tbuckley/cabot-search huggingface dataset:
Mitochondrial Cardiomyopathy Caused by Elevated Reactive Oxygen Species and Impaired Cardiomyocyte Proliferation
Authors: Donghui Zhang, Yifei Li, Danielle Heims-Waldron, Vassilios Bezzerides, Silvia Guatimosim, Yuxuan Guo, Fei Gu, Pingzhu Zhou, Zhiqiang Lin, Qing Ma, Jianming Liu, Da-Zhi Wang, William T. Pu
Journal: Circulation Research (2017)

Rationale: Although mitochondrial diseases often cause abnormal myocardial development, the mechanisms by which mitochondria influence heart growth and function are poorly understood. Objective: To investigate these disease mechanisms, we studied a genetic model of mitochondrial dysfunction caused by inactivation of Tfam (transcription factor A, mitochondrial), a nuclear-encoded gene that is essential for mitochondrial gene transcription and mitochondrial DNA replication. Methods and Results: Tfam inactivation by Nkx2.5 Cre caused mitochondrial dysfunction and embryonic lethal myocardial hypoplasia. Tfam inactivation was accompanied by elevated production of reactive oxygen species (ROS) and reduced cardiomyocyte proliferation. Mosaic embryonic Tfam inactivation confirmed that the block to cardiomyocyte proliferation was cell autonomous. Transcriptional profiling by RNA-seq demonstrated the activation of the DNA damage pathway. Pharmacological inhibition of ROS or the DNA damage response pathway restored cardiomyocyte proliferation in cultured fetal cardiomyocytes. Neonatal Tfam inactivation by AAV9-cTnT-Cre caused progressive, lethal dilated cardiomyopathy. Remarkably, postnatal Tfam inactivation and disruption of mitochondrial function did not impair cardiomyocyte maturation. Rather, it elevated ROS production, activated the DNA damage response pathway, and decreased cardiomyocyte proliferation. We identified a transient window during the first postnatal week when inhibition of ROS or the DNA damage response pathway ameliorated the detrimental effect of Tfam inactivation. Conclusions: Mitochondrial dysfunction caused by Tfam inactivation induced ROS production, activated the DNA damage response, and caused cardiomyocyte cell cycle arrest, ultimately resulting in lethal cardiomyopathy. Normal mitochondrial function was not required for cardiomyocyte maturation. Pharmacological inhibition of ROS or DNA damage response pathways is a potential strategy to prevent cardiac dysfunction caused by some forms of mitochondrial dysfunction.
Reply to Kovesi, to Chabra, and to Farber: “Palivizumab Prophylaxis and Recurrent Wheezing” and “Precise Gestational Age Definitions Needed for Palivizumab Prophylaxis in Preterm Infants” and “Imbalance in Level of Tobacco Smoke Exposure Between Groups Likely Explains the “Effect” of Palivizumab on Subsequent Wheezing”
Authors: Eric A. F. Simões, Hiroyuki Mochizuki
Journal: American Journal of Respiratory and Critical Care Medicine (2017)
Pharmacokinetics (PK) and pharmacodynamics (PD) of a novel carcinoembryonic antigen (CEA) T-cell bispecific antibody (CEA-CD3 TCB) for the treatment of CEA-positive solid tumors
Authors: I. Melero, N.H. Segal, J. Saro, W. Ros, M. Martinez-Garcia, G. Argiles, V. Moreno, S. Ponce, A. Marabelle, J.M. Cleary, H.I. Hurwitz, J.P. Eder, C. Jamois, E. Andersson, S. Bouseida, F. Sandoval, M. Bacac, T. Nayak, V. Karanikas, E. Calvo
Journal: Annals of Oncology (2017)
Quantitative assessment of inotuzumab ozogamicin (InO) response relative to investigator’s choice of chemotherapy (ICC) in adults with relapsed or refractory (R/R) CD22+ B-Cell acute lymphoblastic leukemia (ALL)
Authors: A. Ruiz-Garcia, E. Vandendries, D.J. DeAngelo, H.M. Kantarjian, J. Boni
Journal: Annals of Oncology (2017)
GW28-e1207 Familial Sudden Cardiac Death Caused by DSG2 Mutation as Genetic Backgrounds: Whole Exome Sequencing and Valid Therapy of Catheter Ablation
Authors: Yubi Lin, Qianhuan Zhang, Jia Chen, Ruiling Feng, Siqi He, ZhiAn Zhong, Yang Liu, Weitao Ye, Xin Li, Hongtao Liao, Hongwen Fei, Fang Rao, Zhixin Shan, Chunyu Deng, XianZhang Zhan, Yumei Xue, Hui Liu, Bin Zhang, Kejian Wang, Shulin Wu
Journal: Journal of the American College of Cardiology (2017)
Safety, pharmacokinetics (PK) and pharmacodynamics (PD) data from a phase I dose-escalation study of OX40 agonistic monoclonal antibody (mAb) PF-04518600 (PF-8600) in combination with utomilumab, a 4-1BB agonistic mAb
Authors: O. Hamid, W. Ros, J.A. Thompson, S. Hu-Lieskovan, F.A.L.M. Eskens, A. Diab, T. Doi, J. Wasser, J-P. Spano, N.A. Rizvi, E. Angevin, A. Chiappori, P.A. Ott, B.J. Ganguly, C. Fleener, V. Dell, K. Liao, T. Joh, J. Chou, A. El-Khoueiry
Journal: Annals of Oncology (2017)
Spending on junk food advertising is nearly 30 times what government spends on promoting healthy eating
Authors: Adrian O’Dowd
Journal: BMJ (2017)

UK experts are urging the government to take steps to restrict advertising of junk food after a new analysis was published showing that food companies spend much more on such advertising than the government spends on promoting healthy eating.

The concerns have been raised by the Obesity Health Alliance of more than 40 leading health charities, medical royal colleges, and campaign groups, which released details of the analysis on 11 October to coincide with world obesity day.

The analysis used data from The Grocer magazine’s top 100 list of advertising spending on fast moving consumer brands, which identifies brands commonly associated with crisps, confectionery, and sugary drinks.1

The analysis showed that companies …
Dynamic changes in eIF4F-mRNA interactions revealed by global analyses of environmental stress responses
Authors: Joseph L. Costello, Christopher J. Kershaw, Lydia M. Castelli, David Talavera, William Rowe, Paul F. G. Sims, Mark P. Ashe, Christopher M. Grant, Simon J. Hubbard, Graham D. Pavitt
Journal: Genome biology (2017)

Translation factors eIF4E and eIF4G form eIF4F, which interacts with the messenger RNA (mRNA) 5' cap to promote ribosome recruitment and translation initiation. Variations in the association of eIF4F with individual mRNAs likely contribute to differences in translation initiation frequencies between mRNAs. As translation initiation is globally reprogrammed by environmental stresses, we were interested in determining whether eIF4F interactions with individual mRNAs are reprogrammed and how this may contribute to global environmental stress responses.Using a tagged-factor protein capture and RNA-sequencing (RNA-seq) approach, we have assessed how mRNA associations with eIF4E, eIF4G1 and eIF4G2 change globally in response to three defined stresses that each cause a rapid attenuation of protein synthesis: oxidative stress induced by hydrogen peroxide and nutrient stresses caused by amino acid or glucose withdrawal. We find that acute stress leads to dynamic and unexpected changes in eIF4F-mRNA interactions that are shared among each factor and across the stresses imposed. eIF4F-mRNA interactions stabilised by stress are predominantly associated with translational repression, while more actively initiating mRNAs become relatively depleted for eIF4F. Simultaneously, other mRNAs are insulated from these stress-induced changes in eIF4F association.Dynamic eIF4F-mRNA interaction changes are part of a coordinated early translational control response shared across environmental stresses. Our data are compatible with a model where multiple mRNA closed-loop complexes form with differing stability. Hence, unexpectedly, in the absence of other stabilising factors, rapid translation initiation on mRNAs correlates with less stable eIF4F interactions.
A phase 3, randomized study of first-line durvalumab (D) ± tremelimumab (T) + platinum-based chemotherapy (CT) vs CT alone in extensive disease small-cell lung cancer (ED-SCLC): Caspian.
Authors: Luis G. Paz-Ares, Haiyi Jiang, Yifan Huang, Phillip A. Dennis
Journal: Journal of Clinical Oncology (2017)

TPS8586 Background: SCLC accounts for ~13% of all lung cancers and is characterized by rapid growth and early metastases development. Standard of care CT for pts presenting with ED-SCLC is associated with the development of resistance, leading to poor treatment outcomes. As such, new therapies are needed. The high mutation burden associated with SCLC provides a rationale for investigating immune checkpoint blockade in this tumor type. D is a selective, high-affinity, engineered human IgG1 mAb that blocks PD-L1 binding to PD-1 and CD80. T is a selective human IgG2 mAb against CTLA-4. D alone and in combination with T has demonstrated a manageable safety profile and encouraging antitumor activity in non-small cell lung cancer (NSCLC). D ± T in combination with CT has also shown acceptable tolerability and preliminary signs of clinical activity in advanced NSCLC and thus may provide benefit in SCLC. Methods: CASPIAN (NCT03043872) is a Phase 3, randomized, multicenter, open-label, global study to determine the efficacy of CT in combination with D ± T as first-line treatment in ED-SCLC (Stage IV). Treatment-naïve pts (N = ~795; WHO/ECOG PS 0 or 1) will be randomized 1:1:1 to receive D (1500 mg) + T (75 mg) i.v. every 3 weeks (q3w) + CT (Arm 1); D (75 mg) i.v. q3w + CT (Arm 2); or CT alone (Arm 3). D ± T will be concurrently administered with CT in Arms 1 and 2 and will continue post-CT (1 further dose for T; until confirmed progressive disease for D). CT (etoposide [80–100 mg/m 2 ] i.v. on Days 1–3 q3w + carboplatin [AUC 5–6] i.v. on Day 1 q3w or cisplatin [75–80 mg/m 2 ] i.v. on Day 1 q3w) will be given for up to 4 cycles in Arms 1 and 2 and up to 6 cycles in Arm 3. The co-primary endpoints are overall survival (OS) and progression-free survival (PFS) using blinded independent central review (RECIST v1.1), for Arm 1 vs Arm 3. Secondary endpoints include OS and PFS for Arm 2 vs Arm 3 and Arm 1 vs Arm 2, ORR, OS at 18 months, proportion of patients alive and progression free at 6 and 12 months, PK, immunogenicity, HRQoL, and safety and tolerability. Exploratory endpoints include PFS after subsequent anticancer therapy and correlation of biomarkers with response to treatment. Recruitment is ongoing. Clinical trial information: NCT03043872.
Effects of Exposure to Gun Violence in Movies on Children’s Interest in Real Guns
Authors: Kelly P. Dillon, Brad J. Bushman
Journal: JAMA Pediatrics (2017)

<h3>Importance</h3> More US children die by accidental gun use than children in other developed countries. One factor that can influence children's interest in guns is exposure to media containing guns. <h3>Objective</h3> To test whether children who see a movie containing guns will handle a real gun longer and will pull the trigger more times than children who see the same movie not containing guns. <h3>Design, Setting, and Participants</h3> One hundred four children aged 8 to 12 years recruited through advertisements were randomly assigned in pairs to watch a 20-minute PG-rated movie containing or not containing guns in a university laboratory. Children then played with toys and games in a room for 20 minutes while being video recorded. A cabinet in the room contained a real (disabled) gun with a sensor counting trigger pulls. Recordings were coded for the time spent holding the gun and in aggressive play. Data were collected from July 15, 2015, through January 1, 2016, and analyzed using generalized estimating equations (Tweedie log-link for time spent holding the gun; Poisson log-link for pulling the trigger). <h3>Main Outcomes and Measures</h3> The 2 main outcomes were time spent holding the gun and the number of trigger pulls. Control variables included sex, age, trait aggressiveness, exposure to violent media, interest in guns, and number of guns at home. <h3>Results</h3> Among the 104 study participants (62 boys [59.6%] and 42 girls [40.4%]; mean (SD) age, 9.9 [1.5] years), the adjusted median number of trigger pulls among children who saw the movie containing guns was 2.8 (interquartile range [IQR], 0.2-2.8) compared with 0.01 (IQR, 0.01-0.2) among children who saw the movie not containing guns (adjusted odds ratio, 22.3; 95% CI, 6.0-83.4;<i>P</i> &lt; .001). The adjusted median number of seconds spent holding the gun among children who saw a movie containing guns was 53.1 (IQR, 35.5-53.1) compared with 11.1 (IQR, 10.7-16.7) among children who saw the movie not containing guns (adjusted odds ratio, 3.0; 95% CI, 0.9-9.9;<i>P</i> = .07). Qualitative analyses on 4 pairs from each condition found that children who saw the movie containing guns also played more aggressively and sometimes fired the gun at people (ie, self, partner, or passersby on street). <h3>Conclusions and Relevance</h3> Children in the United States frequently have access to unsecured firearms and frequently consume media containing guns. This experiment shows that children who see movie characters use guns are more likely to use guns themselves. <h3>Trial Registration</h3> clinicaltrials.gov Identifier NCT03220412
Communicating with relatives
Authors: Muna Al-Jawad, Rebecca Winter, Ellen Jones
Journal: BMJ (2017)

#### What you need to know

A doctor’s first duty is to his or her patient, but this needs to be balanced with respect and understanding for the network of other people who provide care and emotional support.1

The four commonly accepted principles of healthcare ethics are summarised in box 1. In relation to communication with relatives, respect for autonomy is, in our opinion, the ethical principle that may be most problematic in clinical settings. This article aims to provide doctors with help when communicating with relatives and explores some ethical guidance for doing this while supporting the expectations of relatives such as those set out in box 2. The term “relative” is used to mean a close friend or family member who is part of the patient’s network. Where legal considerations are highlighted, these are based on guidance within the UK. We recognise that there are cultural differences in concepts such as autonomy and collusion, but they are beyond the scope of this article.

#### Box 1: Overview of ethical principles in medicine2

#### Box 2: A relative’s expectations

I have considerable experience of NHS services as a relative. I have a daughter with a chronic health condition. I am currently family carer for my mother, who has late stage dementia. I have supported other relatives who have had cancer, heart disease, and severe …
Spotlight on measles 2010: Measles outbreak in Ireland 2009-2010
Authors: S Gee, S Cotter, D O’Flanagan, Collective on behalf of the national incident management team
Journal: Eurosurveillance (2010)

Measles cases are increasing in Ireland, with 320 cases notified since August 2009. Nearly two-thirds of these cases (n=206) were unvaccinated. In the early stages of the outbreak a substantial number of cases were linked to the Traveller community with some cases also reported among the Roma community, other citizens from eastern Europe and children whose parents objected to vaccination. By February 2010, there had been considerable spread to the general population.
Electrospinning: 3D Near‐Field Electrospinning of Biomaterial Microfibers with Potential for Blended Microfiber‐Cell‐Loaded Gel Composite Structures (Adv. Healthcare Mater. 19/2017)
Authors: Pouria Fattahi, Jordan T. Dover, Justin L. Brown
Journal: Advanced Healthcare Materials (2017)

3D near-field electrospinning is capable of depositing single nano- and microfibers with extraordinary precision. This image demonstrates a stem cell attached to perpendicular microfibers. As described by Justin L. Brown and co-workers in article number 1700456, this process can be multiplexed with other 3D printing techniques to build a wide array of complex structures for applications, such as, regenerative medicine.
GW28-e1155 Effectiveness and safety of percutaneous left atrial appendage closure in atrial septal defect and atrial fibrillation patients
Authors: Chunsheng Cui, Zhu Xianyang, Wang Jianming, Zhang Duanzhen, Sheng Xiaotang, Wang Qiguang, Wang Shuang
Journal: Journal of the American College of Cardiology (2017)
Vigilancia de la tuberculosis en Europa
Authors: V Schwoebel, H. L. Rieder, J M Watson, M. C. Raviglione
Journal: Eurosurveillance (1996)

El indicador mas accesible y que proporciona mayor informacion sobre la morbilidad por tuberculosis es la incidencia de la enfermedad. En Europa, las diferencias entre paises en las definiciones de caso, sistemas de notificacion, y recogida de informacion hacen dificiles las comparaciones (1,2) y dificultan el analisis de su evolucion temporal, la identificacion de grupos de elevada incidencia, y la coordinacion internacional de medidas para el control de la tuberculosis en Europa.
The CAN BEAR study: A systematic review and meta-analysis investigating adverse events (AEs) of targeted agents added to endocrine therapy (ET) in patients (pts) with hormone-receptor positive (HR+) metastatic breast cancer (MBC)
Authors: S. Martel, M. Bruzzone, M. Ceppi, C. Maurer, N. Falbel Ponde, A.R. Ferreira, G. Viglietti, L. Delmastro, C. Prady, E. De Azambuja, M. Lambertini
Journal: Annals of Oncology (2017)
Abstract P237: Exercise Training Prevents Hypercholesterolemia-Induced Cardiac Mitochondrial Dysfunction
Authors: Allison M McGee, Kyle S McCommis, M H Laughlin, Douglas K Bowles, Christopher P Baines
Journal: Circulation Research (2011)

Hypercholesterolemia has been suggested to have direct negative effects on myocardial function due to increased reactive oxygen species (ROS) generation and increased myocyte death. Mitochondrial permeability transition (MPT) is a significant mediator of cell death, which is enhanced by ROS generation and attenuated by exercise training. The purpose of this study was to investigate the effect of hypercholesterolemia on the MPT response of cardiac mitochondria. We hypothesized that familial hypercholesterolemic (FH) pigs would have an enhanced MPT response, and that exercise training could reverse this phenotype. FH pigs were obtained from the University of Wisconsin. Control, normolipidemic farm pigs were maintained on standard pig chow. After 4 months on a high-fat diet, the FH pigs were switched to the standard pig chow, and randomized to sedentary or exercise groups. The exercise group underwent a progressive treadmill-based training program for 4 months. At the end of the training protocol the animals were sacrificed and the heart removed. MPT was assessed by mitochondrial swelling in response to Ca2+. Protein nitrotyrosylation, GSH levels, and antioxidant enzyme expression were also examined. FH pigs did show an increased MPT response despite no change in the expression of putative MPT pore components adenine nucleotide translocase (ANT), mitochondrial phosphate carrier (PiC), and cyclophilin-D (CypD). FH also caused increased oxidative stress, depicted by increased protein nitrotyrosylation and decreased GSH levels. This was associated with concomitant decreases in the expression of mitochondrial antioxidant enzymes manganese superoxide dismutase (MnSOD) and thioredoxin-2 (Trx2). However, chronic exercise training was able to normalize the MPT response in FH pigs, reduce oxidative stress, and increase MnSOD expression. We conclude that hypercholesterolemia causes increased oxidative stress and enhances the MPT response in the porcine myocardium, and that exercise training can correct for both the increased oxidative stress and MPT alterations observed with hypercholesterolemia.
Phosphatidylinositol 3-kinase (PI3Kα)/AKT axis blockade with taselisib or ipatasertib enhances the efficacy of anti-microtubule drugs in human breast cancer cells
Authors: A. Diana, F. Morgillo, C.M. Della Corte, C. Di Mauro, V. Ciaramella, G. Barra, V. Belli, E. Franzese, R. Bianco, E. Maiello, F. De Vita, F. Ciardiello, M. Orditura
Journal: Annals of Oncology (2017)
Intratumoral HPV16-Specific T Cells Constitute a Type I–Oriented Tumor Microenvironment to Improve Survival in HPV16-Driven Oropharyngeal Cancer
Authors: Marij J.P. Welters, Wenbo Ma, Saskia J.A.M. Santegoets, Renske Goedemans, Ilina Ehsan, Ekaterina S. Jordanova, Vanessa J. van Ham, Vincent van Unen, Frits Koning, Sylvia I. van Egmond, Pornpimol Charoentong, Zlatko Trajanoski, Lilly-Ann van der Velden, Sjoerd H. van der Burg
Journal: Clinical Cancer Research (2017)

Abstract Purpose: Human papillomavirus (HPV)–associated oropharyngeal squamous cell cancer (OPSCC) has a much better prognosis than HPV-negative OPSCC, and this is linked to dense tumor immune infiltration. As the viral antigens may trigger potent immunity, we studied the relationship between the presence of intratumoral HPV-specific T-cell responses, the immune contexture in the tumor microenvironment, and clinical outcome. Experimental Design: To this purpose, an in-depth analysis of tumor-infiltrating immune cells in a prospective cohort of 97 patients with HPV16-positive and HPV16-negative OPSCC was performed using functional T-cell assays, mass cytometry (CyTOF), flow cytometry, and fluorescent immunostaining of tumor tissues. Key findings were validated in a cohort of 75 patients with HPV16-positive OPSCC present in the publicly available The Cancer Genome Atlas database. Results: In 64% of the HPV16-positive tumors, type I HPV16-specific T cells were present. Their presence was not only strongly related to a better overall survival, a smaller tumor size, and less lymph node metastases but also to a type I–oriented tumor microenvironment, including high numbers of activated CD161+ T cells, CD103+ tissue-resident T cells, dendritic cells (DC), and DC-like macrophages. Conclusions: The viral antigens trigger a tumor-specific T-cell response that shapes a favorable immune contexture for the response to standard therapy. Hence, reinforcement of HPV16-specific T-cell reactivity is expected to boost this process. Clin Cancer Res; 24(3); 634–47. ©2017 AACR. See related commentary by Laban and Hoffmann, p. 505
Consequences of Recent Anti-Immigration Policy—Reply
Authors: Alicia Fernandez, Rudolph A. Rodriguez
Journal: JAMA Internal Medicine (2017)

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