tbuckley/cabot-search huggingface dataset:
Dual Targeting of Histone Methyltransferase G9a and DNA‐Methyltransferase 1 for the Treatment of Experimental Hepatocellular Carcinoma
Authors: Marina Bárcena‐Varela, Stefano Caruso, Susana Llerena, Gloria Álvarez‐Sola, Iker Uriarte, M. Ujue Latasa, Raquel Urtasun, Sandra Rebouissou, Laura Alvarez, Maddalen Jimenez, Eva Santamaría, Carlos Rodriguez‐Ortigosa, Giuseppe Mazza, Krista Rombouts, Edurne San José‐Eneriz, Obdulia Rabal, Xabier Agirre, Maria Iraburu, Alvaro Santos‐Laso, Jesus M. Banales, Jessica Zucman‐Rossi, Felipe Prósper, Julen Oyarzabal, Carmen Berasain, Matías A. Ávila, Maite G. Fernández‐Barrena
Journal: Hepatology (2018)

Abstract Epigenetic modifications such as DNA and histone methylation functionally cooperate in fostering tumor growth, including that of hepatocellular carcinoma (HCC). Pharmacological targeting of these mechanisms may open new therapeutic avenues. We aimed to determine the therapeutic efficacy and potential mechanism of action of our dual G9a histone‐methyltransferase and DNA‐methyltransferase 1 (DNMT1) inhibitor in human HCC cells and their crosstalk with fibrogenic cells. The expression of G9a and DNMT1 , along with that of their molecular adaptor ubiquitin‐like with PHD and RING finger domains‐1 ( UHRF1 ), was measured in human HCCs (n = 268), peritumoral tissues (n = 154), and HCC cell lines (n = 32). We evaluated the effect of individual and combined inhibition of G9a and DNMT1 on HCC cell growth by pharmacological and genetic approaches. The activity of our lead compound, CM‐272, was examined in HCC cells under normoxia and hypoxia, human hepatic stellate cells and LX2 cells, and xenograft tumors formed by HCC or combined HCC+LX2 cells. We found a significant and correlative overexpression of G9a , DNMT1 , and UHRF1 in HCCs in association with poor prognosis. Independent G9a and DNMT1 pharmacological targeting synergistically inhibited HCC cell growth. CM‐272 potently reduced HCC and LX2 cells proliferation and quelled tumor growth, particularly in HCC+LX2 xenografts. Mechanistically, CM‐272 inhibited the metabolic adaptation of HCC cells to hypoxia and induced a differentiated phenotype in HCC and fibrogenic cells. The expression of the metabolic tumor suppressor gene fructose‐1,6‐bisphosphatase ( FBP1 ), epigenetically repressed in HCC, was restored by CM‐272. Conclusion: Combined targeting of G9a/DNMT1 with compounds such as CM‐272 is a promising strategy for HCC treatment. Our findings also underscore the potential of differentiation therapy in HCC.
Doctors and vets working together for antibiotic stewardship
Authors: Ingrid Torjesen
Journal: BMJ (2018)

Doctors and the farming industry are often blamed for overuse of antibiotics that spurs the growing problem of antimicrobial resistance. <b>Ingrid Torjesen</b> reports from an expert discussion jointly hosted by both <i>The BMJ</i> and <i>Vet Record</i> to identify ways to tackle it
Regarding the Congruence Between 2 Circulating Tumor DNA Sequencing Assays
Authors: Chi-Chun Yeh
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
Circulating Mononuclear Cells in the Obese Are in a Proinflammatory State
Authors: HusamGhanim, AhmadAljada, DeborahHofmeyer, TufailSyed, PriyaMohanty, PareshDandona
Journal: Circulation (2004)

Background— In view of the increase in plasma concentrations of proinflammatory mediators tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and C-reactive protein (CRP) in obesity, we investigated whether peripheral blood mononuclear cells (MNC) from obese subjects are in a proinflammatory state. Methods and Results— MNC were prepared from fasting blood samples of obese (n=16; body mass index [BMI]=37.7±5.0 kg/m2) and normal-weight control (n=16; BMI=23.8±1.9 kg/m2) subjects. Nuclear factor κB (NF-κB) binding to DNA in nuclear extracts was elevated (P<0.05) and the inhibitor of NFκB-β (IκB-β) was significantly lower (P<0.001) in the obese group. Reverse transcription–polymerase chain reaction revealed elevated levels of migration inhibitor factor (MIF), IL-6, TNF-α, and matrix metalloproteinase-9 (MMP-9) mRNA expression in the obese subjects (P<0.05). Plasma concentrations of MIF, IL-6, TNF-α, MMP-9, and CRP were also significantly higher. Plasma glucose, insulin, and free fatty acids (FFAs) were mea...
Psychiatrist wins injunction to stop disciplinary proceedings against her
Authors: Clare Dyer
Journal: BMJ (2018)

A consultant psychiatrist has won a High Court interim injunction stopping her employers going ahead this month with disciplinary proceedings that could result in her summary dismissal.1

Caroline Ardron has launched a High Court action claiming that the gross misconduct proceedings are a breach of her employment contract with Sussex Partnership NHS Foundation Trust.

Pushpinder Saini QC, sitting as a deputy High Court judge, halted the disciplinary proceedings pending an expedited trial of her breach of contract claim against Sussex Partnership NHS Foundation Trust. She claims that the findings of facts …
Trends in outpatient antibiotic use and prescribing practice among US older adults, 2011-15: observational study
Authors: Scott W Olesen, Michael L Barnett, Derek R MacFadden, Marc Lipsitch, Yonatan H Grad
Journal: BMJ (2018)

Abstract Objective To identify temporal trends in outpatient antibiotic use and antibiotic prescribing practice among older adults in a high income country. Design Observational study using United States Medicare administrative claims in 2011-15. Setting Medicare, a US national healthcare program for which 98% of older adults are eligible. Participants 4.5 million fee-for-service Medicare beneficiaries aged 65 years old and older. Main outcome measurements Overall rates of antibiotic prescription claims, rates of potentially appropriate and inappropriate prescribing, rates for each of the most frequently prescribed antibiotics, and rates of antibiotic claims associated with specific diagnoses. Trends in antibiotic use were estimated by multivariable regression adjusting for beneficiaries’ demographic and clinical covariates. Results The number of antibiotic claims fell from 1364.7 to 1309.3 claims per 1000 beneficiaries per year in 2011-14 (adjusted reduction of 2.1% (95% confidence interval 2.0% to 2.2%)), but then rose to 1364.3 claims per 1000 beneficiaries per year in 2015 (adjusted reduction of 0.20% over 2011-15 (0.09% to 0.30%)). Potentially inappropriate antibiotic claims fell from 552.7 to 522.1 per 1000 beneficiaries over 2011-14, an adjusted reduction of 3.9% (3.7% to 4.1%). Individual antibiotics had heterogeneous changes in use. For example, azithromycin claims per beneficiary decreased by 18.5% (18.2% to 18.8%) while levofloxacin claims increased by 27.7% (27.2% to 28.3%). Azithromycin use associated with each of the potentially appropriate and inappropriate respiratory diagnoses decreased, while levofloxacin use associated with each of those diagnoses increased. Conclusion Among US Medicare beneficiaries, overall antibiotic use and potentially inappropriate use in 2011-15 remained steady or fell modestly, but individual drugs had divergent changes in use. Trends in drug use across indications were stronger than trends in use for individual indications, suggesting that guidelines and concerns about antibiotic resistance were not major drivers of change in antibiotic use.
Does MRI add value in general practice for patients with traumatic knee complaints? A 1-year randomised controlled trial
Authors: Nynke M Swart, Kim van Oudenaarde, Sita Ma Bierma-Zeinstra, Hans Jl Bloem, Wilbert B van den Hout, Paul R Algra, Patrick Je Bindels, Bart W Koes, Rob Ghh Nelissen, Jan An Verhaar, Monique Reijnierse, Pim Aj Luijsterburg
Journal: British Journal of Sports Medicine (2018)

Objective To determine whether referral to MRI by the general practitioner (GP) is non-inferior to usual care (no access to MRI by GPs) in patients with traumatic knee complaints regarding knee-related daily function. Methods This was a multicentre, non-inferiority randomised controlled trial with 1-year follow-up. GPs invited eligible patients during or after their consultation. Eligible patients (18–45 years) consulted a GP with knee complaints due to a trauma during the previous 6 months. Patients allocated to the MRI group received an MRI at (median) 7 (IQR 1–33) days after the baseline questionnaire. Patients in the usual care group received information on the course of knee complaints, and a referral to a physiotherapist or orthopaedic surgeon when indicated. The primary outcome measure was knee-related daily function measured with the Lysholm scale (0 to 100; 100=excellent function) over 1 year, with a non-inferiority margin of 6 points. Results A total of 356 patients were included and randomised to MRI (n=179) or usual care (n=177) from November 2012 to December 2015. MRI was non-inferior to usual care concerning knee-related daily function during 1-year follow-up, for the intention-to-treat (overall adjusted estimate: 0.33; 95% CI −1.73 to 2.39) and per-protocol (overall adjusted estimate: 0.06; 95% CI −2.08 to 2.19) analysis. There were no differences between both groups in the amount of patients visiting other healthcare providers. Conclusion MRI in general practice in patients with traumatic knee complaints was non-inferior to usual care regarding knee-related daily function during 1-year follow-up. Trial registration number NTR3689.
Patient-derived Models of Abiraterone- and Enzalutamide-resistant Prostate Cancer Reveal Sensitivity to Ribosome-directed Therapy
Authors: Mitchell G. Lawrence, Daisuke Obinata, Shahneen Sandhu, Luke A. Selth, Stephen Q. Wong, Laura H. Porter, Natalie Lister, David Pook, Carmel J. Pezaro, David L. Goode, Richard J. Rebello, Ashlee K. Clark, Melissa Papargiris, Jenna Van Gramberg, Adrienne R. Hanson, Patricia Banks, Hong Wang, Birunthi Niranjan, Shivakumar Keerthikumar, Shelley Hedwards, Alisee Huglo, Rendong Yang, Christine Henzler, Yingming Li, Fernando Lopez-Campos, Elena Castro, Roxanne Toivanen, Arun Azad, Damien Bolton, Jeremy Goad, Jeremy Grummet, Laurence Harewood, John Kourambas, Nathan Lawrentschuk, Daniel Moon, Declan G. Murphy, Shomik Sengupta, Ross Snow, Heather Thorne, Catherine Mitchell, John Pedersen, David Clouston, Sam Norden, Andrew Ryan, Scott M. Dehm, Wayne D. Tilley, Richard B. Pearson, Ross D. Hannan, Mark Frydenberg, Luc Furic, Renea A. Taylor, Gail P. Risbridger
Journal: European Urology (2018)
Vascular Endothelial Growth Factor (VEGF) and VEGF-C Show Overlapping Binding Sites in Embryonic Endothelia and Distinct Sites in Differentiated Adult Endothelia
Authors: AthinaLymboussaki, BirgittaOlofsson, UlfEriksson, KariAlitalo
Journal: Circulation Research (1999)

Abstract—Vascular endothelial growth factor (VEGF) is a key modulator of angiogenesis during development and in adult tissues, whereas the related VEGF-C has been shown to induce both lymphangiogenesis and angiogenesis. To better understand the specific functions of these growth factors, we have here analyzed their binding to sections of mouse embryonic and adult tissues and compared the distribution of the bound growth factors with the expression patterns of the 3 known members of the VEGF receptor family as well as with neuropilin-1, a coreceptor for VEGF165. Partially overlapping patterns of VEGF and VEGF-C binding were obtained in embryonic tissues, consistent with the expression of all known VEGF receptors by vascular endothelial cells. However, the most striking differences of binding were observed in the developing and adult heart, in which VEGF decorated all vessels, whereas strong VEGF-C signals were obtained only from epicardial vessels. In the lymph nodes, VEGF and VEGF-C showed distinct bindin...
Aging Reduces Intermittent Hypoxia–induced Lung Carcinoma Growth in a Mouse Model of Sleep Apnea
Authors: Marta Torres, Noelia Campillo, Paula N. Nonaka, Josep M. Montserrat, David Gozal, Miguel Angel Martínez-García, Francisco Campos-Rodriguez, Daniel Navajas, Ramon Farré, Isaac Almendros
Journal: American Journal of Respiratory and Critical Care Medicine (2018)
Xenografted Human Amniotic Membrane–Derived Mesenchymal Stem Cells Are Immunologically Tolerated and Transdifferentiated Into Cardiomyocytes
Authors: HirokoTsuji, ShunichiroMiyoshi, YukinoriIkegami, NaokoHida, HironoriAsada, IkukoTogashi, JunshiSuzuki, MasakiSatake, HikaruNakamizo, MamoruTanaka, TaisukeMori, KaoruSegawa, NobuhiroNishiyama, JunkoInoue, HatsuneMakino, KenjiMiyado, SatoshiOgawa, YasunoriYoshimura, AkihiroUmezawa
Journal: Circulation Research (2010)

Rationale: Amniotic membrane is known to have the ability to transdifferentiate into multiple organs and is expected to stimulate a reduced immunologic reaction. Objective: Determine whether human amniotic membrane–derived mesenchymal cells (hAMCs) can be an ideal allograftable stem cell source for cardiac regenerative medicine. Methods and Results: We established hAMCs. After cardiomyogenic induction in vitro, hAMCs beat spontaneously, and the calculated cardiomyogenic transdifferentiation efficiency was 33%. Transplantation of hAMCs 2 weeks after myocardial infarction improved impaired left ventricular fractional shortening measured by echocardiogram (34±2% [n=8] to 39±2% [n=11]; P<0.05) and decreased myocardial fibrosis area (18±1% [n=9] to 13±1% [n=10]; P<0.05), significantly. Furthermore hAMCs transplanted into the infarcted myocardium of Wistar rats were transdifferentiated into cardiomyocytes in situ and survived for more than 4 weeks after the transplantation without using any immunosuppressant. I...
Fibroblast injection vs. fibroblasts on amniotic membrane in RDEB
Authors: H. Moravvej, F. Abdollahimajd, M.-H. Naseh, Z. Piravar, E. Abolhasani, N. Mozafari, H. Niknejad
Journal: British Journal of Dermatology (2018)

Epidermolysis bullosa (EB) is a blistering disorder caused by at least 18 variable gene mutations (meaning ‘mistakes’ in certain genes). Recessive dystrophic EB (RDEB) is a distinct subtype of EB that is caused by different mutations in the type‐VII collagen gene (COL7A1). Different methods of application of cells called fibroblasts have been examined to treat RDEB. This study, from Iran, aimed to compare the effects of injections of fibroblasts (called cultured allogeneic fibroblasts) in healing RDEB wounds, with that of fibroblasts seeded on amniotic membrane scaffolds (FAMS – a type of skin graft), or ‐ as a control group ‐ standard wound care (SWC) with petroleum jelly gauze as controls. Seven patients were recruited, and seven wounds were assessed in each patient: three wounds were treated with injection of intradermal fibroblasts, three were treated with FAMS, and one was dressed with SWC. Changes in wound size were assessed after 2 and 12 weeks of treatment. A scoring system called QWS was also used to assess wound severity. Additionally, biopsies and tests were performed to detect type‐VII collagen. In both treated areas, the QWS and wound size were decreased, whereas there were no changes in control group. After 2 and 12 weeks of treatment, the wound size was decreased in wounds that were treated with fibroblast injection compared with those treated with FAMS, but no significant changes were found in control group.
Mitochondrial uncoupler BAM15 inhibits artery constriction and potently activates AMPK in vascular smooth muscle cells
Authors: Yu Tai, Lanjun Li, Xuan Peng, Junxue Zhu, Xihai Mao, Nan Qin, Minghui Ma, Rong Huo, Yunlong Bai, Deli Dong
Journal: Acta Pharmaceutica Sinica B (2018)

Our previous studies found that mitochondrial uncouplers CCCP and niclosamide inhibited artery constriction and the mechanism involved AMPK activation in vascular smooth muscle cells. BAM15 is a novel type of mitochondrial uncoupler. The aim of the present study is to identify the vasoactivity of BAM15 and characterize the BAM15-induced AMPK activation in vascular smooth muscle cells (A10 cells). BAM15 relaxed phenylephrine (PE)-induced constricted rat mesenteric arteries with intact and denuded endothelium. Pretreatment with BAM15 inhibited PE-induced constriction of rat mesenteric arteries with intact and denuded endothelium. BAM15, CCCP, and niclosamide had the comparable IC50 value of vasorelaxation in PE-induced constriction of rat mesenteric arteries. BAM15 was less cytotoxic in A10 cells compared with CCCP and niclosamide. BAM15 depolarized mitochondrial membrane potential, induced mitochondrial fission, increased mitochondrial ROS production, and increased mitochondrial oxygen consumption rate in A10 cells. BAM15 potently activated AMPK in A10 cells and the efficacy of BAM15 was stronger than that of CCCP, niclosamide, and AMPK positive activators metformin and AICAR. In conclusion, BAM15 activates AMPK in vascular smooth muscle cells with higher potency than that of CCCP, niclosamide and the known AMPK activators metformin and AICAR. The present work indicates that BAM15 is a potent AMPK activator.
Mouse Models of Cardiac Arrhythmias
Authors: Dobromir Dobrev, Xander H.T. Wehrens
Journal: Circulation Research (2018)

M ouse models have been invaluable for delineating the contributions of specific genes and signaling pathways to the pathogenesis of cardiac arrhythmias.Considering that there are important differences between mice and humans, here we discuss the strengths and limitations of mouse models of cardiac arrhythmias.
Mucosal HPV E6/E7 Peptide Vaccination in Combination with Immune Checkpoint Modulation Induces Regression of HPV+ Oral Cancers
Authors: Stephanie Dorta-Estremera, Renee L. Chin, Gloria Sierra, Courtney Nicholas, Ananta V. Yanamandra, Sita M.K. Nookala, Guojun Yang, Shail Singh, Michael A. Curran, K. Jagannadha Sastry
Journal: Cancer Research (2018)

Abstract High-risk human papillomavirus (HPV)–associated squamous cell carcinomas of the oropharynx (SCCOP) are among the fastest growing cancers. After standard-of-care treatment, however, patients with HPV+ SCCOP have better overall and disease-specific survival than patients with HPV− SCCOP, suggesting the importance of HPV-specific immunity. We reasoned that therapeutic vaccination targeting the HPV-16 E6 and E7 oncogenes could elicit high-affinity, high-frequency tumor antigen–specific T-cell responses, which could then be augmented and shielded from suppression in the tumor microenvironment by immune checkpoint modulation. In this study, we used a preclinical syngeneic mouse model of oral cancer comprised of mouse tonsil-derived epithelial cells stably expressing HPV-16 E6 and E7 genes along with H-ras oncogene (mEER) to identify combinations of vaccination and checkpoint antibodies capable of promoting tumor regression. Intranasal HPV E6/E7 peptide vaccination and single checkpoint antibodies failed to elicit responses in more than half of animals; however, 4-1BB agonist antibody along with either CD40 agonist antibody or CTLA-4 blockade eliminated the majority of established mEER tumors. The combination of intranasal HPV peptide vaccine and α4-1BB and αCTLA-4 antibodies produced curative efficacy and a better safety profile against orally implanted mEER tumors. Correlates of protective immunity included enhanced intratumoral levels of CD8 T cells relative to immunosuppressive regulatory T cells and myeloid-derived suppressor cells. Overall, our results demonstrate combination vaccine-immunotherapy modalities as novel treatment options for HPV+ SCCOP. Significance: Combinations of vaccine and checkpoint modulation are effective and safe treatment options for HPV+ oral cancers. Cancer Res; 78(18); 5327–39. ©2018 AACR.
Methotrexate injections for psoriasis
Authors: T. Tsakok, Z.K. Jabbar-Lopez, C.H. Smith
Journal: British Journal of Dermatology (2018)

This article is a review of a study, published in the Lancet, by R.Warren and colleagues, based in the U.K. and western Europe. The authors compared 17.5mg weekly methotrexate, given by subcutaneous injection, with placebo in 120 patients with moderate to severe psoriasis who had not previously received the drug. The first sixteen weeks of the study were a randomised controlled trial, meaning patients were randomly selected to either receive the drug or a placebo; patients continued an open study on methotrexate for up to a year. The dose was increased to 22.5 mg weekly if they did not improve on the lower dose to achieve PASI 50 at week 24. PASI is used to record the redness, thickness and scaling of a patient's psoriasis and to measure how well a treatment works, as a reduction in the PASI score means a reduction in these symptoms; for example PASI 75 means the patient has a 75% or more reduction in their PASI score from the start. The authors took blood tests and skin biopsies from patients on methotrexate and found changes on microscopic examination, including a decrease in CD3 positive lymphocytes and cytokine markers, and this implies that the drug works by its effect on the immune system. Blood tests showed no significant abnormality. At week 16, 41% of patients on methotrexate achieved PASI 75 improvement, compared to 10% of patients on placebo. The reviewers observed that, although methotrexate is widely used as a systemic treatment for psoriasis, there have been no previous randomised placebo controlled trials. This trial is therefore welcome, although only the first phase is placebo controlled. Traditionally, patients are given a small test dose (e.g. 5 or 7.5mg), and the dose is increased gradually over successive weeks. The investigators encountered no adverse events from starting on a higher dose. The reviewers noted that methotrexate by injection was not compared with the oral form of the drug (taken by mouth), which might be equally effective and is substantially cheaper. The unusually high response to placebo may be due in part to alcohol avoidance, which is advised for patients on methotrexate. The changes on skin biopsy are of interest, but it was not possible to correlate them with clinical response to the drug.