tbuckley/cabot-search huggingface dataset:
Abstract 5305: DNA methylation and gene expression in melanoma: A large-scale integrated analysis
Authors: Saverio Candido, Giuseppe A. Parasiliti Palumbo, Giulia Russo, Luca Falzone, Giulia C. Leonardi, Francesco Pappalardo, Massimo Libra
Journal: Cancer Research (2018)

Abstract Dysregulation of DNA methyltransferase activity, through global hypomethylation and localized hypermethylation phenomena, has been associated with cancer development. Even though the role of promoter methylation in gene regulation has been widely described, the regulatory function of methylation status of intergenic and intragenic regions has been not yet clarified. High-throughput technology and bioinformatics analysis represent useful tools to investigate the functional role of global methylation patterns in gene regulation. Therefore, a specific bionformatic tool was generated to identify methylation hotspots as well as extended genomic methylation regions in order to analyze specific genetic methylation patterns associated with cancer gene deregulation. In the present study, melanoma was selected as tumor model for its aggressive phenotype. Melanoma samples were obtained from the Cancer Genome Atlas (TCGA) to analyze DNA methylation and gene expression profiling data. We developed an algorithm, using R language, that performs cyclic correlation analysis between gene expression and methylation levels of all genes. Our results show that in melanoma there are different methylation patterns that positively and negatively correlate with gene expression. In particular, the hypomethylation of the promoter (TSS1500, TSS200, 5'UTR) leads to the over-expression of selected gene (p&amp;lt;0.01) while the hypermethylation of gene body and 3'UTR regions were associated with gene over-expression. Furthermore, the frequency of genes showing a global hypomethylation status was higher compared to those that were hypermethylated (70% vs 30%). We have also identified the main individual CG probesets and methylated regions that are differentially correlated with gene expression. A further pathway analysis shows that the identified genes are implicated in central cellular processes associated with melanoma. Our algorithm allows the identification of methylation hotspots involved in the regulation of key genes for melanoma development. This may contribute to the development of new therapeutic strategies targeting methylome alterations in melanoma cells. Moreover, the identification of methylation hotspots associated to cancer initiation and progression can represent useful biomarkers for patients' risk stratification. Citation Format: Saverio Candido, Giuseppe A. Parasiliti Palumbo, Giulia Russo, Luca Falzone, Giulia C. Leonardi, Francesco Pappalardo, Massimo Libra. DNA methylation and gene expression in melanoma: A large-scale integrated analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5305.
Hereditary Breast and Ovarian Cancer Testing in the Genomic Era
Authors: Stephanie L. Greville-Heygate, Diana M. Eccles, Lucy E. Side
Journal: JAMA Oncology (2018)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Oncology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Oncology journal
Reducing the opioid overdose death toll in North America
Authors: Wayne D. Hall, Michael Farrell
Journal: PLoS Medicine (2018)

Over the past two decades, the United States population has experienced an extraordinary increase in the rates of death from opioid overdose.A steep rise in fatal overdoses caused by pharmaceutical opioids observed over the last 15 years [1] has been overtaken by rapidly increasing rates of heroin and illicit fentanyl overdose death as the supply of prescription opioids has been reduced [2].In 2017, there were estimated to be 68,400 drug overdose deaths in the US [3], more than the annual number of deaths from AIDS at the height of that epidemic.These deaths have contributed to an overall decrease in life expectancy among middle-aged white people in the US [4].Research by Angela Russolillo and colleagues, published this week in PLOS Medicine [5], highlights an effective way of reducing these opioid overdose deaths, namely by increasing the number of opioid-dependent persons who receive methadone-assisted treatment.The authors studied mortality in a high-risk population of 14,530 opioid-dependent offenders in British Columbia, Canada who were treated and followed-up using death and treatment registers from 1998 to 2015.Their findings showed that receipt of methadone-assisted treatment in the community substantially reduced mortality from external causes of death (adjusted hazard ratio [AHR] = 0.41 [95% CI 0.33-0.51])and nonexternal causes of death (AHR = 0.27 [95% CI 0.23-0.33])as well as substantially reducing the risk of death from opioid overdose (AHR = 0.39 [95% CI 0.30-0.50]).These differences persisted after controlling for potential confounders and when a competing risks analysis was conducted.Opioid-dependent offenders are a population at high risk of fatal opioid overdose for several reasons.They have a very elevated risk of overdosing when they leave prison with a reduced tolerance and return to opioid use, as most do without treatment [6].The risk of dying accumulates with repeated cycles of incarceration and release.These offenders are also often of low socioeconomic status, have high rates of homelessness, and are less likely to seek, or receive, treatment for their opioid dependence.As Russolillo and colleagues show, despite these disadvantages, opioid-dependent offenders who were enrolled in methadone-assisted treatment had a much lower risk of dying from an opioid overdose.There are additional good public health reasons for expanding methadone-assisted treatment for opioid dependence.Systematic reviews of clinical trials and observational studies show that methadone reduces the frequency of illicit opioid use, the criminal activity that users engage in to fund their opioid use, and their risk of rearrest [7].It also reduces infection and transmission of blood-borne virus infections, such as hepatitis C and HIV [7].US President Donald Trump has declared opioid overdose deaths a public health emergency and appointed a commission to advise him on how to end it [8].The Commission's
Acute Regulation of Fatty Acid Oxidation and AMP-Activated Protein Kinase in Human Umbilical Vein Endothelial Cells
Authors: ZeinaDagher, NeilRuderman, KeithTornheim, YasuoIdo
Journal: Circulation Research (2001)

Abstract—It is generally accepted that endothelial cells generate most of their ATP by anaerobic glycolysis and that very little ATP is derived from the oxidation of fatty acids or glucose. Previously, we have reported that, in cultured human umbilical vein endothelial cells (HUVECs), activation of AMP-activated protein kinase (AMPK) by the cell-permeable activator 5-aminoimidazole-4-carboximide riboside (AICAR) is associated with an increase in the oxidation of 3H-palmitate. In the present study, experiments carried out with cultured HUVECs revealed the following: (1) AICAR-induced increases in palmitate oxidation during a 2-hour incubation are associated with a decrease in the concentration of malonyl coenzyme A (CoA) (an inhibitor of carnitine palmitoyl transferase 1), which temporally parallels the increase in AMPK activity and a decrease in the activity of acetyl CoA carboxylase (ACC). (2) AICAR does not stimulate either palmitate oxidation when carnitine is omitted from the medium or oxidation of th...
Abstract 14824: Lysine Demethylase 6A and 7A Regulated by MicroRNA-3679-5p Mediates TNF-α-induced Inflammatory Signaling in Vascular Endothelium
Authors: Yoshiki Higashijima, Tsuyoshi Inoue, Masaomi Nangaku, Youichiro Wada, Tetsushi Furukawa, Yasuharu Kanki
Journal: Circulation (2017)

Endothelial cell (EC) activation and dysfunction underlie many vascular disorders such as diabetic nephropathy and atherosclerosis. We have already reported that various kinds of inflammatory cytok...
Abstract 2830: Understanding chemotherapy-induced replicative stress to identify rational combination therapies
Authors: Ozan Alkan, Birgit Schoeberl, Millie Shah, Alexander Koshkaryev, Tim Heinemann, Daryl Drummond, Michael B. Yaffe, Andreas Raue
Journal: Cancer Research (2018)

Abstract Cells respond to DNA damage by activating complex signaling networks that decide cell fate, promoting not only DNA damage repair and survival but also cell death. We have developed a multi-scale computational model using the U2OS osteosarcoma cancer cell line that quantitatively links chemotherapy-induced DNA damage response signaling to cell fate. The computational model was trained and calibrated based on an extensive data set that comprises cell cycle distribution of the initial cell population, signaling data measured by western blot, and cell fate data in response to chemotherapy treatment measured by time-lapse microscopy. The resulting mechanistic model can predict the cellular responses to chemotherapy alone and in combination with targeted inhibitors of the DNA damage response pathway, which we were able to confirm experimentally. Computational models, like the one presented here, can be used to understand the molecular basis that defines the complex interplay between cell survival and cell death, as well as to rationally identify chemotherapy-potentiating drug combinations. Citation Format: Ozan Alkan, Birgit Schoeberl, Millie Shah, Alexander Koshkaryev, Tim Heinemann, Daryl Drummond, Michael B. Yaffe, Andreas Raue. Understanding chemotherapy-induced replicative stress to identify rational combination therapies [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 2830.
Counteracting roles of MHCI and CD8+ T cells in the peripheral and central nervous system of ALS SOD1G93A mice
Authors: Giovanni Nardo, Maria Chiara Trolese, Mattia Verderio, Alessandro Mariani, Massimiliano de Paola, Nilo Riva, Giorgia Dina, Nicolò Panini, Eugenio Erba, Angelo Quattrini, Caterina Bendotti
Journal: Molecular Neurodegeneration (2018)

The major histocompatibility complex I (MHCI) is a key molecule for the interaction of mononucleated cells with CD8+T lymphocytes. We previously showed that MHCI is upregulated in the spinal cord microglia and motor axons of transgenic SOD1G93A mice.To assess the role of MHCI in the disease, we examined transgenic SOD1G93A mice crossbred with β2 microglobulin-deficient mice, which express little if any MHCI on the cell surface and are defective for CD8+ T cells.The lack of MHCI and CD8+ T cells in the sciatic nerve affects the motor axon stability, anticipating the muscle atrophy and the disease onset. In contrast, MHCI depletion in resident microglia and the lack of CD8+ T cell infiltration in the spinal cord protect the cervical motor neurons delaying the paralysis of forelimbs and prolonging the survival of SOD1G93A mice.We provided straightforward evidence for a dual role of MHCI in the peripheral nervous system (PNS) compared to the CNS, pointing out regional and temporal differences in the clinical responses of ALS mice. These findings offer a possible explanation for the failure of systemic immunomodulatory treatments and suggest new potential strategies to prevent the progression of ALS.
Abstract 118: Immuno-modulation of macrophages by ovarian cancer stem cells in an in vitro 3D spheroid platform
Authors: Shreya Raghavan, Geeta Mehta
Journal: Cancer Research (2018)

Abstract The ascites microenvironment of ovarian cancers is enriched in ovarian cancer stem cells (OvCSCs) and macrophages (MPs). The immune system is complicit in the progression, chemoresistance and metastasis of ovarian cancer, yet little is known about the exact nature of interactions between OvCSCs and MPs, especially in the malignant ascites microenvironment. Here, we describe the use of the 3D in vitro hanging drop spheroid platform to study the reciprocal interactions between OvCSCs and MPs. Hetero-spheroids contained: i) monocyte-derived Macrophages (MP); and ii) OvCSCs (ALDH+ CD133+ OVCAR3). For immuno-modulation, we characterized MP polarization markers by flow cytometry and gene expression analysis. Using qPCR, we quantified changes in IL6, IL10, IL12, and Wnt7A, to understand signaling involved in OvCSC/MP hetero-spheroids. CD68 expression (~50%) was observed in OvCSC/MP hetero-spheroids, indicating the presence of MPs. OvCSCs drove higher CD206 expression in MPs (75%) when compared to unsorted ovarian cancer cells (OvCa; 40%). Even if MPs were pre-polarized to inflammatory M1 (HLA-DR+ CD206-), co-culture with OvCSCs reversed the M1 phenotype, and strongly induced CD206 expression. Pre-polarized M2 MPs resulted in 2-fold increase in ALDH+ cells in hetero-spheroids. Apart from CD206, MPs in hetero-spheroids also expressed iNOS, IFN-ϒ, and CD163. Gene expression analysis revealed increased immuno-suppressive IL10 in hetero-spheroids, with more IL10 in OvCSC/MP (3.5 fold) compared to OvCa/MP. OvCSC/MP and OvCa/MP spheroid also had consistently elevated (2-3 fold) increase in IL6 gene expression, consistent with the importance of the IL6/STAT3 axis in both cancer stem cell and macrophage signaling. Lastly, Wnt7A was significantly elevated in both differentiated MPs, and OvCSC/MP spheroids, indicating reciprocal trophic and immuno-suppressive signaling components at play. The 3D spheroid model can simulate biological interactions between OvCSCs and MPs within the malignant ascites. We describe that OvCSCs primarily polarize macrophages into a mixed phenotype that express both inflammatory and pro-tumoral markers. We believe that the putative involvement of Wnt7a in OvCSC/MP interactions drives this phenotype, and could have functional implications for tumorigenicity, response to chemotherapeutics and metastatic potential. This work was supported by the DOD OCRP W81XWH-13-1-0134, MIOCA, Rivkin Center for Ovarian Cancer and NIH T32DE00007057-41 and P30CA046592. Citation Format: Shreya Raghavan, Geeta Mehta. Immuno-modulation of macrophages by ovarian cancer stem cells in an in vitro 3D spheroid platform [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 118.
Abstract 11968: Uninterrupted Chest Compressions does not Improve Hemodynamics During and After Cardiopulmonary Resuscitation in Asphyxiated Newborn Pigs
Authors: Anne Lee Solevåg, Georg M Schmölzer, Megan O’Reilly, Min Lu, Tze-Fun Lee, Etienne Fortin-Pellerin?, Lisa Hornberger, Po-Yin Cheung
Journal: Circulation (2015)

Introduction: Since asphyxia is the most common cause of a need for newborn cardiopulmonary resuscitation (CPR) the primary focus of CPR should be effective ventilation. Any intervention that interferes with ventilation should be introduced with caution. Thus, in newborn CPR it is recommended that chest compressions (CC) and ventilation be synchronized with a pause after every 3rd CC to deliver one effective ventilation, i.e. a CC to ventilation (C:V) ratio of 3:1. However, this recommendation is based on physiological plausibility, not scientific evidence. In adult CPR uninterrupted CC has been shown to improve hemodynamics including coronary perfusion pressure (CPP) and outcomes. Hypothesis: In a newborn piglet model, we hypothesized that continuous CC and asynchronous ventilation (CCaV) would improve CPR hemodynamics and time to return of spontaneous circulation (ROSC) vs. 3:1 C:V CPR. Methods: Thirty-two intubated piglets (1-3d old) were instrumented with a catheter in the left common carotid artery, asphyxiated until cardiac arrest and randomized to 3:1 C:V CPR or CCaV (n=16 in each group). In both groups, manual CC were performed and a metronome was used to help achieve 120 events (90 CC and 30 assisted ventilations)min-1. CPR characteristics and time to ROSC were compared between groups with the Mann-Whitney U test. Lactate was determined from homogenized left ventricle (LV) tissue collected 4 h after ROSC. Results: At cardiac arrest, median (IQR) arterial pH was 6.6 (6.5-6.9), paCO2 78 (48-97) mmHg and lactate 18 (15-19) mmol/L with no differences between groups. Characteristics of CPR and post-CPR recovery are presented in Table 1. Conclusions: Despite a modestly higher number of CCmin-1 CCaV did not improve DBP, a proxy for CPP during CPR, or ROSC. Mean arterial blood pressure after ROSC was slightly lower and LV lactate higher following CCaV vs. 3:1 C:V CPR. The results confirm the assumption that extrapolating evidence from adults to newborns is inappropriate.
Lats2 Is a Negative Regulator of Myocyte Size in the Heart
Authors: YutakaMatsui, NoritsuguNakano, DanShao, ShuminGao, WentingLuo, ChullHong, PeiyongZhai, EricHolle, XianzhongYu, NorikazuYabuta, WufanTao, ThomasWagner, HiroshiNojima, JunichiSadoshima
Journal: Circulation Research (2008)

Mammalian sterile 20–like kinase (Mst)1 plays an important role in mediating apoptosis and inhibiting hypertrophy in the heart. Because Hippo, a Drosophila homolog of Mst1, forms a signaling complex with Warts, a serine/threonine kinase, which in turn stimulates cell death and inhibits cell proliferation, mammalian homologs of Warts, termed Lats1 and Lats2, may mediate the function of Mst1. We here show that Lats2, but not Lats1, dose-dependently increased apoptosis in cultured cardiac myocytes. Lats2 also dose-dependently reduced [3H]phenylalanine incorporation and cardiac myocyte size, whereas dominant negative Lats2 (DN-Lats2) increased them, suggesting that endogenous Lats2 negatively regulates myocyte growth. DN-Lats2 significantly attenuated induction of apoptosis and inhibition of hypertrophy by Mst1, indicating that Lats2 mediates the function of Mst1 in cardiac myocytes. Cardiac specific overexpression of Lats2 in transgenic mice significantly reduced the size of left and right ventricles, wherea...
Determination of the Upper Limit of Vulnerability Using Implantable Cardioverter-Defibrillator Electrograms
Authors: CharlesSwerdlow, KalyanamShivkumar, JianxinZhang
Journal: Circulation (2003)

Background— The upper limit of vulnerability (ULV) correlates with the defibrillation threshold and can be determined with 1 episode of ventricular fibrillation (VF). To automate the ULV in an implantable cardioverter-defibrillator (ICD), the most vulnerable intervals must be identified from an ICD electrogram rather than the latest-peaking surface T wave (Tpeak). We hypothesized that the recovery time (TR), defined as the maximum derivative (dV/dt) of the T wave of the shock electrogram, correlates with the most vulnerable intervals. Methods and Results— We determined ULV, defibrillation threshold, and the most vulnerable intervals in 25 patients at ICD implantation. The ULV was the weakest T-wave shock that did not induce VF. The most vulnerable intervals were the ones associated with the strongest shocks that induced VF. Telemetered shock electrograms were stored on digital tape and differentiated offline to measure TR. Tpeak and TR were highly correlated (Tpeak−TR=−2±11 ms; ρ=0.80, P<0.001). At least ...
Хвороба Вільсона — Коновалова: алгоритм діагностики та підходи до лікування
Authors: S.L. Melanich
Journal: GASTROENTEROLOGY (2020)

Хвороба Вільсона — Коновалова — спадкове захворювання, що характеризується прогресуючим накопиченням міді з переважним ураженням печінки та головного мозку. Відноситься до рідкісних захворювань і часто діагностується на пізніх стадіях, але тепер зустрічається все частіше. У статті розглядаються особливості клінічної симптоматики, діагностичного алгоритму встановлення діагнозу хвороби Вільсона — Коновалова. Висвітлено питання лікування, профілактики та прогнозу захворювання.
Rupture of a Papillary Muscle of the Tricuspid Valve Following Acute Myocardial Infarction Report of a Case
Authors: Shlomoeisenberg, Joesuyemoto
Journal: Circulation (1964)

A case of rupture of a tricuspid papillary muscle due to myocardial infarction, apparently the first to be reported in the English literature, is presented. Anatomic, physiologic, and pathologic reasons for the rarity of such a rupture are advanced.
Isoform Switching as a Mechanism of Acquired Resistance to Mutant Isocitrate Dehydrogenase Inhibition
Authors: James J. Harding, Maeve A. Lowery, Alan H. Shih, Juan M. Schvartzman, Shengqi Hou, Christopher Famulare, Minal Patel, Mikhail Roshal, Richard K. Do, Ahmet Zehir, Daoqi You, S. Duygu Selcuklu, Agnes Viale, Martin S. Tallman, David M. Hyman, Ed Reznik, Lydia W.S. Finley, Elli Papaemmanuil, Alessandra Tosolini, Mark G. Frattini, Kyle J. MacBeth, Guowen Liu, Bin Fan, Sung Choe, Bin Wu, Yelena Y. Janjigian, Ingo K. Mellinghoff, Luis A. Diaz, Ross L. Levine, Ghassan K. Abou-Alfa, Eytan M. Stein, Andrew M. Intlekofer
Journal: Cancer Discovery (2018)

Abstract Somatic mutations in cytosolic or mitochondrial isoforms of isocitrate dehydrogenase (IDH1 or IDH2, respectively) contribute to oncogenesis via production of the metabolite 2-hydroxyglutarate (2HG). Isoform-selective IDH inhibitors suppress 2HG production and induce clinical responses in patients with IDH1- and IDH2-mutant malignancies. Despite the promising activity of IDH inhibitors, the mechanisms that mediate resistance to IDH inhibition are poorly understood. Here, we describe four clinical cases that identify mutant IDH isoform switching, either from mutant IDH1 to mutant IDH2 or vice versa, as a mechanism of acquired clinical resistance to IDH inhibition in solid and liquid tumors. Significance: IDH-mutant cancers can develop resistance to isoform-selective IDH inhibition by “isoform switching” from mutant IDH1 to mutant IDH2 or vice versa, thereby restoring 2HG production by the tumor. These findings underscore a role for continued 2HG production in tumor progression and suggest therapeutic strategies to prevent or overcome resistance. This article is highlighted in the In This Issue feature, p. 1494
Reflex Changes on the Pulmonary and Systemic Pressures Elicited by Stimulation of Baroreceptors in the Pulmonary Artery
Authors: JoseOsorio, MauricioRussek
Journal: Circulation Research (1962)

The distention of a large branch of the pulmonary artery, with or without occlusion of the circulation, produces pulmonary hypertension. The occlusion of an entire hilum, without adequate stimulation of the arterial baroreceptors produces only a negligible increase in pulmonary arterial pressure. Together with the pulmonary hypertension, variable changes in the systemic pressure were observed. The most frequent reaction was hypotension. The vagal fibers play no role in the pulmonary hypertensive response.