tbuckley/cabot-search huggingface dataset:
Abstract 100: Dual Activation of PKA and PKG by PDE1 Inhibition Facilitates Proteasomal Degradation of Misfolded Proteins and Protects Against Proteinopathy-Based HFpEF
Authors: Hanming Zhang, Bo Pan, Penglong Wu, Mark D Rekhter, Alfred L Goldberg, Xuejun Wang
Journal: Circulation Research (2019)

No current treatment is intended to target cardiac proteotoxicity or can reduce mortality of heart failure with preserved ejection fraction (HFpEF), a prevalent form of heart failure (HF). Selective degradation of misfolded proteins by the ubiquitin-proteasome system (UPS) is vital to the cell. Proteasome impairment is recently implicated in HF genesis. Activation of the cGMP-protein kinase G (PKG) or the cAMP-protein kinase A (PKA) pathways facilitates proteasome functioning. Phosphodiesterase 1 (PDE1) hydrolyzes both cyclic nucleotides and accounts for the majority of PDE activities in human myocardium. Here we report the preclinical therapeutic efficacy and a new mechanism of action of PDE1 inhibition (IC86430) for cardiac proteinopathy caused by Arg120Gly missense mutant αB-crystallin (CryAB R120G ). In mice expressing GFPdgn, an inverse reporter of UPS proteolytic activity, IC86430 treatment increased myocardial 26S proteasome activities and substantially decreased GFPdgn protein levels. Myocardial PDE1A expression was highly upregulated in CryAB R120G mice. HFpEF was detected in CryAB R120G mice at 4 months; IC86430 treatment initiated at this stage markedly attenuated HFpEF, substantially delayed mouse premature death, increased myocardial levels of Ser14-phosphorylated Rpn6 (the primary proteasome target of PKA), and reduced the steady state level of the misfolded CryAB species in these mice. In cultured cardiomyocytes, IC86430 treatment increased proteasome activities and accelerated proteasomal degradation of GFPu and CryAB R120G in a PKA- and PKG- dependent manner. We conclude that PDE1 inhibition induces PKA- and PKG-mediated promotion of proteasomal degradation of misfolded proteins in cardiomyocytes and effectively treats HFpEF caused by CryAB R120G ; hence, PDE1 inhibition represents a potentially new therapeutic strategy for HFpEF and heart disease with increased proteotoxic stress.
Response to: ‘Diabetes mellitus in ankylosing spondylitis’ by Lee and Song
Authors: Shih-Wei Lai, Yu-Hung Kuo, Kuan-Fu Liao
Journal: Annals of the Rheumatic Diseases (2019)

We would like to thank Dr Lee and Dr Song for their correspondence to our preliminary study recently published in Annals of the Rheumatic Diseases .1 2 Dr Lee and Dr Song have raised some concerns. We make a response as follows. First, the non-ankylosing spondylitis group included persons without a diagnosis code of ankylosing spondylitis (based on International …
The Role of Magnetic Resonance Elastography in the Diagnosis of Noncirrhotic Portal Hypertension
Authors: Patrick J. Navin, Tolga Gidener, Alina M. Allen, Meng Yin, Naoki Takahashi, Michael S. Torbenson, Patrick S. Kamath, Richard L. Ehman, Sudhakar K. Venkatesh
Journal: Clinical Gastroenterology and Hepatology (2019)
Abstract 582: Obg-like Atpase 1 (OLA1) Regulates Cardiomyocyte Hypertrophic Response via Gsk3β Signaling
Authors: Hien T Luong, Gayathri Narasimhan, John Henderson, Phuong Quach, Divya Annamalai, Prasanna Krishnamurthy
Journal: Circulation Research (2019)

Background: OLA1 that possesses both GTP and ATP hydrolyzing activities has been reported as a translational regulator of cell growth and survival. However, its role in cardiac hypertrophy, a process involving enhanced protein synthesis and increased cell size has not been studied. Hence, we hypothesized that OLA1 expression is regulated by oxidative stress and inflammatory responses in angiotensin-II induced cardiac hypertrophy and its aberrant expression mediates altered GSK3β-β-Catenin signaling. Methods: Protein expression of OLA1, GSK3β/P-GSK3β, β-Catenin/P-β-Catenin in total protein extracts of human cardiomyocytes with and without angiotensin II (500nM) treatment were studied. Knockdown of OLA1 expression in cardiomyocytes was achieved by SiRNA transfection and total protein extracts were isolated. In addition, phosphokinase array in OLA1 knockdown cells with and without angiotensin II was performed. H 2 O 2 and LPS treatment in cardiomyocytes for 24h was performed in culture and their total protein extracts were isolated to study the expression of OLA1, GSK3β/P-GSK3β and β-Catenin/P-β-Catenin. Results: A significant increase in OLA1 expression from 1 to 3.86±0.72 in angiotensin II treated cells was observed. GSK3β phosphorylation was also increased to 1.27±.10 in angiotensin II treated cells. While, β-Catenin phosphorylation was reduced, total β-Catenin level was significantly increased to 2.26±.34 in angiotensin II treated cells. OLA1 knockdown cells showed a significant reduction (0.12±0.0006) in GSK3β phosphorylation both with and without angiotensin II treatment. Also, phosphorylation of β-Catenin (1.28±.16) was induced in OLA1 knockdown cells. OLA1 expression was up-regulated in both H 2 O 2 and LPS treated cardiomyocytes after 24h. GSK3β phosphorylation and total β-Catenin levels were increased in these cells similar to angiotensin II treated cells. We also found cell proliferation and survival-related phosphoproteins were up-regulated in OLA1 knockdown cells with and without angiotensin II treatment. Conclusion: OLA1 was up-regulated during inflammation and reactive oxygen species production which then lead to GSK3β phosphorylation and β-Catenin accumulation in angiotensin II treated cardiomyocytes.
The Influence of Bleeding on Trigger Changes for Platelet Transfusion in Chemotherapy-Induced Thrombocytopenic Patients
Authors: Benjamin Rioux-Masse, Vincent Laroche, Robert J. Bowman, Bruce R. Lindgren, Claudia S. Cohn, Shelley M. Pulkrabek, Terri Carr, Darin Sumstad, Jeffrey McCullough
Journal: Blood (2011)
Long Non-Coding RNA NEAT1 Is Upregulated By Heat Shock Factor 1 (HSF1) and Associated with Multiple Myeloma Progression
Authors: Saki Watanabe, Tsukasa Oda, Yuko Kuroda, Kazuki Homma, Yuki Murakami, Rei Ishihara, Eiko Yamane, Masanobu Sunaga, Nobuhiko Kobayashi, Yohei Osaki, Takuma Ishizaki, Hiroaki Shimizu, Hiromi Koiso, Hirono Iriuchishima, Makiko Takizawa, Akihiko Yokohama, Norifumi Tsukamoto, Gotoh Nanami, Rumi Ino, Takayuki Saitoh, Hirokazu Murakami, Hiroshi Handa
Journal: Blood (2018)
Rapid induction of clinical remission by immunoadsorption for refractory lupus retinopathy complicated with life-threatening neuropsychiatric lupus
Authors: Guangfeng Zhang, Xiao Zhang, Yunfei Chai, Siwen Zang, Yunzhen Shi, Haijun Wu
Journal: Annals of the Rheumatic Diseases (2019)

Central nervous system involvement in systemic lupus erythematosus (SLE), termed neuropsychiatric SLE (NPSLE), is a relatively common manifestation of the disease. A previous study showed that patients with NPSLE with eye involvement are less common, with a prevalence of 0.66%.1 However, retinopathy occasionally presents as the primary manifestation of NPSLE, making diagnosis and management more challenge.2 Limited data exist regarding the optimisation of NPSLE treatment.1 3 Patients with NPSLE are usually treated with high doses of corticosteroids, cyclophosphamide (CTX), mycophenolate mofetil and azathioprine. In the case of refractory NPSLE, rituximab might be an alternative option.2 3 A few case reports on the use of immunoadsorption as a rescue treatment for patients with life-threatening NPSLE; however, none reported on refractory NPSLE patients with eye involvement.

We report on a patient with refractory NPSLE and progressive retinopathy who was successfully treated with immunoadsorption.

An 18-year-old female patient was first diagnosed with SLE in July 2016 had been treated with oral methylprednisolone (MP) (4 mg) and hydroxychloroquine (200 mg) daily, more recently photophobia in both eyes had developed. Laboratory tests revealed the presence of anti-nuclear antibody positive (1:1280), with antibodies to Smith (+), double-stranded DNA (dsDNA) (47 IU/L), Anti-Ro-52/ sjogren syndrome A antibody (RO-52) (+++), Anti-Ro-60/ sjogren syndrome A antibody (SSA) (+++), anti-UI-ribonucleoprotein antibody (U1-RNP) (+++), Anti–ribosomal-P antibodies (rib-P) (+) and white blood cell count was 2.62×109/L. Despite the prompt withdrawal of hydroxychloroquine which was suspected to be the cause of visual loss initially, the patient complained of worsened vision loss a week later. Retinal vasculitis was confirmed by ophthalmological examinations and multiple haemorrhages, multiple arteriolar occlusions, extensive avascular areas and macular oedema in …
Abstract 186: Superiority of Sacubitril/Valsartan Over Valsartan Alone in Attenuating Pressure Overload-induced Cardiac Fibrosis and Oxidative Stress
Authors: Xiaofei Li, Julie Braza, Ulrike Mende, Peng Zhang
Journal: Circulation Research (2019)

Background: Sacubitril/valsartan, a first-in-class Angiotensin Receptor-Neprilysin Inhibitor (ARNi), is superior to valsartan in reducing blood pressure in hypertensive patients. However, cardiac effects of sacubitril/valsartan in hypertension treatment and its potential superiority over valsartan are unclear. This study was designed to investigate effects of sacubitril/valsartan on cardiac structural remodeling and oxidative stress using a pressure overload rat model induced by ascending aortic constriction (AAC) and to address whether direct regulation of cardiac myocytes and/or fibroblasts is involved in the cardiac effects independent of afterload changes. Methods and Results: 1 week after AAC surgery, adult male Sprague-Dawley rats were randomized for 10 weeks treatment with vehicle, valsartan, or sacubitril/valsartan. Sacubitril/valsartan was superior to valsartan in inhibiting ventricular fibrosis, while both equally inhibited cardiomyocyte hypertrophy at the cellular level. These findings were supported by in vitro experiments showing that combined LBQ657 (sacubitrilat, active form of sacubitril) and valsartan was superior to valsartan alone in inhibiting angiotensin II (Ang II)-induced adult ventricular fibroblast activation, but not adult cardiomyocyte hypertrophy. In adult cardiomyocytes LBQ657 effectively inhibited Ang II-induced mitochondrial superoxide, and combined LBQ657 and valsartan was superior to valsartan or LBQ657 alone. Importantly, sacubitril/valsartan was also superior to valsartan in reducing mitochondrial superoxide in cardiomyocytes from pressure-overloaded hearts and improved cardiomyocyte mitochondrial maximal and spare respiration capacity. Conclusions: These findings provide direct evidence and novel mechanistic insights on the superior cardioprotective effects of sacubitril/valsartan in the setting of pressure overload: independent of afterload reduction, sacubitril/valsartan is superior to valsartan in attenuating cardiac fibrosis and myocyte oxidative stress and improves myocyte mitochondrial function in rats. Our study thus suggests a greater therapeutic effect of sacubitril/valsartan in the early stage of hypertensive heart disease before heart failure.
Patterns of palliative symptom management (PSM) medication use at end-of-life (EoL) among Medicare beneficiaries with advanced lung cancer (advLC).
Authors: Amy J. Davidoff, Elizabeth Horn Prsic, Maureen Saphire, Maureen Canavan, Shi-Yi Wang, Ruth McCorkle, Carolyn J Presley
Journal: Journal of Clinical Oncology (2019)

130 Background: Patients with advLC experience high symptom burden; undertreatment may result in poor quality of life for patients and caregivers. Hospice enrollment often happens late or not at all, yet little is known about EoL outpatient PSM medication use in the non-hospice setting. Methods: Using SEER-Medicare linked registry and claims data, we selected decedents diagnosed with advLC between 2008-2013 who survived ≥6 months (death between 2008-2014). Using non-hospice claims, we identified receipt of oral and parenteral medications to manage symptoms such as pain (any pain medications, any opioids), nausea/ vomiting and dyspnea at 6 (EoL-6) and 1 (EoL-1) months prior to death. Antiemetics were excluded if concurrent with chemotherapy (CTx). T-tests compared sample proportions receiving PSM between EoL-6 and EoL-1. Logistic regression estimated associations between PSM medication receipt at EoL-1 and patient demographic characteristics, comorbidity, and ongoing CTx or radiation. Results: We identified 16,246 decedents: mean age 77 years, 50% male, and 81% non-Hispanic white. PSM medication for individual symptom areas increased from EoL-6 to EoL-1 [Table]. Adjusted results indicate that pain medication receipt was higher for females, and patients with multimorbidity, dual Medicare/Medicaid, higher poverty, living in rural areas, and receiving concurrent radiation but lower among those with increasing age and for non-white race/ethnicity groups. We saw similar trends for PSM using opioids, and for emotional distress, and dyspnea. Conclusions: Among patients with advLC at EoL, medication use for symptom relief was common and increasing toward EoL-1. Lower use by males, older adults, and non-whites may reflect poor access or poor patient-provider communication. Further research is needed to assess adequacy of PSM in the outpatient setting. [Table: see text]
Effective Stimulant Dosing in Attention-Deficit/Hyperactivity Disorder
Authors: Zhilei Cui, Huanzhong Liu
Journal: JAMA Pediatrics (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 Pediatrics 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 Pediatrics journal
Prognostic Significance of Severe Thrombocytopenia in Overall Survival of Patients with Myelodysplastic Syndromes Treated with Azacytidine. a Multicenter Study By the Hellenic MDS Study Group
Authors: Athanasios Galanopoulos, Evdoxia Kamouza, Christos K. Kontos, Argiris Symeonidis, Vassiliki Pappa, Alexandra Kourakli, Nora-Athina Viniou, Sotirios Papageorgiou, Charalampos Pontikoglou, Menelaos Konstantinos Papoutselis, Helen A. Papadaki, Eleftheria Hatzimichael, Panagiotis Zikos, Maria Dimou, Panayiotis Panayiotidis, Dimitrios Tsokanas, Despina Mparmparousi, Flora Kontopidou, Eleni Variami, Panagiotis Repousis, Elias Poulakidas, Dimitrios Christoulas, Theodoros Vassilakopoulos, Michael Voulgarelis, Aikaterini Megalakaki, Maria Kotsopoulou, Giorgos Karianakis, Despina Kaliontzi, Ioannis Adamopoulos, Maria Dalekou, Anastasia Sioni, Maria Papaioannou, Dimitrios Gogos, Panagiotis Theodorou Diamantopoulos, Elena E. Solomou, Ioannis Kotsianidis
Journal: Blood (2018)
Arginine Methylation Of RBM15 By PRMT1 Controls Alternative Splicing Of Genes Involved In Megakaryocyte Differentiation
Authors: Xinyang Zhao, Li Zhang, Rui Wang, Ngoc Tung Trans, Hairui Su, Omar Abdel-Wahab, Todd Hrick, Ross L. Levine, Haiteng Deng, Yanyan Liu, Yujun Zheng, Minkui Luo
Journal: Blood (2013)
The LSD1 Inhibitor RN-1 Increases γ-Globin Expression in Baboons By Targeting an Early Event Responsible for γ-Globin Repression
Authors: Kestis Vaitkus, Vinzon Ibanez, Maria Armila Ruiz, Ramasamy Jagadeeswaran, Yogenthiran Saunthararajah, James Douglas Engel, Joseph DeSimone, Angela Rivers, Donald Lavelle
Journal: Blood (2018)
Sustained discontinuation of infliximab with a raising-dose strategy after obtaining remission in patients with rheumatoid arthritis: the RRRR study, a randomised controlled trial
Authors: Yoshiya Tanaka, Koji Oba, Takao Koike, Nobuyuki Miyasaka, Tsuneyo Mimori, Tsutomu Takeuchi, Shintaro Hirata, Eiichi Tanaka, Hidekata Yasuoka, Yuko Kaneko, Kosaku Murakami, Tomohiro Koga, Kazuhisa Nakano, Koichi Amano, Kazuyasu Ushio, Tatsuya Atsumi, Masayuki Inoo, Kazuhiro Hatta, Shinichi Mizuki, Shouhei Nagaoka, Shinichiro Tsunoda, Hiroaki Dobashi, Nao Horie, Norihiro Sato
Journal: Annals of the Rheumatic Diseases (2019)

The aim of this study is to determine whether the 'programmed' infliximab (IFX) treatment strategy (for which the dose of IFX was adjusted based on the baseline serum tumour necrosis factor α (TNF-α)) is beneficial to induction of clinical remission after 54 weeks and sustained discontinuation of IFX for 1 year.In this multicentre randomised trial, patients with IFX-naïve rheumatoid arthritis with inadequate response to methotrexate were randomised to two groups; patients in programmed treatment group received 3 mg/kg IFX until week 6 and after 14 weeks the dose of IFX was adjusted based on the baseline levels of serum TNF-α until week 54; patients in the standard treatment group received 3 mg/kg of IFX. Patients who achieved a simplified disease activity index (SDAI) ≤3.3 at week 54 discontinued IFX. The primary endpoint was the proportion of patients who sustained discontinuation of IFX at week 106.A total of 337 patients were randomised. At week 54, 39.4% (67/170) in the programmed group and 32.3% (54/167) in the standard group attained remission (SDAI ≤3.3). At week 106, the 1-year sustained discontinuation rate was not significantly different between two groups; the programmed group 23.5% (40/170) and the standard group 21.6% (36/167), respectively (2.2% difference, 95% CI -6.6% to 11.0%; p=0.631). Baseline SDAI <26.0 was a statistically significant predictor of the successfully sustained discontinuation of IFX at week 106.Programmed treatment strategy did not statistically increase the sustained remission rate after 1 year discontinuation of IFX treatment.
Soccer and Mortality — Good News and Bad News
Authors: Robert A. Stern
Journal: New England Journal of Medicine (2019)

In the general population, moderate exercise, physical activity, and participation in sports have important health benefits, including slowing cognitive decline and preventing dementia.1 Participation in elite-level sports, not surprisingly, is also associated with reductions in all-cause mortality and the risk of cardiovascular disease. In recent years, however, there has been evidence that participation in some contact and collision sports may increase the risk of cognitive and neuropsychiatric impairment later in life,2 as well as the risk of neurodegenerative disease and chronic traumatic encephalopathy (CTE),3 because of repetitive brain trauma. It appears that it is not just the "big hits" resulting . . .
Abstract 736: Increased Cell Death in Regions of Elevated Aortic Wall Shear Stress in Bicuspid Valve Aortopathy
Authors: Ashna K Maredia, Fatima Iqbal, David G Guzzardi, Alex J Barker, Patrick M McCarthy, Paul W Fedak, Steven C Greenway
Journal: Circulation Research (2019)

Bicuspid aortic valve (BAV) is a common congenital malformation associated with aortopathy and potential rupture. Identifying those patients at greatest risk for dissection is difficult at present. Abnormal hemodynamics in the ascending aorta creates regions of increased wall shear stress (WSS) which causes extracellular matrix dysregulation and may affect cell death. Dying cells release fragmented DNA into the blood and levels of aorta-specific cell-free DNA (cfDNA), identified by the presence of tissue-specific differentially methylated regions (DMRs), could be leveraged as a biomarker. Our objective was to determine if a relationship between elevated WSS and apoptosis in the ascending aorta existed and identify aorta-specific DMRs in the cfDNA of BAV patients. We hypothesized that areas of increased WSS would demonstrate increased cell death that would correlate with increases in aorta-specific cfDNA from patient blood. BAV patients undergoing 4D-flow cardiac magnetic resonance imaging (CMR) and surgery for ascending aorta dilation (range 36-63 mm) were recruited. Blood was collected from 23 patients at the time of CMR and used for the isolation of plasma cfDNA. Aortic wall samples (n = 30) corresponding to regions of high and low WSS were collected at surgery from 15 patients and stained for cell death using the TUNEL assay. Publicly-available methylomes and Metilene were used to identify aorta-specific DMRs in silico . Regions of elevated WSS were seen in all individuals regardless of absolute aortic dimension. These regions of elevated WSS by CMR showed significantly greater cell death when compared to the region of normal WSS in the ascending aorta (0.14 ± 0.05 vs. 0.08 ± 0.06, p=0.00006). Levels of cell death did not correlate with maximal aortic diameter. Twenty-three aorta-specific DMRs were identified. Of the four that were tested, three were found to be hypomethylated in genomic DNA from the aorta compared to 14 other tissues. Levels of aorta-specific cfDNA based on our DMRs did not correlate with maximal aortic diameter. Increased regional cell death corresponding to elevated WSS may implicate abnormal hemodynamic flow in the progression of aortopathy and provides a biological rationale for the use of cfDNA as a biomarker for aortopathy.
Identification of Three Novel Chromosomal Translocation Partners Involving the Immunoglobulin Loci in Newly Diagnosed Myeloma and Human Myeloma Cell Lines.
Authors: Ichiro Hanamura, Shinsuke Iida, Ryuzo Ueda, Michael Kuehl, Contance Cullraro, Leif Bergsagel, Jeffrey Sawyer, Bart Barlogie, John Shaughnessy
Journal: Blood (2005)
Costimulatory Molecule Profiles After Autologous Hematopoietic Cell Transplantation (HCT) in Multiple Myeloma (MM) Patients
Authors: Myo Htut, Ghislaine Gallez-Hawkins, Joycelynne Palmer, Xueli Liu, R. Spielberger, Pablo Parker, Len Farol, Anne Franck, Xiuli Li, Jeannet Laëtitia, Eunicia Reburiano, Valerie Jimenez, Lupe Duarte, Chatchada Karanes, Stephen J. Forman, John Zaia, Amrita Krishnan
Journal: Blood (2011)
Survivorship: Leveraging the EMR to better care.
Authors: Amy Walde, Emma Bootle
Journal: Journal of Clinical Oncology (2019)

283 Background: UCHealth is a 10-hospital health system located on the Front Range of the Rocky Mountains. In 2018, UCHealth Cancer Care diagnosed or treated more than 8,400 analytic cases. In this presentation, we will discuss how we formulated a response to our organizational need for the creation of a Cancer Survivorship Program that not only met the ASCO QOPI &amp; Commission on Cancer (CoC) Standards but also the needs of our patients. Methods: Our response plan included devising processes for the development and delivery of treatment summary care plans (TS/SCP). The development phase comprised the formation of UCHealth Cancer Care governance structure, creation of 22 disease specific templates containing the Institute of Medicine (IOM) / National Comprehensive Care Network (NCCN) recommended elements of survivorship care, Electronic Health Record (EHR) automation to increase efficiency and finally designing dashboard reports to identify eligible patients and capture compliance. The delivery phase consisted of securing dedicated resources, a communication plan and education for staff and providers regarding the benefits of a Cancer Survivorship program. Results: A jump in compliance from 7% in 2015 to 29% in 2018, demonstrates the success and impact of TS/SCPs at UCHealth. We will also discuss the 2019 work plan to achieve 50% compliance as required by the CoC. Conclusions: Leveraging the EHR is necessary when developing a Cancer Survivorship Program. UCHealth will provide examples of the treatment summary care plans, reference and reporting metrics to get other programs started on their journey.