tbuckley/cabot-search huggingface dataset:
Methylation of C/EBPα by PRMT1 Inhibits Its Tumor-Suppressive Function in Breast Cancer
Authors: Li-Ming Liu, Wen-Zheng Sun, Xue-Zhe Fan, Ya-Li Xu, Mo-Bin Cheng, Ye Zhang
Journal: Cancer Research (2019)

C/EBPα is an essential transcription factor involved in regulating the expression or function of certain cell-cycle regulators, including in breast cancer cells. Although protein arginine methyltransferases have been shown to play oncogenic roles in a variety of cancers, little is known about the role of arginine methylation in regulating the antiproliferation activity of C/EBPα. Here, we report that the protein arginine methyltransferase 1 (PRMT1) is overexpressed in human breast cancer and that elevated PRMT1 correlates with cancer malignancy. RNA-sequencing analysis revealed that knockdown of PRMT1 in breast cancer cells is accompanied by a decrease in the expression of pro-proliferative genes, including cyclin D1. Furthermore, tandem affinity purification followed by mass spectrometry identified PRMT1 as a component of the C/EBPα complex. C/EBPα associated with and was methylated by PRMT1 at three arginine residues (R35, R156, and R165). PRMT1-dependent methylation of C/EBPα promoted the expression of cyclin D1 by blocking the interaction between C/EBPα and its corepressor HDAC3, which resulted in rapid growth of tumor cells during the pathogenesis of breast cancer. Inhibition of PRMT1 significantly impeded the growth of cancer cells from patients with triple-negative breast cancer. This evidence that PRMT1 mediates C/EBPα methylation sheds light on a novel pathway and potential therapeutic target in breast cancer. SIGNIFICANCE: This study provides novel mechanistic insight of the role of the arginine methyltransferase PRMT1 in breast cancer pathogenesis.
We Can Learn From the Past, but We Must Pave the Future of Congenital Heart Disease Research
Authors: Sara Hussain, Emilie P. Belley-Côté, Richard P. Whitlock
Journal: JAMA Cardiology (2019)

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 Cardiology 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 Cardiology journal
Clinical Utility of Circulating Tumour Cell Androgen Receptor Splice Variant-7 Status in Metastatic Castration-resistant Prostate Cancer
Authors: Adam Sharp, Jon C. Welti, Maryou B.K. Lambros, David Dolling, Daniel Nava Rodrigues, Lorna Pope, Caterina Aversa, Ines Figueiredo, Jennifer Fraser, Zai Ahmad, Changxue Lu, Pasquale Rescigno, Michael Kolinsky, Claudia Bertan, George Seed, Ruth Riisnaes, Susana Miranda, Mateus Crespo, Rita Pereira, Ana Ferreira, Gemma Fowler, Berni Ebbs, Penny Flohr, Antje Neeb, Diletta Bianchini, Antonella Petremolo, Semini Sumanasuriya, Alec Paschalis, Joaquin Mateo, Nina Tunariu, Wei Yuan, Suzanne Carreira, Stephen R. Plymate, Jun Luo, Johann S. de Bono
Journal: European Urology (2019)

Detection of androgen receptor splice variant-7 (AR-V7) mRNA in circulating tumour cells (CTCs) is associated with worse outcome in metastatic castration-resistant prostate cancer (mCRPC). However, studies rarely report comparisons with CTC counts and biopsy AR-V7 protein expression. To determine the reproducibility of AdnaTest CTC AR-V7 testing, and associations with clinical characteristics, CellSearch CTC counts, tumour biopsy AR-V7 protein expression and overall survival (OS). CTC AR-V7 status was determined for 227 peripheral blood samples, from 181 mCRPC patients with CTC counts (202 samples; 136 patients) and matched mCRPC biopsies (65 samples; 58 patients). CTC AR-V7 status was associated with clinical characteristics, CTC counts, and tissue biopsy AR-V7 protein expression. The association of CTC AR-V7 status and other baseline variables with OS was determined. Of the samples, 35% were CTC+/AR-V7+. CTC+/AR-V7+ samples had higher CellSearch CTC counts (median CTC; interquartile range [IQR]: 60, 19–184 vs 9, 2–64; Mann-Whitney test p < 0.001) and biopsy AR-V7 protein expression (median H-score, IQR: 100, 63–148 vs 15, 0–113; Mann-Whitney test p = 0.004) than CTC+/AR-V7− samples. However, both CTC− (63%) and CTC+/AR-V7− (62%) patients had detectable AR-V7 protein in contemporaneous biopsies. After accounting for baseline characteristics, there was shorter OS in CTC+/AR-V7+ patients than in CTC− patients (hazard ratio [HR] 2.13; 95% confidence interval [CI] 1.23–3.71; p = 0.02); surprisingly, there was no evidence that CTC+/AR-V7+ patients had worse OS than CTC+/AR-V7− patients (HR 1.26; 95% CI 0.73–2.17; p = 0.4). A limitation of this study was the heterogeneity of treatment received. Studies reporting the prognostic relevance of CTC AR-V7 status must account for CTC counts. Discordant CTC AR-V7 results and AR-V7 protein expression in matched, same-patient biopsies are reported. Liquid biopsies that determine circulating tumour cell androgen receptor splice variant-7 status have the potential to impact treatment decisions in metastatic castration-resistant prostate cancer patients. Robust clinical qualification of these assays is required before their routine use.
TMOD-08. ELUCIDATING EPIGENETIC MECHANISMS IN DIFFUSE INTRINSIC PONTINE GLIOMA HARBORING ACVR1 G328V AND H3.1 K27M
Authors: Flor Mendez, Felipe Nunez, Padma Kadiyala, Ramya Ravindran, Fernando Nunez, Sheeba Pawar, Jessica Williams, Rocío Zorrilla-Veloz, Umayal Swarnam, Michelle Alcantara, Ethan Parker, Marta Edwards, Pedro Lowenstein, Maria Castro
Journal: Neuro-Oncology (2019)

Diffuse intrinsic pontine glioma (DIPG) is a deadly pediatric brainstem tumor that originates in the pons. Mutations in Activin-A Receptor Type 1 (ACVR1), a bone morphogenetic protein (BMP) receptor, are highly recurrent and specific for DIPG. The ACVR1 mutations co-occur with the H3.1 K27M mutation. The K27M mutations are found in 80% of DIPG patients, occur on either HIST1H3B/C or H3F3A genes, and result in global hypo-methylation of H3K27me3. We used the Sleeping Beauty Transposase (SB) system to deliver plasmids encoding NRASV12, short hair pin for TP53 (shp53), ACVR1-G328V with or without H3.1 K27M, into the brainstem of neonatal mice, to generate endogenous brainstem tumors. We also introduced the H3.1 K27M mutation to primary neurospheres harboring the ACVR1 G328V mutation. In vitro, tumor neurospheres harboring ACVR1-G328V exhibit elevated phopho-Smad1/5, transducer of the BMP pathway and expression of the H3.1 K27M mutation in these cells resulted in decreased levels of H3K27me3. To identify changes in the chromatin landscape induced by the H3.1 K27M mutation we performed ChIP-seq analysis for H3K27me3, H3k27ac, H3K27me1, and H3K4me3 on tumor neurospheres harboring ACVR1 G328V and neurospheres harboring ACVR1 G328V and H3.1 K27M. In summary, we used the SB transposase system to develop a mouse model that accurately represents the molecular characteristics of brainstem gliomas encoding ACVR1 G328V and H3.1 K27M mutations. We also developed an in vitro model using primary neurospheres from the SB model. In the future we aim to elucidate the epigenetic mechanisms by which ACVR1 and H3.1 K27M contribute to tumor development, and uncover novel therapeutic targets for DIPG. Work supported by NIH/NINDS; Leah’s Happy Hearts Foundation and the ChadTough Foundation. FM is supported by an F31 Training Fellowship from NIH/NINDS.
Association of Exposure to Persistent Organic Pollutants With Mortality Risk
Authors: P. Monica Lind, Samira Salihovic, Jordan Stubleski, Anna Kärrman, Lars Lind
Journal: JAMA Network Open (2019)

<h3>Importance</h3> It has been suggested that persistent organic pollutants (POPs) are harmful to human health. <h3>Objective</h3> To investigate if POP levels in plasma are associated with future mortality. <h3>Design, Setting, and Participants</h3> Cohort study using data from the population-based Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study, collected between May 2001 and June 2004 when participants reached age 70 years. Participants were followed up for 5 years after the first examination. Mortality was tracked from age 70 to 80 years. Data analysis was conducted in January and February 2018. <h3>Exposures</h3> Eighteen POPs identified by the Stockholm Convention, including polychlorinated biphenyls (PCBs), organochlorine pesticides, and a brominated flame retardant, were measured in plasma levels by gas chromatography–mass spectrometry. <h3>Main Outcomes and Measures</h3> All-cause mortality. <h3>Results</h3> The study sample initially included 992 individuals (497 [50.1%] men) aged 70 years, who were examined between 2001 and 2004. At the second examination 5 years later, 814 individuals (82.1%; 412 [50.7%] women) completed follow-up. During a follow-up period of 10.0 years, 158 deaths occurred. When updated information on POP levels at ages 70 and 75 years was associated with all-cause mortality using Cox proportional hazard analyses, a significant association was found between hexa-chloro- through octa-chloro-substituted (highly chlorinated) PCBs and all-cause mortality (except PCB 194). The most significant association was observed for PCB 206 (hazard ratio [HR] for 1-SD higher natural log–transformed circulating PCB 206 levels, 1.55; 95% CI, 1.26-1.91;<i>P</i> &lt; .001). Following adjustment for hypertension, diabetes, smoking, body mass index, and cardiovascular disease at baseline, most associations were no longer statistically significant, but PCBs 206, 189, 170, and 209 were still significantly associated with all-cause mortality (PCB 206: adjusted HR, 1.47; 95% CI, 1.19-1.81; PCB 189: adjusted HR, 1.29; 95% CI, 1.08-1.55; PCB 170: adjusted HR, 1.24; 95% CI, 1.02-1.52; PCB 209: adjusted HR, 1.29; 95% CI, 1.04-1.60). In a secondary analysis, these associations were mainly because of death from cardiovascular diseases rather than noncardiovascular diseases. Three organochlorine pesticides, including dichlorodiphenyldichloroethylene, and the brominated flame retardant diphenyl ether 47 were also evaluated but did not show any significant associations with all-cause mortality. <h3>Conclusions and Relevance</h3> Higher levels of highly chlorinated PCBs were associated with an increased mortality risk, especially from cardiovascular diseases. These results suggest that public health actions should be undertaken to minimize exposure to highly chlorinated PCBs.
Lowering Cost and Increasing Access to Drugs Without Jeopardizing Innovation
Authors: Robert M. Califf, Andrew Slavitt
Journal: JAMA (2019)

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 HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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 journal
Raymond Nim-Wah Chan
Authors: Alice Chan
Journal: BMJ (2019)

Raymond Nim-Wah Chan (“Ray”) was a well known orthopaedic surgeon who practised in Leicestershire from 1976 to 1999. He was one of the first Chinese orthopaedic surgeons in Leicester, if not the UK.

A native Hong Kong British national overseas (BNO) citizen, Ray was born in Hong Kong and endured difficult years as a young boy, living as a camp follower with his mother and siblings in China, after the evacuation of Hong Kong during the second world war.

He was sent to Campbell College in Northern Ireland with his brother for sixth form and went on to Corpus Christi College, Cambridge. He graduated in 1962 and went on for further training at University College Hospital in …
Abstract 17410: High-Dose Dobutamine for Inducibility of Atrial Arrhythmias During Atrial Fibrillation Ablation
Authors: Carola Gianni, Javier E Sanchez, Sanghamitra Mohanty, Chintan Trivedi, Domenico G Della Rocca, Amin Al-Ahmad, J D Burkardt, G J Gallinghouse, Rodney P Horton, Patrick M Hranitzky, Luigi Di Biase, Andrea Natale
Journal: Circulation (2017)

Introduction: High-dose isoproterenol (IPN) is commonly used to elicit triggers during AF ablation. However, it is not available worldwide and, in the US, its cost per dose has significantly increa...
The TICking clock of EGFR therapy resistance in glioblastoma: Target Independence or target Compensation
Authors: Hamza Saleem, U. Kulsoom Abdul, Asli Küçükosmanoglu, Megan Houweling, Fleur M.G. Cornelissen, Dieter H. Heiland, Monika E. Hegi, Mathilde C.M. Kouwenhoven, David Bailey, Tom Würdinger, Bart A. Westerman
Journal: Drug Resistance Updates (2019)

Targeted therapy against driver mutations responsible for cancer progression has been shown to be effective in many tumor types. For glioblastoma (GBM), the epidermal growth factor receptor (EGFR) gene is the most frequently mutated oncogenic driver and has therefore been considered an attractive target for therapy. However, so far responses to EGFR-pathway inhibitors have been disappointing. We performed an exhaustive analysis of the mechanisms that might account for therapy resistance against EGFR inhibition. We define two major mechanisms of resistance and propose modalities to overcome them. The first resistance mechanism concerns target independence. In this case, cells have lost expression of the EGFR protein and experience no negative impact of EGFR targeting. Loss of extrachromosomally encoded EGFR as present in double minute DNA is a frequent mechanism for this type of drug resistance. The second mechanism concerns target compensation. In this case, cells will counteract EGFR inhibition by activation of compensatory pathways that render them independent of EGFR signaling. Compensatory pathway candidates are platelet-derived growth factor β (PDGFβ), Insulin-like growth factor 1 (IGFR1) and cMET and their downstream targets, all not commonly mutated at the time of diagnosis alongside EGFR mutation. Given that both mechanisms make cells independent of EGFR expression, other means have to be found to eradicate drug resistant cells. To this end we suggest rational strategies which include the use of multi-target therapies that hit truncation mutations (mechanism 1) or multi-target therapies to co-inhibit compensatory proteins (mechanism 2).
The cumulative effect of inflammation and infection on structural lung disease in early cystic fibrosis
Authors: Tim Rosenow, L. Clara Mok, Lidija Turkovic, Luke J. Berry, Peter D. Sly, Sarath Ranganathan, Harm A.W.M. Tiddens, Stephen M. Stick
Journal: European Respiratory Journal (2019)

Introduction Pulmonary inflammation and infection are important clinical and prognostic markers of lung disease in cystic fibrosis (CF). However, whether in young children they are transient findings or have cumulative, long-term impacts on respiratory health is largely unknown. We aimed to determine whether their repeated detection has a deleterious effect on structural lung disease. Methods All patients aged &lt;6 years with annual computed tomography (CT) and bronchoalveolar lavage (BAL) were included. Structural lung disease on CT (%Disease) was determined using the PRAGMA-CF (Perth–Rotterdam Annotated Grid Morphometric Analysis for CF) method. The number of times free neutrophil elastase (NE) and infection were detected in BAL were counted, to determine cumulative BAL history. Linear mixed model analysis, accounting for repeat visits and adjusted for age, was used to determine associations. Results 265 children (683 scans) were included for analysis, with BAL history comprising 1161 visits. %Disease was significantly associated with the number of prior NE (0.31, 95% CI 0.09–0.54; p=0.007) but not infection (0.23, 95% CI −0.01–0.47; p=0.060) detections. Reference equations were determined. Conclusions Pulmonary inflammation in surveillance BAL has a cumulative effect on structural lung disease extent, more so than infection. This provides a strong rationale for therapies aimed at reducing inflammation in young children.
LGG-05. SINGLE CELL RNA SEQUENCING REVEALS MITOGENIC AND PROGENITOR GENE PROGRAMS IN BRAF-REARRANGED PILOCYTIC ASTROCYTOMAS
Authors: Zachary Reitman, Brenton Paolella, Guillaume Bergthold, Kristine Pelton, Sarah Becker, Robert Jones, Claire Sinai, Hayley Malkin, Ying Huang, Leslie Grimmet, Zachary Herbert, Yu Sun, Jessica Weatherbee, Kenin Qian, Alexandra-Larisa Condurat, John Alberta, John Daley, Orit Rozenblatt-Rozen, Rosalind Segal, Daphne Haas-Kogan, Mariella Filbin, Mario Suva, Aviv Regev, Charles Stiles, Mark Kieran, Liliana Goumnerova, Keith Ligon, Alex Shalek, Rameen Beroukhim, Pratiti Bandopadhayay
Journal: Neuro-Oncology (2019)

Pilocytic astrocytoma (PA) is the most common pediatric low-grade glioma. While PAs exhibit a favorable prognosis compared to higher-grade gliomas, treatment morbidity and tumor recurrence still represent major challenges for some PA patients. PAs frequently harbor rearrangements resulting in expression of oncogenic KIAA1549-BRAF fusion transcripts. We performed scRNAseq of both tumor and non-tumor cells in newly-diagnosed PAs that contained KIAA1549-BRAF rearrangements. To confidently distinguish tumor cells from nontumor cells, we sorted cells by glial progenitor marker A2B5 status and profiled KIAA1549-BRAF fusion status of cells using a quantitative PCR-based assay. Results were validated using RNA in situ hybridization and compared to bulk expression data from 151 pediatric low grade gliomas. When compared to higher-grade gliomas, a higher proportion of the PA tumor cells exhibited a differentiated, astrocyte-like phenotype. A smaller proportion of cells exhibited a progenitor-like phenotype with evidence of proliferation. These progenitor-like tumor cells expressed a mitogen-activated protein kinase (MAPK) gene program that was absent from higher-grade gliomas. Similar patterns of expression of genes associated with the astrocyte-like and MAPK gene programs were also seen in formalin fixed, paraffin embedded PA tissues using RNA in situ hybridization. Immune cells, especially microglia, comprised almost half of all cells in the PAs and accounted for many differences seen in bulk pediatric low grade glioma expression profiles. These single cell transcriptional data reveal a transcriptional developmental hierarchy in a pediatric low-grade glioma that is skewed towards more mature brain cells compared to higher-grade gliomas. The results indicate that future analyses of bulk PA tissues should attempt to account for considerable infiltration by nontumor cells. Finally, the finding that a MAPK gene program is not uniformly expressed in PA tumor cells has implications for ongoing clinical investigations of therapies directed at the MAPK pathway for the treatment of PA.
Parallel symposium B. 간질환에 대한 영상검사 및 중재적 시술 : 간 자기공명영상의 최신지견
Authors: 원형진 ( Hyung Jin Won )
Journal: Clinical and Molecular Hepatology (2010)

최근 간 자기공명영상(Magnetic Resonance Imaging, MRI)의 발전에 힘입어, 간 영상에서 MR의 중요성이 커지고 있다. 그 중에서 새로운 간세포 특이적 조영제인 gadoxetate (Gd-EOB-DTPA)는 기존의 비특이적 세포외액조영제의 역동적 영상뿐만 아니라 간세포의 기능적 영상을 함께 얻을 수 있어서 주목 받고 있다. Gadoxetate는 간 국소 병변의 특성화에 추가적인 진단적 가치를 보이며, 간세포암 등의 발견에 있어서도 다중검출 CT (Multidetector CT)보다 우수한 성적이 보고되고 있다. 또 다른 새로운 영상기법으로는 확산강조영상(Diffusion-weighted imaging, DWI)을 들 수 있다. 확산강조영상은 조직내의 물 분자의 확산 특성을 영상화하는 자기공명영상 기법이며, 간국소 병변의 검출과 감별진단에 도움을 준다. 이 글에서는 gadoxetate와 확산강조영상의 기본원리를 소개하고, 흔하게 마주치는 간 국소 병변, 특히 간세포암에 대하여 영상 소견과 진단적 가치를 기술하고자 한다.
Mechanism of Synchronization in Isorhythmic A-V Dissociation
Authors: MATTHEW N. LEVY, HARRISON ZIESKE
Journal: Circulation Research (1971)

An analog computer model has been developed to study the mechanism of the atrioventricular synchronization in one type of isorhythmic A-V dissociation (pattern I). The computer model simulates the following biological feedback control system: (1) the ventricular pacemaker frequency is independent of arterial blood pressure (analogous to artificial ventricular pacing); (2) the frequency of the atrial pacemaker (usually the S-A node) varies inversely as the arterial blood pressure; (3) the phase difference (P-R interval) between these pacemakers is a determinant of the stroke volume; (4) for a given systemic arterial impedance and heart rate, the stroke volume determines the arterial blood pressure; and (5) after a finite delay, the arterial blood pressure exerts an inverse effect on the atrial frequency, to close the loop. Stroke volume increases progressively as the P-R interval increases from 0 to some optimum value. Stable synchronization can exist only when the mean P-R interval falls within this range of values, because only within this range does negative feedback prevail. Over the range of ventricular pacing frequencies within which synchronization can persist, the mean cardiac output and arterial blood pressure will vary inversely as the ventricular pacing frequency. Synchronization will persist only when there is an adequate closed-loop gain (consisting of the change in arterial blood pressure per unit change in P-R interval and change in heart rate per unit change in blood pressure).
US State Regulation of Decisions for Pregnant Women Without Decisional Capacity
Authors: Erin S. DeMartino, Beau P. Sperry, Cavan K. Doyle, Julie Chor, Daniel B. Kramer, David M. Dudzinski, Paul S. Mueller
Journal: JAMA (2019)

This study characterizes the prevalence and content of US state statutes governing treatment decisions for decisionally incapacitated pregnant women.