPSC-CMs can be utilized as an in vitro model to investigate the mechanisms of delayed DOX-induced cardiotoxicity. The GATA4-targeted test compound exhibited cardioprotective potential against subacute DOX toxicity. Over chronic exposure the compound was, however, toxic to CMs, indicating that further structural optimization is required to develop non-toxic derivatives.
The curious phenomenon of dual-positive circulating cells: Longtime overlooked tumor cells
Authors: Carolina Reduzzi, Marta Vismara, Lorenzo Gerratana, Marco Silvestri, Filippo De Braud, Francesco Raspagliesi, Elena Verzoni, Serena Di Cosimo, Laura D. Locati, Massimo Cristofanilli, Maria Grazia Daidone, Vera Cappelletti
Journal: Seminars in Cancer Biology (2019)

The presence in the blood of patients with solid tumors of circulating cells expressing both epithelial and leukocyte markers (dual-positive cells, DPcells), has often been reported, though it has never been investigated in detail. A recent study suggested that DPcells are hybrid cells derived from the fusion of tumor cells with macrophages. Such fusion hybrids acquire macrophage-associated features endowing them with accelerated growth, increased motility, enhanced invasion activity and thus, a higher efficiency in metastasis formation. However, no direct evidence proving the tumor origin of circulating DPcells was provided in patients. Here we contribute a review of literature data on DPcells and on the hybrid theory with the aim of putting the current evidence both in a biological and clinical perspective and to generate new hypotheses on the mechanisms underlying tumor progression. To add further biological and clinical context to our literature review, we also report some preliminary data from our laboratory on the identification of DPcells in several solid tumors and confirmation of their malignant genotype, thus classifying them as DP-CTCs.
Modeling of the Epigenome of the Cell-of-Origin Identifies Cancer-Specific DNA Methylation Patterns in CLL
Authors: Justyna Anna Wierzbinska, Reka Toth, Naveed Ishaque, Jan-Phillip Mallm, Karsten Rippe, Daniel Mertens, Thomas Hielscher, Thorsten Zenz, Marc Seifert, Ralf Küppers, Yassen Assenov, Stephan Stilgenbauer, John C. Byrd, Christopher C. Oakes, Daniel B. Lipka, Christoph Plass
Journal: Blood (2018)
Abstract 801: Characterization of Cardiac Myeloid Cells in Aged Mice and Their Role in Cardiac Dysfunction During Bacterial Infection
Authors: Noushin Saljoughian, Qian Wu, Cameron Kashef, Sonali Patel, Latha P. Ganesan, William P. Lafuse, Murugesan V.S. Rajaram
Journal: Circulation Research (2019)

Biological aging is a risk factor for the development of cardiovascular disease. The changes in the normal immune cell phenotype and function in the myocardium due to immunosenescence is the major source for cardiac distress. Cardiac resident macrophages in the heart play a critical role in the maintenance of homeostatic functions and tissue repair during myocarditis. Recently, we have demonstrated that non-tuberculosis Mycobacterium avium (NTM- common in lung infections in the elderly population in the U.S.) infection predisposes the aged mice to cardiac dysfunction; however the mechanism is not known. Here, we investigated the various subsets of myeloid cells and their contribution to the heart function in old mice. We infected young (10 weeks) and old mice (18 months) with NTM and characterized the resident and infiltrated myeloid cells. Our results revealed that before infection old mice showed elevated numbers of myeloid cells in heart tissue compared to young mice. In contrast, NTM infection (30 day post infection) significantly increased the frequency of different myeloid cell subsets in the young mice. Although, the number of cardiac macrophages in young and old mice are not significantly different in infected and uninfected mice, we found that MHCII low macrophages (cardiac resident) are significantly higher in the heart tissue of old mice than young mice before infection which significantly decreased after infection. Interestingly, we observed that MHCII high and MerTK + macrophage (infiltrated macrophages) populations are increased in young and old mice but with a higher rate in young mice. Notably, we found that the number of myeloid-derived suppressor cells (MDSCs) in the heart of aged mice is decreased by infection, which was increased in young mice. In conclusion our data indicates that the NTM infection alters the myeloid cell population and function in the aged heart and failed to maintain the normal heart function, where as in young mice, infection leads to the recruitment of myeloid cells which help to confront the infection and maintain the normal heart function. Further MDSCs accumulation in the heart of young mice after infection is responsible for anti-inflammatory effects to control the hypertrophy, fibrosis and inflammation.
Of FACT complex and oxidative stress response: a KEAP1/NRF2-dependent novel mechanism sustaining hepatocellular carcinoma progression
Authors: Beatrice Foglia, Maurizio Parola
Journal: Gut (2019)

Hepatocellular carcinoma (HCC) is the most common primary liver cancer that usually develops in cirrhotic patients, except for progressive non-alcoholic fatty liver disease (where the tumour may develop also in non-cirrhotic liver).1 HCC is currently the leading cause of mortality in cirrhotic patients, representing the fifth most common cancer and the second leading cause of cancer mortality worldwide.1 Although screening programmes can allow to identify HCC at an earlier stage in patients at risks, still a minority of patients can survive at 5 years from diagnosis, despite treatment. Current treatment options have limitations and first-line drugs approved for systemic therapy, like sorafenib and lenvatinib, can at best offer additional 3 months of survival to HCC patients, emphasising the urgent need to identify novel molecular targets to develop more effective therapies.1 

Chronic liver disease progression towards HCC development as well as HCC progression are highly affected by microenvironmental cues in a very complex scenario involving inter-relationships between cells (cancer cells, tumour-associated macrophages or fibroblasts and cancer stem cells) as well as processes or events like inflammatory response, fibrogenic progression, autophagy, hypoxic conditions and oxidative stress.2 In particular, an increase in intracellular levels of reactive oxygen species (ROS) represents a common feature of cancer cells which is usually counterbalanced by an upregulation of antioxidant defenses, particularly through the relevant Kelch-like ECH-associated protein 1 (KEAP1) and nuclear factor erythroid 2-related factor 2 (NRF2) pathway.3 In this pathway, KEAP1, a E2-ligase which is normally negatively regulating NRF2 protein stability via ubiquitin–proteasome degradation, is inactivated under oxidative stress; this preserves NRF2 from degradation and allows its nuclear translocation and binding to antioxidant response element (ARE) sequences in the promoter of antioxidant genes, displacing BTB domain and CNC homolog 1 (BACH1, the selective …
Abstract 625: Mixed Lineage Kinase 3 Regulates Blood Pressure Through Kinase Independent Effects in the Vasculature
Authors: Timothy D Calamaras, Robert A Baumgartner, Mark Aronovitz, Joseph McCarthy, Kelly Tam, Seung Kyum Kim, Gregory Martin, Daniel A Richards, Paulina Baca, Iris Z Jaffe, Robert M BLANTON
Journal: Circulation Research (2019)

Background: Mixed lineage kinase 3 (MLK3) opposes pathologic cardiac remodeling, but its role in blood pressure (BP) has not been studied. MLK3 activates JNK signaling through kinase-dependent effects, and opposes RhoA activation through kinase-independent mechanisms, but the relevance of these mechanisms to BP is unknown. We investigated the effect of genetic deletion of MLK3 on BP. Methods and Results: Using ambulatory telemetric monitoring in 3 month old male mice, MLK3 -/- mice had significant hypertension compared to wild type (WT) littermates (WT systolic BP 121 ± 2 mmHg, MLK3-/- 162 ± 5 mmHg; n=3; p&lt;0.05). The MLK3 kinase inhibitor URMC-099 (10 mg/kg IP) did not affect BP in WT mice. By contrast, inhibition of downstream RhoA dependent Kinase (ROCK) with Y-27632 (15 mg/kg) fully normalized BP in MLK3 -/- mice (SBP WT baseline 126 ± 2 mmHg; WT ROCK inhibitor 94 ± 2 mmHg; MLK-/- baseline 163 ±6 mmHg; MLK3 -/- ROCK inhibitor 94 ± 12 mmHg; n=5 WT, 9 MLK3-/-). Aortic pulse wave velocity was elevated in MLK-/- mice (2.7 ± 0.1 mm/ms WT vs 3.6 ± 0.2 mm/ms MLK3-/-; p&lt;0.05) indicating increased aortic stiffness. Pressure myography in mesenteric resistance arterioles of MLK3 -/- mice revealed reduced distensibility compared to WT. Both pressure myography and direct histological measurement in resistance arterioles demonstrated reduced passive luminal diameter but preserved wall cross sectional area in MLK3-/- arterioles, indicating eutrophic remodeling. Compared with dispersed aortic smooth muscle cells from WT littermates, MLK3 -/- cells had increased actin stress fiber accumulation and cell area. Summary and Conclusions: These data demonstrate that MLK3 deletion leads to hypertension with increased arterial stiffness, reduced distensibility and eutrophic remodeling of resistance vessels, but retained BP responsiveness to downstream ROCK inhibition. Together with previous work, these findings support that MLK3 modulates cardiac remodeling through a kinase dependent mechanism while modulating blood pressure through kinase-independent effects. Because hypotension limits many heart failure therapies, delineating vascular versus cardiac mechanisms of MLK3 signaling has the potential to suggest novel approaches to heart failure treatment.
Abstract 701: Mesenchymal Stem Cells Overexpressing FGF21 Improve Functional Recovery After Traumatic Brain Injury
Authors: Kai-Yun Chen, Rami A Shahror, Chung-Che Wu, Yung-Hsiao Chiang
Journal: Circulation Research (2019)

Traumatic Brain Injury (TBI) is a progressive and complex brain injury that results in many adverse and long term neurological consequences. Fibroblast growth factor 21 (FGF21) is a novel metabolic regulator that has emerged as a therapeutic agent for the treatment of neurodegenerative diseases and brain injuries, as it has been shown to exhibit neuroprotective effects, promote remyelination, enhances angiogenesis, and to stimulate the neurite growth of glia-like cells. In this study, MSCs were genetically engineered to overexpress fibroblast growth factor 21 (FGF21) in order to improve their efficacy in TBI. MSCs overexpressing FGF21 (MSC-FGF21) were transplanted to mouse brain by intracerebroventricular (ICV) injection 24 hours after TBI. Spatial learning and memory tests were performed to examine the effects of MSC-FGF21 at 24 hours following controlled cortical impact (CCI) insult in TBI mice model. We found the FGF21 levels were reduced in the hippocampus of vehicle- treated group mice and that MSC-FGF21 treatment restored the FGF21 level significantly. MSC-FGF21 treatment significantly reduced spatial learning/memory decline at 21 days post injury as measured in the Morris water maze test. Both MSC-mCherry (vehicle control) and MSC-FGF21 treatments induced a significant improvement in short term memory formation as determined by the novel object recognition test (NOR) after 14 days of injury. In addition, MSC-FGF21treatment significantly increased the impaired neurogenesis and restored the dendritic process and morphology of immature neurons in the hippocampal dentate gyrus (DG). Taken together, these data provide compelling evidence that MSC-FGF21 treatment promotes neurogenesis and hippocampal neuroplasticity following TBI insult.
Abstract 735: A Novel Class of Sphingolipids Mediate Autophagy and Apoptosis in Models of Ischemia
Authors: Anna Kovilakath, A. Lauren Cowart
Journal: Circulation Research (2019)

Rationale: Heart failure caused by ischemic cardiomyopathy is the leading cause of death and disability in the USA and world, accounting for 10 million deaths in 2016. Sphingolipids including ceramides and sphingosine-1-phosphate have been demonstrated to play roles in myocardial injury. In general, these lipids are synthesized from serine palmitoyltransferase (SPT) derived using serine and palmitoyl-CoA. While the standard SPT enzyme exists as a heterodimer of two subunits, Sptlc1 and Sptlc2, a new subunit was recently discovered, Sptlc3, which enables the SPT complex to use myristoyl-CoA, thereby synthesizing a previously underappreciated group of atypical sphingolipids. We previously demonstrated that these atypical lipids are a major component of myocardial sphingolipid pools. Furthermore, in contrast to canonical sphingolipids, the atypical lipids promote cardiomyocyte apoptosis. Therefore, the goal of this research is to determine the contribution of these novel lipids to cardiomyocyte apoptosis and therefore whether they may contribute to ischemic injury. Objectives: To determine the contribution of Sptlc3 and atypical sphingolipids to cardiomyocyte apoptosis and ischemic injury and to assess the potential relevance of Sptlc3 to human HF. Methods: Murine primary cardiac fibroblasts and cardiomyocytes were isolated and subject to ischemic induction. Following this, cells were analyzed with TUNEL staining, lipidomic analysis or treatment with a Sptlc3 mimetic. Results: Ischemic cells show significantly increased Sptlc3 expression, non-canonical sphingolipids in the sphingolipid pool and apoptotic cells as compared to their controls. The cells treated with the Sptlc3 mimetic show apoptotic and a non-canonical autophagic pathway being induced in cells. Conclusions: We have identified a novel class of sphingolipids enriched in myocardium of mice with cardiomyopathies. Furthermore, the enzyme that produces these, Sptlc3, is robustly increased in human heart failure. Because the Sptlc3-derived lipids promoted cardiomyocyte apoptosis, we propose that Sptlc3 may mediate myocardial injury in ischemia.
Intensification Of Treosulfan and Fludarabine-Based Conditioning With 4 Gy TBI For Allogeneic Stem Cell Transplantation In Patients With Hematological Malignancies
Authors: Fabio Giglio, Corrado Zuanelli Brambilla, Francesca Lorentino, Simona Piemontese, Lara Crucitti, Giorgia Levati, Raffaella Greco, Mara Morelli, Carlo Messina, Alessandra Forcina, Maria Teresa Lupo Stanghellini, Luca Vago, Sarah Marktel, Magda Marcatti, Andrea Assanelli, Consuelo Corti, Massimo Bernardi, Chiara Bonini, Fabio Ciceri, Jacopo Peccatori
Journal: Blood (2013)