tbuckley/cabot-search huggingface dataset:
KDM4 Inhibition Targets Breast Cancer Stem–like Cells
Authors: Eric Metzger, Stella S. Stepputtis, Juliane Strietz, Bogdan-Tiberius Preca, Sylvia Urban, Dominica Willmann, Anita Allen, Fides Zenk, Nicola Iovino, Peter Bronsert, Amelie Proske, Marie Follo, Melanie Boerries, Elmar Stickeler, Jiangchun Xu, Michael B. Wallace, Jeffrey A. Stafford, Toufike Kanouni, Jochen Maurer, Roland Schüle
Journal: Cancer Research (2017)

Abstract Traditional treatments for breast cancer fail to address therapy-resistant cancer stem–like cells that have been characterized by changes in epigenetic regulators such as the lysine demethylase KDM4. Here, we describe an orally available, selective and potent KDM4 inhibitor (QC6352) with unique preclinical characteristics. To assess the antitumor properties of QC6352, we established a method to isolate and propagate breast cancer stem–like cells (BCSC) from individual triple-negative tumors resected from patients after neoadjuvant chemotherapy. Limiting-dilution orthotopic xenografts of these BCSCs regenerated original patient tumor histology and gene expression. QC6352 blocked BCSC proliferation, sphere formation, and xenograft tumor formation. QC6352 also abrogated expression of EGFR, which drives the growth of therapy-resistant triple-negative breast cancer cells. Our findings validate a unique BCSC culture system for drug screening and offer preclinical proof of concept for KDM4 inhibition as a new strategy to treat triple-negative breast cancer. Cancer Res; 77(21); 5900–12. ©2017 AACR.
Liver size: Waning by day, Waxing by Night
Authors: Hans Reinke, Gad Asher
Journal: Hepatology (2017)

1University of Düsseldorf Medical Faculty Institute of Clinical Chemistry and Laboratory DiagnosticsDüsseldorfGermany 2IUF‐Leibniz Research Institute for Environmental MedicineDüsseldorfGermany 3Department of Biomolecular SciencesWeizmann Institute of ScienceRehovotIsrael
Margaret McCartney: Why GPs are always running late
Authors: Margaret McCartney
Journal: BMJ (2017)

An intelligent, kind friend says to me, “My GP is always running late—why?”

I try to explain that her GP is probably similar to me. Even arriving early and staying late, I still only have about 12 minutes for each patient. And I have to fit a lot into those 12 minutes.

I must go to the waiting room to locate and invite the patient into a private room. I must introduce myself and find out why the patient’s here. There’s probably more than one reason.

Then, history taking: sometimes complicated, sometimes not. Examination, if needed. Assistance may be required. Clothing may need to be removed. …
膵管腺癌の局所化学療法を提供するための調整可能な送達プラットフォーム【Powered by NICT】
Authors: Indolfi Laura, Ligorio Matteo, T Ting David, Xega Kristina, R Tzafriri Abraham, Bersani Francesca, Aceto Nicola, Thapar Vishal, C Fuchs Bryan, Deshpande Vikram, B Baker Aaron, R Ferrone Cristina, A Haber Daniel, Langer Robert, W Clark Jeffrey, R Edelman Elazer
Journal: Biomaterials (2016)
急性肺損傷の画像監視修復のためのアップコンバージョンナノ粒子で標識したヒト羊水幹細胞【Powered by NICT】
Authors: Xu Yunyun, Xiang Jian, Zhao He, Liang Hansi, Huang Jie, Li Yan, Pan Jian, Zhou Huiting, Zhang Xueguang, Wang Jiang Huai, Liu Zhuang, Wang Jian
Journal: Biomaterials (2016)
Association of Evidence-Based Care Processes With Mortality in <i>Staphylococcus aureus</i> Bacteremia at Veterans Health Administration Hospitals, 2003-2014
Authors: Michihiko Goto, Marin L. Schweizer, Mary S. Vaughan-Sarrazin, Eli N. Perencevich, Daniel J. Livorsi, Daniel J. Diekema, Kelly K. Richardson, Brice F. Beck, Bruce Alexander, Michael E. Ohl
Journal: JAMA Internal Medicine (2017)

Staphylococcus aureus bacteremia is common and frequently associated with poor outcomes. Evidence indicates that specific care processes are associated with improved outcomes for patients with S aureus bacteremia, including appropriate antibiotic prescribing, use of echocardiography to identify endocarditis, and consultation with infectious diseases (ID) specialists. Whether use of these care processes has increased in routine care for S aureus bacteremia or whether use of these processes has led to large-scale improvements in survival is unknown.To examine the association of evidence-based care processes in routine care for S aureus bacteremia with mortality.This retrospective observational cohort study examined all patients admitted to Veterans Health Administration (VHA) acute care hospitals who had a first episode of S aureus bacteremia from January 1, 2003, through December 31, 2014.Use of appropriate antibiotic therapy, echocardiography, and ID consultation.Thirty-day all-cause mortality.Analyses included 36 868 patients in 124 hospitals (mean [SD] age, 66.4 [12.5] years; 36 036 [97.7%] male), including 19 325 (52.4%) with infection due to methicillin-resistant S aureus and 17 543 (47.6%) with infection due to methicillin-susceptible S aureus. Risk-adjusted mortality decreased from 23.5% (95% CI, 23.3%-23.8%) in 2003 to 18.2% (95% CI, 17.9%-18.5%) in 2014. Rates of appropriate antibiotic prescribing increased from 2467 (66.4%) to 1991 (78.9%), echocardiography from 1256 (33.8%) to 1837 (72.8%), and ID consultation from 1390 (37.4%) to 1717 (68.0%). After adjustment for patient characteristics, cohort year, and other care processes, receipt of care processes was associated with lower mortality, with adjusted odds ratios of 0.74 (95% CI, 0.68-0.79) for appropriate antibiotics, 0.73 (95% CI, 0.68-0.78) for echocardiography, and 0.61 (95% CI, 0.56-0.65) for ID consultation. Mortality decreased progressively as the number of care processes that a patient received increased (adjusted odds ratio for all 3 processes compared with none, 0.33; 95% CI, 0.30-0.36). An estimated 57.3% (95% CI, 48.4%-69.9%) of the decrease in mortality between 2003 and 2014 could be attributed to increased use of these evidence-based care processes.Mortality associated with S aureus bacteremia decreased significantly in VHA hospitals, and a substantial portion of the decreasing mortality may have been attributable to increased use of evidence-based care processes. The experience in VHA hospitals demonstrates that increasing application of these care processes may improve survival among patients with S aureus bacteremia in routine health care settings.
Closed-Loop Control During Intense Prolonged Outdoor Exercise in Adolescents With Type 1 Diabetes: The Artificial Pancreas Ski Study
Authors: Marc D. Breton, Daniel R. Cherñavvsky, Gregory P. Forlenza, Mark D. DeBoer, Jessica Robic, R. Paul Wadwa, Laurel H. Messer, Boris P. Kovatchev, David M. Maahs
Journal: Diabetes Care (2017)

Intense exercise is a major challenge to the management of type 1 diabetes (T1D). Closed-loop control (CLC) systems (artificial pancreas) improve glycemic control during limited intensity and short duration of physical activity (PA). However, CLC has not been tested during extended vigorous outdoor exercise common among adolescents.Skiing presents unique metabolic challenges: intense prolonged PA, cold, altitude, and stress/fear/excitement. In a randomized controlled trial, 32 adolescents with T1D (ages 10-16 years) participated in a 5-day ski camp (∼5 h skiing/day) at two sites: Wintergreen, VA, and Breckenridge, CO. Participants were randomized to the University of Virginia CLC system or remotely monitored sensor-augmented pump (RM-SAP). The CLC and RM-SAP groups were coarsely paired by age and hemoglobin A1c (HbA1c). All subjects were remotely monitored 24 h per day by the study physicians and clinical team.Compared with physician-monitored open loop, percent time in range (70-180 mg/dL) improved using CLC: 71.3 vs. 64.7% (+6.6% [95% CI 1-12]; P = 0.005), with maximum effect late at night. Hypoglycemia exposure and carbohydrate treatments were improved overall (P = 0.001 and P = 0.007) and during the daytime with strong ski level effects (P = 0.0001 and P = 0.006); ski/snowboard proficiency was balanced between groups but with a very strong site effect: naive in Virginia and experienced in Colorado. There was no adverse event associated with CLC; the participants' feedback was overwhelmingly positive.CLC in adolescents with T1D improved glycemic control and reduced exposure to hypoglycemia during prolonged intensive winter sport activities, despite the added challenges of cold and altitude.
CELF1 Mediates Connexin 43 mRNA Degradation in Dilated Cardiomyopathy
Authors: Kuei-Ting Chang, Ching-Feng Cheng, Pei-Chih King, Shin-Yi Liu, Guey-Shin Wang
Journal: Circulation Research (2017)

Downregulation of Cx43 (connexin 43), the major cardiac gap junction protein, is often associated with arrhythmia, dilated cardiomyopathy (DCM), and heart failure. However, the cause of the reduced expression remains elusive. Reinduction of a nuclear RNA-binding protein CELF1 (CUGBP Elav-like family member 1) in the adult heart has been implicated in the cardiac pathogenesis of myotonic dystrophy type 1. However, how elevated CELF1 level leads to cardiac dysfunction, such as conduction defect, DCM, and heart failure, remains unclear.We investigated the mechanism of CELF1-mediated Cx43 mRNA degradation and determined whether elevated CELF1 expression is also a shared feature of the DCM heart.RNA immunoprecipitation revealed the involvement of CELF1-regulated genes, including Cx43, in controlling contractility and conduction. CELF1 mediated Cx43 mRNA degradation by binding the UG-rich element in the 3' untranslated region of Cx43. Mutation of the nuclear localization signal in CELF1 abolished the ability to downregulate Cx43 mRNA, so nuclear localization was required for its function. We further identified a 3' to 5' exoribonuclease, RRP6 (ribosomal RNA processing protein 6), as a CELF1-interacting protein. The interaction of CELF1 and RRP6 was RNA-independent and nucleus specific. With knockdown of endogenous RRP6, CELF1 failed to downregulate Cx43 mRNA, which suggests that RRP6 was required for CELF1-mediated Cx43 mRNA degradation. In addition, increased CELF1 level accompanied upregulated RRP6, and reduced Cx43 level was detected in mouse models with DCM, including myotonic dystrophy type 1 and CELF1 overexpression models and a myocardial infarction model. Importantly, depletion of CELF1 in the infarcted heart preserved Cx43 mRNA level and ameliorated the cardiac phenotypes of the infarcted heart.Our results suggest a mechanism for increased CELF1 expression downregulating Cx43 mRNA level and a pathogenic role for elevated CELF1 level in the DCM heart.
Meta-Epidemiology of Testosterone’s Risks and Benefits—Will We Ever Know the Answer?—Reply
Authors: T. Craig Cheetham, Stephen K. VanDenEeden, Steven J. Jacobsen
Journal: JAMA Internal Medicine (2017)

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 Internal Medicine 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 Internal Medicine journal
眼環境におけるコロナ形成を模倣したナノ粒子‐蛋白質錯体【Powered by NICT】
Authors: Jo Dong Hyun, Kim Jin Hyoung, Son Jin Gyeong, Dan Ki Soon, Song Sang Hoon, Lee Tae Geol, Kim Jeong Hun
Journal: Biomaterials (2016)
Randomized controlled phase III study evaluating the impact of secondary cytoreductive surgery in recurrent ovarian cancer: AGO DESKTOP III/ENGOT ov20.
Authors: Andreas Du Bois, Ignace Vergote, Gwenael Ferron, Alexander Reuss, Werner Meier, Stefano Greggi, Pernille Tina Jensen, Frédéric Selle, Frederic Guyon, Christophe Pomel, Fabrice Lecuru, Rongyu Zang, Elisabeth Avall-Lundqvist, Jae Weon Kim, Jordi Ponce, Francesco Raspagliesi, Sadaf Ghaem-Maghami, Alexander Reinthaller, Philipp Harter, Jalid Sehouli
Journal: Journal of Clinical Oncology (2017)

5501 Background: The role of secondary cytoreductive surgery in recurrent ovarian cancer (OC) has not been defined by level-1 evidence. Methods: Pts with OC and 1st relapse after 6+ mos platin-free interval (TFIp) were eligible if they presented with a positive AGO-score (PS ECOG 0, ascites ≤500 ml, and complete resection at initial surgery) and were randomized to 2 nd -line chemotherapy alone vs cytoreductive surgery followed by chemo. Chemo regimens were selected according to the institutional standard. We report here results of the predetermined interim analysis. Results: 407pts were randomized 2010-2014. The TFIp exceeded 12 mos in 75% and 76% pts in both arms. 8.9% of 203 pts were operated despite of randomization to the no-surgery arm, whereas 6.9% of 204 pts in the surgery arm did not undergo operation. Complete resection was achieved in 67% of pts; 87% and 88% received a platinum-containing 2 nd -line therapy. Median PFS was 14 mos without and 19.6 mos with surgery (HR: 0.66, 95%CI 0.52-0.83, p&lt;0.001). Median time to start of first subsequent therapy (TFST) was 21 vs 13.9 mos in favor of the surgery arm (HR 0.61, 95%CI 0.48-0.77, p=p&lt;0.001). PFS-2 between 1 st and 2nd relapse equaled or even exceeded PFS-1 before 1 st relapse in 26% after surgery and only 16% without-surgery. Analysis of the primary endpoint OS is kept blinded due to immaturity and will be evaluated after extended follow-up (the observed pooled unblinded 2-YSR was 83% instead of the initially in the protocol assumed 55-66%). 60d mortality rates were 0 and 0.5% in the surgery and no-surgery arm. Re-laparatomies were performed in 7 pts (3.5%) in the surgery arm.With the exception of myelosuppression which occurred more frequently in the no-surgery arm no further significant differences were observed with respect to grade 3+ acute adverse events. Conclusions: Surgery in pts with 1st relapse of OC after a TFIp of 6+ mos and selected by a positive AGO-Score resulted in a clinically meaningful increase of PFS and TFST with acceptable treatment burden. Until final OS data will definitively define the role of secondary cytoreductive surgery it should at least be considered as valuable option in pts with a positive AGO-Score. Clinical trial information: NCT01166737.
A novel formulation of inhaled sodium cromoglicate (PA101) in idiopathic pulmonary fibrosis and chronic cough: a randomised, double-blind, proof-of-concept, phase 2 trial
Authors: Surinder S Birring, Marlies S Wijsenbeek, Sanjay Agrawal, Jan W K van den Berg, Helen Stone, Toby M Maher, Ahmet Tutuncu, Alyn H Morice
Journal: The Lancet Respiratory Medicine (2017)
Lupus‐Associated Functional Polymorphism in <i>PNP</i> Causes Cell Cycle Abnormalities and Interferon Pathway Activation in Human Immune Cells
Authors: Yogita Ghodke‐Puranik, Jessica M. Dorschner, Danielle M. Vsetecka, Shreyasee Amin, Ashima Makol, Floranne Ernste, Thomas Osborn, Kevin Moder, Vaidehi Chowdhary, Elias Eliopoulos, Maria I. Zervou, George N. Goulielmos, Mark A. Jensen, Timothy B. Niewold
Journal: Arthritis & Rheumatology (2017)

Systemic lupus erythematosus (SLE) is frequently characterized by activation of the type I interferon (IFN) pathway. We previously observed that a missense single-nucleotide polymorphism (rs1049564) in the purine nucleoside phosphorylase (PNP) gene was associated with high levels of IFN in SLE. PNP is a key enzyme involved in purine metabolism. In this study, we performed functional follow-up of this polymorphism in human cells.Type I IFN was measured in patient sera, using a reporter cell assay. Structural modeling of the PNP variant was performed using PyMOL software. PNP messenger RNA (mRNA) and protein levels and type I IFN-induced gene expression were measured in lymphoblastoid cell lines with known PNP rs1049564 genotypes. The cell cycle was assayed using flow cytometry.Structural modeling indicated no major disruption in folding related to rs1049564. We observed that homozygous rs1049564 TT lymphoblastoid cells had decreased PNP mRNA expression and protein levels, and that cells with the TT genotype had reduced PNP enzymatic activity even when the amount of PNP was controlled. Cells with the TT genotype had a 2-fold increase in S-phase block as compared with cells with the homozygous CC phenotype. The S-phase block could be pharmacologically reversed with hypoxanthine and adenosine, supporting the notion that relative PNP deficiency is the cause of the S-phase block. Type I IFN-induced transcripts were increased in a dose-response manner related to the rs1049564 T allele, at both baseline and after type I IFN stimulation.The PNP rs1049564 T allele is a loss-of-function variant that induces S-phase block and IFN pathway activation in lymphocytes. The S-phase block could be rescued in our in vitro experiments, suggesting the potential for personalized treatment.
Mast cell hyperactivity underpins the development of oxygen-induced retinopathy
Authors: Kenshiro Matsuda, Noriko Okamoto, Masatoshi Kondo, Peter D. Arkwright, Kaoru Karasawa, Saori Ishizaka, Shinichi Yokota, Akira Matsuda, Kyungsook Jung, Kumiko Oida, Yosuke Amagai, Hyosun Jang, Eiichiro Noda, Ryota Kakinuma, Koujirou Yasui, Uiko Kaku, Yasuo Mori, Nobuyuki Onai, Toshiaki Ohteki, Akane Tanaka, Hiroshi Matsuda
Journal: Journal of Clinical Investigation (2017)

Mast cells are classically thought to play an important role in protection against helminth infections and in the induction of allergic diseases; however, recent studies indicate that these cells also contribute to neovascularization, which is critical for tissue remodeling, chronic inflammation, and carcinogenesis. Here, we demonstrate that mast cells are essential for sprouting angiogenesis in a murine model of oxygen-induced retinopathy (OIR). Although mouse strains lacking mast cells did not exhibit retinal neovascularization following hypoxia, these mice developed OIR following infusion of mast cells or after injection of mast cell tryptase (MCT). Relative hypoxia stimulated mast cell degranulation via transient receptor potential ankyrin 1. Subsequent surges in MCT stimulated retinal endothelial cells to produce monocyte chemotactic protein-1 (MCP1) and angiogenic factors, leading to sprouting angiogenesis. Mast cell stabilizers as well as specific tryptase and MCP1 inhibitors prevented the development of OIR in WT mice. Preterm infants with early retinopathy of prematurity had markedly higher plasma MCT levels than age-matched infants without disease, suggesting mast cells contribute to human disease. Together, these results suggest therapies that suppress mast cell activity should be further explored as a potential option for preventing eye diseases and subsequent blindness induced by neovascularization.
Genomic overview of right-sided and left-sided colorectal cancer using comprehensive genomic sequencing.
Authors: Yoshifumi Shimada, Hitoshi Kameyama, Masayuki Nagahashi, Hiroshi Ichikawa, Ryoma Yagi, Yosuke Tajima, Kizuki Yuza, Masato Nakano, Masato Nakajima, Takashi Ishikawa, Jun Sakata, Takashi Kobayashi, Hitoshi Nogami, Satoshi Maruyama, Yasumasa Takii, Jennifer E. Ring, Stephen Lyle, Shujiro Okuda, Kazuaki Takabe, Toshifumi Wakai
Journal: Journal of Clinical Oncology (2017)

e15101 Background: Although the difference in right vs. left sidedness of colorectal cancer (CRC) in response to targeted therapy has been reported, we hypothesized that right-sided colorectal cancer (RCC) is more likely to have genetic alterations associated with resistance of anti-EGFR therapy. We tested this hypothesis using comprehensive genomic sequencing (CGS) on a set of samples from well-characterized CRC patients. Methods: Two-hundred-one primary colon cancer patients with either RCC or left-sided colorectal cancer (LCC) were analyzed. We investigated gene alterations using 415 gene panel, which includes the gene alterations associated with resistance of anti-EGFR therapy: TK receptors ( ERBB2, MET, EGFR, FGFR1, and PDGFRA), RAS pathway ( KRAS, NRAS, HRAS, BRAF, and MAPK2K1), and PI3K pathway ( PTEN and PIK3CA). We defined the patients who had no alterations in any of the genes as “all wild-type”, who are theoretically considered as responders of anti-EGFR therapy. Other patients with genetic alterations in resistance pathways were defined as “mutant-type”. Results: Fifty-six patients (28%) and 145 patients (72%) had RCC and LCC, respectively. Mutation of PIK3CA, BRAF, ACVR2A, MSH6, and CTNNB1 were significantly associated with RCC. Conversely, mutation of APC and TP53 were significantly associated with LCC. Regarding the gene alterations associated with anti-EGFR therapy, only 6 of 56 patients (11%) of RCC were “all wild-type”; in contrast to 41 of 145 patients (28%) of LCC that were “all wild-type” ( P = 0.009). In 45 Stage IV patients treated with anti-EGFR therapy, RCC showed significantly worse progression-free survival (PFS) than LCC ( P = 0.019), and “mutant-type” RCC showed worse PFS compared to the others ( P = 0.018). Conclusions: RCC is more likely to have the genetic alterations associated with resistance of anti-EGFR therapy compared to LCC. Primary tumor sidedness is a surrogate for the non-random distribution of molecular subtypes in CRC.
Efficacy and safety of 4 months of sublingual immunotherapy with recombinant Mal d 1 and Bet v 1 in patients with birch pollen–related apple allergy
Authors: Tamar Kinaciyan, Birgit Nagl, Sandra Faustmann, Florian Frommlet, Stephan Kopp, Martin Wolkersdorfer, Stefan Wöhrl, Katharina Bastl, Hans Huber, Uwe Berger, Barbara Bohle
Journal: Journal of Allergy and Clinical Immunology (2017)
Effects of Vildagliptin on Ventricular Function in Patients With Type 2 Diabetes Mellitus and Heart Failure
Authors: John J.V. McMurray, Piotr Ponikowski, Geremia B. Bolli, Valentina Lukashevich, Plamen Kozlovski, Wolfgang Kothny, James D. Lewsey, Henry Krum
Journal: JACC Heart Failure (2017)
The importation of the phylogenetic-transition state of Zika virus to China in 2014
Authors: Binghui Wang, Yuebo Liang, Yunnan Lu, Li Zhang, Yaping Li, Yuzhu Song, Chengfeng Qin, Zhongxin Luo, Zhiqing Xia, Weihong Qin, Xueshan Xia
Journal: Journal of Infection (2017)