tbuckley/cabot-search huggingface dataset:
Lifetime stress accelerates epigenetic aging in an urban, African American cohort: relevance of glucocorticoid signaling
Authors: Anthony S. Zannas, Janine Arloth, Tania Carrillo-Roa, Stella Iurato, Simone Röh, Kerry J. Ressler, Charles B. Nemeroff, Alicia K. Smith, Bekh Bradley, Christine Heim, Andreas Menke, Jennifer F. Lange, Tanja Brückl, Marcus Ising, Naomi R. Wray, Angelika Erhardt, Elisabeth B. Binder, Divya Mehta
Journal: Genome biology (2015)

Chronic psychological stress is associated with accelerated aging and increased risk for aging-related diseases, but the underlying molecular mechanisms are unclear. We examined the effect of lifetime stressors on a DNA methylation-based age predictor, epigenetic clock. After controlling for blood cell-type composition and lifestyle parameters, cumulative lifetime stress, but not childhood maltreatment or current stress alone, predicted accelerated epigenetic aging in an urban, African American cohort (n = 392). This effect was primarily driven by personal life stressors, was more pronounced with advancing age, and was blunted in individuals with higher childhood abuse exposure. Hypothesizing that these epigenetic effects could be mediated by glucocorticoid signaling, we found that a high number (n = 85) of epigenetic clock CpG sites were located within glucocorticoid response elements. We further examined the functional effects of glucocorticoids on epigenetic clock CpGs in an independent sample with genome-wide DNA methylation (n = 124) and gene expression data (n = 297) before and after exposure to the glucocorticoid receptor agonist dexamethasone. Dexamethasone induced dynamic changes in methylation in 31.2 % (110/353) of these CpGs and transcription in 81.7 % (139/170) of genes neighboring epigenetic clock CpGs. Disease enrichment analysis of these dexamethasone-regulated genes showed enriched association for aging-related diseases, including coronary artery disease, arteriosclerosis, and leukemias. Cumulative lifetime stress may accelerate epigenetic aging, an effect that could be driven by glucocorticoid-induced epigenetic changes. These findings contribute to our understanding of mechanisms linking chronic stress with accelerated aging and heightened disease risk.
MicroRNA-31 initiates lung tumorigenesis and promotes mutant KRAS-driven lung cancer
Authors: Mick D. Edmonds, Kelli L. Boyd, Tamara Moyo, Ramkrishna Mitra, Robert Duszynski, Maria Pia Arrate, Xi Chen, Zhongming Zhao, Timothy S. Blackwell, Thomas Andl, Christine M. Eischen
Journal: Journal of Clinical Investigation (2015)

MicroRNA (miR) are important regulators of gene expression, and aberrant miR expression has been linked to oncogenesis; however, little is understood about their contribution to lung tumorigenesis. Here, we determined that miR-31 is overexpressed in human lung adenocarcinoma and this overexpression independently correlates with decreased patient survival. We developed a transgenic mouse model that allows for lung-specific expression of miR-31 to test the oncogenic potential of miR-31 in the lung. Using this model, we observed that miR-31 induction results in lung hyperplasia, followed by adenoma formation and later adenocarcinoma development. Moreover, induced expression of miR-31 in mice cooperated with mutant KRAS to accelerate lung tumorigenesis. We determined that miR-31 regulates lung epithelial cell growth and identified 6 negative regulators of RAS/MAPK signaling as direct targets of miR-31. Our study distinguishes miR-31 as a driver of lung tumorigenesis that promotes mutant KRAS-mediated oncogenesis and reveals that miR-31 directly targets and reduces expression of negative regulators of RAS/MAPK signaling.
Functional Human Podocytes Generated in Organoids from Amniotic Fluid Stem Cells
Authors: Christodoulos Xinaris, Valentina Benedetti, Rubina Novelli, Mauro Abbate, Paola Rizzo, Sara Conti, Susanna Tomasoni, Daniela Corna, Michela Pozzobon, Daniela Cavallotti, Takashi Yokoo, Marina Morigi, Ariela Benigni, Giuseppe Remuzzi
Journal: Journal of the American Society of Nephrology (2015)

Generating kidney organoids using human stem cells could offer promising prospects for research and therapeutic purposes. However, no cell-based strategy has generated nephrons displaying an intact three-dimensional epithelial filtering barrier. Here, we generated organoids using murine embryonic kidney cells, and documented that these tissues recapitulated the complex three-dimensional filtering structure of glomerular slits in vivo and accomplished selective glomerular filtration and tubular reabsorption. Exploiting this technology, we mixed human amniotic fluid stem cells with mouse embryonic kidney cells to establish three-dimensional chimeric organoids that engrafted in vivo and grew to form vascularized glomeruli and tubular structures. Human cells contributed to the formation of glomerular structures, differentiated into podocytes with slit diaphragms, and internalized exogenously infused BSA, thus attaining in vivo degrees of specialization and function unprecedented for donor stem cells. In conclusion, human amniotic fluid stem cell chimeric organoids may offer new paths for studying renal development and human podocyte disease, and for facilitating drug discovery and translational research.
Phase I trial of ImmunoBody in melanoma patients.
Authors: Poulam M. Patel, Lindy G Durrant, Christian Ottensmeier, Clive Mulatero, Paul Lorigan, Ruth Plummer, Michelle Cunnell, Rachael Metheringham, Victoria Brentville, Lee Machado, Ian Daniels, Drew Hannaman
Journal: Journal of Clinical Oncology (2014)

3061 Background: ImmunoBody is a DNA vaccine encoding a human IgG1 antibody with T cell epitopes grafted into its CDR regions. SCIB1 has 3 epitopes grafted from gp100 and one from TRP-2 antigens. The vaccine targets dendritic cells in vivo and stimulates high avidity T cells which result in elimination of established tumors in pre-clinical models. A clinical trial was conducted to determine safety and its ability to induce cellular immune responses. Methods: The vaccine was administered via Intramuscular injection with electroporation at 3 weekly intervals for 3 vaccinations, then at 3 and 6 months. In part 1 of the study,one patient with Stage III and 8 with stage IV melanoma were given escalating doses of SCIB1. The 4mg dose was selected for an expansion cohort (part 2) in fully resected patients, 8 with stage III and 6 with stage IV melanoma. Due to lack of toxicity a five further patients with stage IV M1b disease were given 8mg doses. Results: No dose-limiting toxicities were observed. The most common adverse event was injection site pain. 4/6 patients in the 2mg/4mg cohorts who received >3 doses of SCIB1, are still alive with a median survival time of 26 months. One patient had multiple tumor lesions which all decreased in size or disappeared following treatment except for one lesion which was resected. Immunohistochemistry demonstrated strong expression of PD.L1 on the tumor cells. All patients in part 2 remain alive and only three have progressed. The median survival time in Part 2 is 17 months from study entry and 22 months from diagnosis of metastatic disease. In part 1, one patient in the 0.4mg cohort, all three patients in the 2mg dose cohort and two patients in the 4mg dose cohort mounted an immune response to the vaccine-encoded antigens. 4/5 patients in the 8mg cohort made a γIFN elispot response after T cell expansion in-vitro with frequencies exceeding 2% of blood lymphocytes. In part 2, all 14 patients responded immunologically. Six patients responded to all 4 epitopes, five patients responded to 3 epitopes and 3 patients responded to 2 epitopes. Conclusions: We demonstrate that SCIB1 is safe. Of 25 evaluable patients, 23 have shown immune responses following repeat dosing with 2 -8 mg of SCIB1. Detection of an objective clinical response and overall survival times are encouraging. Clinical trial information: NCT01138410.
Effect of low doses of actinomycin D on neuroblastoma cell lines
Authors: Constanza L. Cortes, Sonia R. Veiga, Eugènia Almacellas, Javier Hernández-Losa, Joan C. Ferreres, Sara C. Kozma, Santiago Ambrosio, George Thomas, Albert Tauler
Journal: Molecular Cancer (2016)

Neuroblastoma is a malignant embryonal tumor occurring in young children, consisting of undifferentiated neuroectodermal cells derived from the neural crest. Current therapies for high-risk neuroblastoma are insufficient, resulting in high mortality rates and high incidence of relapse. With the intent to find new therapies for neuroblastomas, we investigated the efficacy of low-doses of actinomycin D, which at low concentrations preferentially inhibit RNA polymerase I-dependent rRNA trasncription and therefore, ribosome biogenesis. Neuroblastoma cell lines with different p53 genetic background were employed to determine the response on cell viability and apoptosis of low-dose of actinomycin D. Subcutaneously-implanted SK-N-JD derived neuroblastoma tumors were used to assess the effect of low-doses of actinomycin D on tumor formation. Low-dose actinomycin D treatment causes a reduction of cell viability in neuroblastoma cell lines and that this effect is stronger in cells that are wild-type for p53. MYCN overexpression contributes to enhance this effect, confirming the importance of this oncogene in ribosome biogenesis. In the wild-type SK-N-JD cell line, apoptosis was the major mechanism responsible for the reduction in viability and we demonstrate that treatment with the MDM2 inhibitor Nutlin-3, had a similar effect to that of actinomycin D. Apoptosis was also detected in p53−/−deficient LA1-55n cells treated with actinomycin D, however, only a small recovery of cell viability was found when apoptosis was inhibited by a pan-caspase inhibitor, suggesting that the treatment could activate an apoptosis-independent cell death pathway in these cells. We also determined whether actinomycin D could increase the efficacy of the histone deacetylase inhibitor, SAHA, which is in being used in neuroblastoma clinical trials. We show that actinomycin D synergizes with SAHA in neuroblastoma cell lines. Moreover, on subcutaneously-implanted neuroblastoma tumors derived from SK-N-JD cells, actinomycin D led to tumor regression, an effect enhanced in combination with SAHA. The results presented in this work demonstrate that actinomycin D, at low concentrations, inhibits proliferation and induces cell death in vitro, as well as tumor regression in vivo. From this study, we propose that use of ribosome biogenesis inhibitors should be clinically considered as a potential therapy to treat neuroblastomas.
Hypomelanotic melanoma mimicking pigmented Bowen disease
Authors: Juliana Casagrande Tavoloni Braga, Francisco Macedo Paschoal, Tatiana Cristina Moraes Pinto Blumetti, Maria Bussade, João Duprat, Gilles Landman, Gisele Gargantini Rezze
Journal: Journal of the American Academy of Dermatology (2015)
In Vivo Imaging of Hypoxia in Atherosclerotic Plaques in Humans
Authors: Fleur M. van der Valk, Judith C. Sluimer, Stefan A. Vöö, Hein J. Verberne, Aart J. Nederveen, Albert D. Windhorst, Erik S.G. Stroes, Philippe Lambin, Mat J.A.P. Daemen
Journal: JACC. Cardiovascular imaging (2015)
Abstract 3510: Novel lysine demethylase LSD1 inhibitors promote differentiation and apoptosis of glioma stem cells
Authors: Gangadhara R. Sareddy, Takayoshi Suzuki, Andrew J. Brenner, Ratna K. Vadlamdui
Journal: Cancer Research (2015)

Abstract Glioblastoma (GBM) is the most common and devastating primary tumor of the central nervous system with dismal prognosis. GBM development is a multistep process, involving alterations in genetic and epigenetic mechanisms. Understanding the mechanisms and enzymes that promote epigenetic changes in GBM are urgently needed to identify novel therapeutic targets. Recent studies demonstrated that Glioma Stem Cells (GSCs) play central roles in GBM development and responsible for tumor propagation, invasion and chemo/radiation resistance. GSCs elimination is critical for development of efficient therapeutic strategies for GBM. Recently, we showed that lysine demethylase LSD1 is overexpressed in GBM and its inhibition reduces proliferation of GBM cells. In this study, we tested whether, LSD1 modulates GSCs differentiation and novel LSD1 inhibitors (NCL-1 and NCD-38) promote differentiation and apoptosis of GSCs. We have isolated GSCs using well established stem markers (CD133 and CD15) from two established and two patient derived GBM cells. Functionality of GSCs was established using self-renewal assays, and by profiling stem cell marker expression. Western analysis of purified GSCs showed that LSD1 is highly expressed in purified GSCs. Differentiation of GSCs resulted in decreased expression of LSD1. Down regulation of LSD1 expression using lentiviral LSD1-shRNA or by pharmacological inhibition (NCL-1 and NCD-38) significantly reduced the proliferation, neurosphere formation and self-renewal ability of GSCs with little or no effect on normal astrocytes and differentiated cells. Accordingly, treatment of GSCs with LSD1 inhibitors resulted in a dramatic reduction in the expression of stemness markers and promoted induction of differentiation markers. RNA sequencing analysis of GSCs treated with or without LSD1 inhibitors, revealed that LSD1 inhibitors modulate several pathways related to stem ness, differentiation and apoptosis. The expression of top five genes and three pathways were validated using q-RT-PCR, and western blot analysis. Chromatin Immunoprecipitation assays confirmed significant alternations in epigenetic markers at LSD1 target genes. Further, LSD1 inhibitors significantly reduced the growth of GSC driven tumors in vivo. Taken together, these results provided the evidence that induction of GSCs differentiation and apoptosis following LSD1 inhibition as a promising approach to eradicate GSCs. Citation Format: Gangadhara R. Sareddy, Takayoshi Suzuki, Andrew J. Brenner, Ratna K. Vadlamdui. Novel lysine demethylase LSD1 inhibitors promote differentiation and apoptosis of glioma stem cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3510. doi:10.1158/1538-7445.AM2015-3510
Insulin Resistance and LVH Progression in Patients With Calcific Aortic Stenosis
Authors: Romain Capoulade, Marie-Annick Clavel, Jean G. Dumesnil, Kwan L. Chan, Koon K. Teo, James W. Tam, Nancy Côté, Patrick Mathieu, Jean-Pierre Després, Philippe Pibarot
Journal: JACC. Cardiovascular imaging (2013)
Erratum to “Saikosaponin b2 is a naturally occurring terpenoid that efficiently inhibits hepatitis C virus entry” [J Hepatol 2015;62:541–548]
Authors: Liang-Tzung Lin, Chueh-Yao Chung, Wen-Chan Hsu, Shun-Pang Chang, Ting-Chun Hung, Justin Shields, Rodney S. Russell, Chih-Chan Lin, Chien-Feng Li, Ming-Hong Yen, D. Lorne J. Tyrrell, Chun-Ching Lin, Christopher D. Richardson
Journal: Journal of Hepatology (2015)
...or are they?
Authors: J. Le Fanu
Journal: BMJ (1995)

and 73% (3147/4286) in those in category 7.Conversely, the proportions of pregnancies that resulted in termination were 50% (362/731) in women in deprivation category 1 and 14% (602/4286) in those in category 7. When planning health services to meet the needs of the population it is obviously essential to have information by deprivation category.
Abstract 16388: Residual SYNTAX Score and Survival Following Coronary Artery Bypass Grafting: Analysis of 1608 Patients
Authors: Giovanni Melina, Emiliano Angeloni, Simone Refice, Cristian V Benegiamo, Andrea Lechiancole, Antonino Roscitano, Roberto Bianchini, Pierpaolo Spitaleri, Fabio Capuano, Cosimo Comito, Massimo Goracci, Stefano Rosato, Fulvia Seccareccia, Francesco Monti, Roberto Serdoz, Furio Colivicchi, Francesco Paneni, Riccardo Sinatra
Journal: Circulation (2014)

Introduction: We and others have previously shown that SYNTAX score predicts outcome in patients undergoing coronary artery bypass grafting (CABG). More recently, the residual SYNTAX score (rSS) has emerged as a reliable tool to quantify the extent and complexity of untreated coronary lesions after percutaneous coronary intervention (PCI). Indeed, rSS is an independent predictor of morbidity and mortality following PCI. Whether rSS may help to stratify mortality risk after CABG remains largely unknown. Hypothesis: The present study was designed to investigate the predictive value of rSS on mortality risk in a prospective cohort of patients undergoing surgical revascularization. Methods: Average baseline SYNTAX score calculated on 1608 patients (mean age 68±6 years, F:M 213:1395) undergoing isolated first-time CABG was 26.6 ± 9.4. The rSS measured after CABG was 3.2 ± 1.8 (p&lt;0.001 vs baseline). Complete revascularization was assumed as rSS=0. Based on rSS tertiles, the study population was stratified in low rSS (0&lt;rSS&lt;2), intermediate rSS (2&lt;rSS&lt;8) and high rSS (rSS&gt;8). Results: Following CABG, 1157/1608 (71.9%) patients had rSS=0, whereas 209/1608 (12.9%) had low rSS, 176/1608 (10.9%) had intermediate rSS and 66/1608 (4.1%) had high rSS. At Kaplan-Meier analysis of survival subjects in the highest rSS tertile (rSS&gt;8) showed significant worse survival as compared to patients with rSS=0, 0&lt;rSS&lt;2 and 2&lt;rSS&lt;8 (χ 2 77.1, p&lt;0.0001). Cox proportional-hazards regression analysis adjusted for age, gender, diabetes, preoperative LV and renal function showed rSS to be an independent predictor of 1-year survival (b 0.48, p&lt;0.0001). Conclusions: These unanticipated findings suggest that residual SYNTAX score may stratify mortality risk in patients undergoing isolated first-time CABG. Our study may set the stage for further investigation addressing this important clinical question.
STUDIES ON FERMENT ACTION
Authors: James W. Jobling, Solomon Strouse
Journal: The Journal of Experimental Medicine (1912)

1. Leucoprotease splits pneumococci into lower cleavage products than are obtained with the autolytic ferment contained in the pneumococci. 2. Such cleavage products injected into rabbits have the property of producing immune bodies in the blood of the injected animals. 3. These experiments indicate that proteolysis plays a part in the production of pneumococcus immunity.
A phase II trial of bortezomib plus lenalidomide for relapsed/refractory mantle cell lymphoma (MCL) (CALGB 50501).
Authors: V. A. Morrison, S. Jung, J. L. Johnson, J. Leonard, B. D. Cheson
Journal: Journal of Clinical Oncology (2011)

TPS223 Background: Despite high response rates to MCL induction therapy, relapse is common. Stem cell transplant (SCT) is often utilized, though not curative in most patients (pts), and many are not candidates due to age or comorbidities. Thalidomide and bortezomib have demonstrated activity in MCL. In a phase II trial of rituximab+thalidomide, including thalidomide maintenance, in relapsed/refractory MCL pts, overall/complete response rate (ORR/CR) was 81/31%; median progression free survival (PFS) was 20.4 months; 3-year overall survival (OS) was 75%. In a phase II bortezomib trial with 141 evaluable MCL pts, ORR/CR was 33/8%, with median remission duration (MRD) 9.2 months (mos), and median time to progression (TTP) 6.2 mos. Grade (gr) 3/4 toxicities were peripheral neuropathy (13%), fatigue (12%), and thrombocytopenia (11%). Bortezomib+lenalidomide has been studied in relapsed/refractory myeloma pts, with 61% achieving >minimal response, with MRD of 10.8 mos and acceptable tolerability. Methods: Eligibility criteria: histologically-documented MCL (CD5+, CD23-, cyclin D1+); measurable disease; prior therapy with >1 regimen, including autologous, but not allogeneic, SCT; age ≥18 yrs; no prior radioimmunotherapy; no ≥gr 3 peripheral neuropathy; performance status 0-2. Treatment: Induction: bortezomib 1.3 mg/m2 IV, d1,4,8,11; lenalidomide 20 mg/day PO, d1-14; 21d cycle, 8 cycles. Maintenance (for responders): bortezomib 1.3 mg/m2 IV, d1,8; lenalidomide 15 mg/day PO, d1-14; 21d cycle, till disease progression. Primary endpoint is ORR/CR; secondary endpoints are TTP, disease-free and OS, and correlation of changes in NK/T-cells and plasma cytokines with response. The protocol was modified in 9/09 with separate dose reductions by agent (e.g., myelosuppression-lenalidomide; neuropathy-bortezomib). Accrual: Accrual goal is 54 (49 evaluable) pts. The study was activated in 11/07; a planned interim analysis occurred after 19 patients, with >10 responses required to continue the trial. As of 1/11/11, 48 pts are accrued, with completion anticipated for 6/2011.
Platelet polymorphisms and ischemic heart disease: moving beyond traditional risk factors∗∗Editorials published in the Journal of the American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of JACCor the American College of Cardiology.
Authors: David E Kandzari, Pascal J Goldschmidt-Clermont
Journal: Journal of the American College of Cardiology (2001)
Abstract 14912: Preventability of 30-Day Readmission After PCI
Authors: Jason H Wasfy, Jordan B Strom, Neil J Wimmer, Adrian Zai, Jennifer Luttrell, John A Spertus, Sharon-Lise T Normand, Laura Mauri, Robert W Yeh
Journal: Circulation (2013)

Introduction: Early readmission after PCI is an important contributor to health care expenditures, and a target for performance measurement. The extent to which 30-day readmissions after PCI are pr...
The Prognostic Value of Monocyte Chemoattractant Protein-1/CCL2 in Acute Coronary Syndromes⁎⁎Editorials published in the Journal of the American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of JACCor the American College of Cardiology.
Authors: Nikolaos G. Frangogiannis
Journal: Journal of the American College of Cardiology (2007)
O044 : Distinct fecal and plasma bile acid metabolome of microbial origin characterizes human nonalcoholic fatty liver disease (NAFLD)
Authors: P. Puri, S.M. Siddiqui, S. Boyette, C. Sargeant, L.D. White, S. Walker, K. Daita, C. Ammons, S. Cazanave, A. Asgharpour, F. Mirshahi, A. Joyce, A.J. Sanyal
Journal: Journal of Hepatology (2015)