tbuckley/cabot-search huggingface dataset:
Early Experience With the California End of Life Option Act
Authors: Stephanie M. Harman, David Magnus
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
Ovarian Function Recovery During Anastrozole in Breast Cancer Patients With Chemotherapy-Induced Ovarian Function Failure
Authors: Irene E G van Hellemond, Ingeborg J H Vriens, Petronella G M Peer, Astrid C P Swinkels, Carolien H Smorenburg, Caroline M Seynaeve, Maurice J C van der Sangen, Judith R Kroep, Hiltje de Graaf, Aafke H Honkoop, Frans L G Erdkamp, Franchette W P J van den Berkmortel, Jos J E M Kitzen, Maaike de Boer, Wïlfred K de Roos, Sabine C Linn, Alexander L T Imholz, Vivianne C G Tjan-Heijnen
Journal: JNCI Journal of the National Cancer Institute (2017)

Aromatase inhibitors (AIs) are given as adjuvant therapy for hormone receptor-positive breast cancer in postmenopausal women, also to those with chemotherapy-induced ovarian function failure. The current analysis reports on endocrine data of patients with chemotherapy-induced ovarian function failure who were included in the phase III DATA study assessing different durations of adjuvant anastrozole after tamoxifen.We identified all patients with chemotherapy-induced ovarian function failure. Women who underwent a bilateral ovariectomy or used luteinizing hormone-releasing hormone agonists before random assignment were excluded. Plasma estradiol and follicle-stimulating hormone levels were monitored until 30 months after random assignment at local laboratories. We aimed to determine the ovarian function recovery (OFR) rate during AI use by the cumulative incidence competing risk method and analyzed the trend of estradiol levels during AI use by a nested case-control approach in which a subset of control subjects were compared with the OFR patients excluding the value at OFR diagnosis.The 329 eligible patients had a median age of 50.0 years (range = 45-57 years) at random assignment. Thirty-nine patients developed OFR, corresponding with a 30-month recovery rate of 12.4%. Of these, 11 (28.2%) were age 50 years or older at AI initiation. The estradiol level decreased statistically significantly by 37.8% (95% CI = 27.4% to 46.7%) over the initial 30 months of AI treatment in both groups. However, the estradiol levels in the women who experienced OFR remained statistically significantly higher (difference = 20.6%, 95% CI = 2.0% to 42.7%) prior to OFR diagnosis compared with those who did not experience OFR.The risk of OFR during AI treatment in breast cancer patients with chemotherapy-induced ovarian function failure is relevant, even beyond 45 years. Furthermore, women experiencing OFR had statistically significant higher estradiol levels during AI treatment (before OFR) than those without, with potential consequences regarding efficacy.
Concussion rates and recovery in elite youth ice hockey players
Authors: Kathryn J Schneider, Alberto Nettel-Aguirre, Luz Palacios-Derflingher, Martin Mrazik, Brian L Brooks, Kaikanani Woollings, Tracy A Blake, Carly D McKay, Constance M Lebrun, Karen Barlow, Kirsten A Taylor, Willem H. Meeuwisse, Carolyn A. Emery
Journal: British Journal of Sports Medicine (2017)

<h3>Objective</h3> To examine rates of concussion and severe concussion (time loss greater than 10 days) in elite youth ice hockey players. <h3>Design</h3> Prospective cohort study <h3>Setting</h3> Alberta, Canada <h3>Participants</h3> Bantam (13–14 years) and Midget (15–17 years) male and female elite (top 30% by division of play) youth ice hockey players. <h3>Assessment of risk factors</h3> Participants completed a demographic and medical history questionnaire and clinical test battery at the beginning of the season. A previously validated injury surveillance system was used to document exposure hours and injury during one season of play (8 months). <h3>Outcome measures</h3> Players with a suspected ice hockey-related concussion were referred to the study sport medicine physicians for assessment. Time loss from hockey participation was documented on an injury report form. <h3>Main results</h3> Overall, 778 elite youth ice hockey players (659 males, 119 females; aged 13–17 years) participated in this study. In total, 143 concussions occurred. The concussion incidence proportion (IP) was 18 concussions/100 players. The concussion incidence rate (IR) was 1.31 concussions/1000 player-hours (95% CI; 1.09, 1.57). Time loss greater than 10 days was reported in 74% of cases (106/143) and 20% (n=28) had time loss of greater than 30 days. <h3>Conclusions</h3> Concussion is a common injury in elite youth ice hockey players. In this study population, a large proportion of concussions (74%) resulted in a time loss of greater than 10 days, possibly reflecting more conservative management or longer recovery in youth athletes. <h3>Competing interests</h3> None.
MEDU-07. A PILOT EXPLORATORY STUDY ON THE ROLE OF A SUBPOPULATION OF MACROPHAGES IN MEDULLOBLASTOMA
Authors: Aixin Yap, M Tarek Elghetany, Angela Major, Jack MF Su, Xiaonan Li, Kam Man Hui, Wan-Yee Teo
Journal: Neuro-Oncology (2017)

Medulloblastoma (MB) is the most common childhood malignant brain tumor. We have previously described the presence of tumor-infiltrating macrophages among patient MBs (n=60). There are diverse subsets of tumor-infiltrating macrophages, we studied one specific subpopulation of macrophage (Subpopulation 1) in MB, and observe that a distinct molecular phenotype of MBs associated with high-macrophage infiltrated MBs. We created an in-vitro system in our laboratory to study the role of macrophages (mixed stages of development) in MB tumorigenesis, using 4 patient-derived primary tumor cell lines in a stimulated versus un-stimulated macrophage environment. Only 1 primary MB cell line demonstrated a higher rate of tumor proliferation in a stimulated environment with macrophages at mixed stages of development. In an un-stimulated environment with macrophages at mixed stages of development, all 4 cell lines did not demonstrate any proliferation differences. After prolonged exposure to MB tumor cells, less mature macrophages are highly attracted towards MB tumor cell microenvironment, while mature macrophages are less migratory. We further refined this in-vitro system to study another subpopulation of macrophages (Subpopulation 2). Subpopulation 2 macrophages in a stimulated environment, demonstrate differential proliferative effects on different MB cell lines. We also observed differential migration of Subpopulation 2 macrophages towards different MB cell lines. We are currently studying the roles of different subsets of the diverse spectrum of macrophages in the tumor microenvironment that affect MB tumor development. This will enable us to identify and target the most important subpopulation of macrophages that promotes aggressive tumor behavior in MB.
Abstract 119: The Scaffolding Protein Enh1 is Essential for the Protein Kinase C or Protein Kinase D-dependent Activation of the Transcription Factor Camp-response Element Binding Protein in Cardiomyocytes
Authors: Jumpei Ito, Andrés D. Maturana
Journal: Circulation Research (2015)

PDZ-LIM proteins form a family of the scaffolding protein essential for both embryonic and post-natal development. ENH1 (PDLIM5) is a PDZ-LIM protein, composed of an N-terminal PDZ domain and 3 LIM domains at the C-terminal end. The enh gene encodes for several splice variants that have opposite functions. ENH1 promotes the cardiomyocytes hypertrophy whereas ENH splice variants lacking LIM domains prevents it. At the molecular level, ENH1 interacts with Protein kinase C (PKC) and Protein Kinase D1 (PKD1) both kinases playing a pivotal role in the pathological remodeling of the heart. In addition, the binding of ENH1’s LIM domains to PKC is sufficient to activate the kinase without any stimulation. However, the downstream events of the ENH1-PKC/PKD1 complex remain unknown. PKC and PKD1 are known to phosphorylate the transcription factor cAMP-response element binding protein (CREB) in cardiomyocytes. We therefore hypothesized that ENH1 could be a play a role in the PKC/PKD1-dependent activation of CREB. We first found that ENH1 expression is necessary to induce the phosphorylation of CREB at Ser133 in neonatal rat ventricular cardiomyocytes. On the contrary, the overexpression of ENH3, a LIM-less cardiac-specific splice variant, inhibited the phosphorylation of CREB-Ser133. Concomitantly, both real-time qPCR and promoter assay showed that the overexpression of ENH1 enhanced but ENH3 prevented the transcriptional activation of a CREB-target gene, the immediately early gene c-fos. Finally, we found that ENH1 regulated the translocation of phosphorylated CREB to the nucleus. Taken all together, our results suggest that ENH1 plays an essential role in CREB’s activation and dependent transcription in cardiomyocytes. At the opposite, ENH3 splice variant inhibited the CREB activity in cardiomyocytes. In conclusion, our work describes a new molecular mechanism involving ENH splice variants with opposing functions.
Response by Flaherty to Letter Regarding Article, “Hemodynamic Support With a Micro-Axial Percutaneous Left Ventricular Assist Device (Impella) Protects Against Acute Kidney Injury in Patients Undergoing High-Risk Percutaneous Coronary Intervention”
Authors: Michael P. Flaherty
Journal: Circulation Research (2017)

Injury in Patients Undergoing High-Risk Percutaneous Coronary Intervention.In their letter, Naranjo et al pointed out the lack of additional experimental arms in our single-center study investigating the renal protective effect of partial hemodynamic support using the microaxial percutaneous left ventricular assist device (pLVAD) Impella 2.5 during high-risk percutaneous coronary intervention.Naranjo et al would have had us include patients supported with intra-aortic balloon pumps (IABP) or other pLVADs.These authors believe that we may have observed similar outcomes with regard to renal protection by including additional pLVADs or IABPs in our analysis.With regard to the inclusion of additional pLVADs, we simply did not have these data to include in any meaningful way.About counterpulsation therapy, ours was a study that sought to determine the impact of systemic hemodynamic support on renal function.2][3] In fact, this lack of congruence in terms of device-related hemodynamic support resulted in IABP being replaced by the Impella 2.5 in the ongoing randomized, multicenter SHIELD II trial (Coronary Interventions in High-Risk Patients Using a Novel Percutaneous Left Ventricular Support Device) comparing the safety and efficacy of HeartMate PHP-supported patients undergoing elective or urgent high-risk percutaneous coronary intervention (https://clinicaltrials.gov/ct2/ show/NCT02468778).In addition, Naranjo et al underscore an important yet unintentional omission from our article about the use of inotrope support in the unsupported control arm.We assume this critique was in reference to our patients with shock hypoperfusion.That inotrope-mediated increase in the effective circulatory volumes in our control patients with cardiogenic shock-related renal hypoperfusion would have provided some degree of protection against acute kidney injury (AKI) is probable. 4However, only 6 (5%) of our unsupported control patients were classified as having cardiogenic shock.Moreover, because this was a retrospective study, our cardiogenic shock classification was based on our institutional guidelines and documented in the medical record and was defined by the following: (1) systolic blood pressure of <90 mm Hg
Longitudinal Assessment of CLL Patients Under Ibrutinib Treatment Reveals Maintained Capacity to Respond to Microenvironmental Stimuli through the Toll-like Receptors
Authors: Maria Gounari, Stavroula Ntoufa, Konstantia Kotta, Maria Giovanna Vilia, Athanasia Nenou, Marina Gerousi, Lydia Scarfò, Aliki Xochelli, Eleonora Fonte, Marta Coscia, Alessandra Tedeschi, Niki Stavroyianni, Marta Muzio, Kostas Stamatopoulos, Paolo Ghia
Journal: Blood (2016)
Q. why doesn’t headgear prevent concussion? a. no one bothered to ask
Authors: Andrew S McIntosh, Declan A Patton
Journal: British Journal of Sports Medicine (2017)

Objective The study identifies barriers to the supply of helmets/headgear/headguards (headgear) that are likely to be effective in preventing concussion. Design Literature review and biomechanical testing. Setting All sports. Outcome measures Sport federation rules on headgear and headgear impact performance with regards to concussion. Main results A review of laws and regulations showed that many sports have not developed relevant performance based technical specifications for headgear. World Rugby performance requirements comprise a drop height of 300 mm and pass level of greater than 200 g in impact energy attenuation tests. Testing of current World Rugby approved headgear showed peak linear headform accelerations (PLA) in the range 400 to 600 g in 200 mm and 300 mm drop tests. The performance of the exemplar models is arguably worse than in similar models tested circa 2000 and exceed informative concussion injury criteria, e.g. PLA&lt;75 g. Combat sports generally do not mandate performance requirements. Similarly, there is a range of performance from good to poor in laboratory-tested combat sport headgear with respect to concussion prevention; e.g. for headgear tested at a 500 mm drop height, PLA ranged from 50 g to 466 g. PLA results were reflected in angular head acceleration performance in impact tests. Other sports will be considered, e.g. ice hockey and American football, where performance standards are mandated. Conclusions The availability of headgear designed to prevent concussion is limited because relevant performance requirements are absent and/or aligned with other head injury prevention goals, e.g. preventing severe head injury. Competing interests None.
Erratum: Corrigendum: NANS-mediated synthesis of sialic acid is required for brain and skeletal development
Authors: Clara D M van Karnebeek, Luisa Bonafé, Xiao-Yan Wen, Maja Tarailo-Graovac, Sara Balzano, Beryl Royer-Bertrand, Angel Ashikov, Livia Garavelli, Isabella Mammi, Licia Turolla, Catherine Breen, Dian Donnai, Valerie Cormier, Delphine Heron, Gen Nishimura, Shinichi Uchikawa, Belinda Campos-Xavier, Antonio Rossi, Thierry Hennet, Koroboshka Brand-Arzamendi, Jacob Rozmus, Keith Harshman, Brian J Stevenson, Enrico Girardi, Giulio Superti-Furga, Tammie Dewan, Alissa Collingridge, Jessie Halparin, Colin J Ross, Margot I Van Allen, Andrea Rossi, Udo F Engelke, Leo A J Kluijtmans, Ed van der Heeft, Herma Renkema, Arjan de Brouwer, Karin Huijben, Fokje Zijlstra, Thorben Heisse, Thomas Boltje, Wyeth W Wasserman, Carlo Rivolta, Sheila Unger, Dirk J Lefeber, Ron A Wevers, Andrea Superti-Furga
Journal: Nature Genetics (2017)
IMMU-22. ADOPTIVE CELL THERAPY AGAINST DIPG USING DEVELOPMENTALLY REGULATED ANTIGENS
Authors: Catherine Flores, Jorge Gil, Rebecca Abraham, Christina Pham, Tyler Wildes, Ginger Moore, Jeffrey Drake, Kyle Dyson, Duane Mitchell
Journal: Neuro-Oncology (2017)

INTRODUCTION: Diffuse intrinsic pontine glioma (DIPG) survival has remained static over decades and DIPG is now the main cause of brain tumor-related deaths in children. Immunotherapy has emerged as a treatment modality with the highest curative potential in patients with refractory malignancies. Our group has pioneered an adoptive cell therapy platform employing total tumor RNA pulsed dendritic cells to generate large amounts of polyclonal antigen-specific T cells in both human and murine systems. As DIPGs are embryonal tumors, our objective in this proposal is to identify a set of developmentally regulated antigens that are overexpressed during oncogenesis of DIPG in order to cause immunological rejection of this tumor without the need for tumor tissue. METHODS: We employ RNA-pulsed bone marrow-derived dendritic cells to ex vivo activate tumor-reactive T cells for use in adoptive cell therapy. Here we use either total RNA isolated from tumor tissue, (TTRNA) or developmental antigens (DevAg) RNA isolated from postnatal day 4 murine brain stem. Either TTRNA-T cells or DevAg-T cells were used in adoptive cell therapy against a preclinical model of DIPG. RESULTS: Pediatric brain tumors are bland relative to peripheral tumors in terms of high expression of immunogenic antigens. Since DIPG antigens remain largely uncharacterized, we used total RNA isolated from tumor cells to generate tumor-specific T cells to use for our therapeutic approach to first demonstrate that immune responses can be generated against this tumor. We also successfully generated immunity against DIPG in a preclinical model using DevAg-T cells for adoptive cell therapy. CONCLUSION: The region- and age- specific nature of DIPG suggests that the underlying pathophysiology likely involves dysregulation of a postnatal neurodevelopmental process which occurs in embryonal tumors. Here we leverage this and demonstrate that DIPG can be effectively treated using adoptive cell therapy against overexpressed developmentally regulated antigens.
Synthesis and characterization of RBI-1033, a potent inhibitor of prostate specific membrane antigen that activates RNase L
Authors: Xinning Wang, Warren D. W. Heston, Hagen Cramer, Robert H. Silverman
Journal: Cancer Research (2005)

Proc Amer Assoc Cancer Res, Volume 46, 2005

3952 

Prostate specific membrane antigen (PSMA) is a type II integral membrane protein. In healthy subjects, PSMA expression is highly expressed in the prostate and its expression is further upregulated in poorly differentiated and advanced prostate cancers. Furthermore, PSMA is also expressed on the tumor vascular endothelium of virtually all solid carcinomas and sarcomas, but not on normal vascular endothelium. Therefore, PSMA is a potentially useful target for diagnosis and therapy across a wide spectrum of solid tumors. RNase L is an interferon-regulated endoribonuclease that maps to the hereditary prostate cancer 1 (HPC1) allele. RNase L functions in the interferon antiviral response by virtue of its ability to degrade single-stranded RNA, thus initiating a cellular stress response that leads to apoptosis. RNase L requires the activator molecule 5’-phosphorylated 2’,5’-linked oligoadenylate (2-5A). The purpose of this study was to design a new compound which can selectively activate RNase L in PSMA-expressing cells. We considered that it might be possible to target 2-5A to specific cells by linking it with a ligand for PSMA. Of the reported low molecular weight ligands for PSMA, ZJ24 appears to be the most readily modified. We modified ZJ24 with 2-5A through a 4-(N-maleimidomethyl) cyclohexane-1-amidate linkage to generate RBI-1033. We measured the effect of RBI-1033 on folate hydrolase activity of PSMA. PSMA-positive membrane preparations were incubated with different concentrations of ZJ24, RBI-1033 and 2-5A with linker (RBI-1032) together with the substrate methotrexate diglutamate (MTXGlu2) for 1h. The amount of methotrexate and MTXGlu2 were then determined by HPLC. Remarkably, we found that compared to ZJ24 (IC50=53.9 nM), RBI-1033 was more than 10 times more potent (IC50=4.8 nM) as a folate hydrolase inhibitor, while the RBI-1032 alone showed an IC50 at 2 μM. Binding studies were performed by incubating membranes with different concentrations of the compounds in the presence of 12 nM of 3H-ZJ24 for 30 min. RBI-1033 inhibited the binding of 3H-ZJ24 to the cell membrane with an IC50 at 1.5 nM, compared to ZJ24 at 15.3 nM and RBI-1032 at 3.5 μM. Therefore, RBI-1033 had 10-times higher affinity for PSMA than ZJ24. In addition, RBI-1033 retained the ability to activate RNase L, albeit less efficiently than 2-5A. These exciting results showed that the new compound, RBI-1033 is more potent as a folate hydrolase inhibitor and has higher binding affinity to PSMA compared to the parent drug, ZJ24. Our studies may lead to superior and highly effective agents for imaging or therapy of cancer. Supported in part by NIH grants CA101069-02 and CA103943-01.
Abstract 11827: Endothelial Microparticles Modulate Vasculitis During the Acute Phase of Kawasaki Disease
Authors: Hideyuki Nakaoka, Keiichi Hirono, Mako Okabe, Nariaki Miyao, Kazuyoshi Saito, Keijiro Ibuki, Sayaka Ozawa, Kei Takahashi, Fukiko Ichida
Journal: Circulation (2016)

Introduction: Kawasaki Disease (KD) is an acute inflammatory disease that takes the form of systemic vasculitis. Endothelial microparticles (EMPs) are vesicles formed by cell membranes after endothelial activation, which contain microRNAs (miRs) recognized as an important transcellular delivery system in the exchange of biological signals. The purpose of this study was to elucidate whether EMPs are involved in vasculitis in acute KD. Methods: We enrolled 50 KD patients (aged 4 months to 14 years), 50 controls (25 non-KD febrile and 25 healthy children). KD patients were divided into two subgroups: those with coronary artery lesions (CAL, Z-socre&gt;2.5, n=4) and those without coronary artery lesions (NCAL, Z-score≦2.5, n=46). Blood samples were collected three times; first, at the time of diagnosis before the initiation of IVIG treatment; second, immediately after the first IVIG infusion; finally, at 2-4 weeks after the onset of the disease. EMPs were measured using flow cytometry and miR expression profiling was performed using microarrays (Affymetrix ® GeneChip ® miRNA 4.0). We also performed miRCURY LNA™ microRNA in situ hybridization using 2 miRs in CAL patients and analyzed THP-1 monocyte stimulation using 2 miRs. Results: The percentage of EMPs was 1.27±0.16% in all of the small vesicles in KD patients prior to treatment, which was significantly higher than in controls (0.09±0.03%: P &lt;0.0001). Furthermore the percentage of EMPs in patients with CAL rapidly increased after the initial treatment, and was significantly higher than those without CAL (p&lt;0.001). We identified two miRs (hsa-miR-145-5p and hsa-miR-320a) out of 2578 miRs (0.08%) specific to the patients with CAL and these two miRs are predicted to affect the monocyte system using in silico analysis. We also detected these two miRs in CAL patients’ endothelial cells, using in situ hybridization, and showed these two miRs suppressed gene expression of the two inflammatory cytokines (IL-6 and TNF-α). Conclusions: EMPs could serve as a sensitive marker of the severity of endothelial dysfunction and vasculitis in acute KD. Moreover, hsa-miR-145-5p and hsa-miR-320a may contribute to regulation of gene expression of cytokines and pathogenesis of KD.