tbuckley/cabot-search huggingface dataset:
Targeting ALK With Crizotinib in Pediatric Anaplastic Large Cell Lymphoma and Inflammatory Myofibroblastic Tumor: A Children’s Oncology Group Study
Authors: Yael P. Mossé, Stephan D. Voss, Megan S. Lim, Delphine Rolland, Charles G. Minard, Elizabeth Fox, Peter Adamson, Keith Wilner, Susan M. Blaney, Brenda J. Weigel
Journal: Journal of Clinical Oncology (2017)

Purpose Fusions involving the ALK gene are the predominant genetic lesion underlying pediatric anaplastic large cell lymphomas (ALCL) and inflammatory myofibroblastic tumors (IMTs). We assessed the activity of the ALK inhibitor crizotinib in patients who had no known curative treatment options at diagnosis or with relapsed/recurrent disease. Methods In this study, 26 patients with relapsed/refractory ALK-positive ALCL and 14 patients with metastatic or inoperable ALK-positive IMT received crizotinib orally twice daily. Study objectives were measurement of efficacy and safety. Correlative studies evaluated the serial detection of NPM-ALK fusion transcripts in patients with ALCL. Results The overall response rates for patients with ALCL treated at doses of 165 (ALCL165) and 280 (ALCL280) mg/m2 were 83% and 90%, respectively. The overall response rate for patients with IMT (treated at 100, 165, and 280 mg/m2/dose) was 86%. A complete response was observed in 83% (five of six) of ALCL165, 80% (16 of 20) of ALCL280, and 36% (five of 14) of patients with IMT. Partial response rates were 0% (none of six), 10% (two of 20), and 50% (seven of 14), respectively. The median duration of therapy was 2.79, 0.4, and 1.63 years, respectively, with 12 patients ceasing protocol therapy to proceed to transplantation. The most common drug-related adverse event was decrease in neutrophil count in 33% and 70% of the ALCL165 and ALCL280 groups, respectively, and in 43% of patients with IMT. Levels of NPM-ALK decreased during therapy in most patients with ALCL. Conclusion The robust and sustained clinical responses to crizotinib therapy in patients with relapsed ALCL and metastatic or unresectable IMT highlight the importance of the ALK pathway in these diseases.
Histone Methyltransferase G9a Is Required for Cardiomyocyte Homeostasis and Hypertrophy
Authors: Roberto Papait, Simone Serio, Christina Pagiatakis, Francesca Rusconi, Pierluigi Carullo, Marta Mazzola, Nicolò Salvarani, Michele Miragoli, Gianluigi Condorelli
Journal: Circulation (2017)

Correct gene expression programming of the cardiomyocyte underlies the normal functioning of the heart. Alterations to this can lead to the loss of cardiac homeostasis, triggering heart dysfunction. Although the role of some histone methyltransferases in establishing the transcriptional program of postnatal cardiomyocytes during heart development has been shown, the function of this class of epigenetic enzymes is largely unexplored in the adult heart. In this study, we investigated the role of G9a/Ehmt2, a histone methyltransferase that defines a repressive epigenetic signature, in defining the transcriptional program for cardiomyocyte homeostasis and cardiac hypertrophy.We investigated the function of G9a in normal and stressed cardiomyocytes with the use of a conditional, cardiac-specific G9a knockout mouse, a specific G9a inhibitor, and high-throughput approaches for the study of the epigenome (chromatin immunoprecipitation sequencing) and transcriptome (RNA sequencing); traditional methods were used to assess cardiac function and cardiovascular disease.We found that G9a is required for cardiomyocyte homeostasis in the adult heart by mediating the repression of key genes regulating cardiomyocyte function via dimethylation of H3 lysine 9 and interaction with enhancer of zeste homolog 2, the catalytic subunit of polycomb repressive complex 2, and MEF2C-dependent gene expression by forming a complex with this transcription factor. The G9a-MEF2C complex was found to be required also for the maintenance of heterochromatin needed for the silencing of developmental genes in the adult heart. Moreover, G9a promoted cardiac hypertrophy by repressing antihypertrophic genes.Taken together, our findings demonstrate that G9a orchestrates critical epigenetic changes in cardiomyocytes in physiological and pathological conditions, thereby providing novel therapeutic avenues for cardiac pathologies associated with dysregulation of these mechanisms.
Highly absorbing multispectral near-infrared polymer nanoparticles from one conjugated backbone for photoacoustic imaging and photothermal therapy
Authors: Haobin Chen, Jian Zhang, Kaiwen Chang, Xiaoju Men, Xiaofeng Fang, Libo Zhou, Dongliang Li, Duyang Gao, Shengyan Yin, Xuanjun Zhang, Zhen Yuan, Changfeng Wu
Journal: Biomaterials (2017)
Antipsychotic-induced Hdac2 transcription via NF-κB leads to synaptic and cognitive side effects
Authors: Daisuke Ibi, Mario de la Fuente Revenga, Nebojsa Kezunovic, Carolina Muguruza, Justin M Saunders, Supriya A Gaitonde, José L Moreno, Maryum K Ijaz, Vishaka Santosh, Alexey Kozlenkov, Terrell Holloway, Jeremy Seto, Aintzane García-Bea, Mitsumasa Kurita, Grace E Mosley, Yan Jiang, Daniel J Christoffel, Luis F Callado, Scott J Russo, Stella Dracheva, Juan F López-Giménez, Yongchao Ge, Carlos R Escalante, J Javier Meana, Schahram Akbarian, George W Huntley, Javier González-Maeso
Journal: Nature Neuroscience (2017)
Dominant B cell receptor clones in peripheral blood predict onset of arthritis in individuals at risk for rheumatoid arthritis
Authors: Paul P Tak, Marieke E Doorenspleet, Maria J H de Hair, Paul L Klarenbeek, Marian H van Beers-Tas, Antoine H C van Kampen, Dirkjan van Schaardenburg, Danielle M Gerlag, Frank Baas, Niek de Vries
Journal: Annals of the Rheumatic Diseases (2017)

This article has been retracted
Reply
Authors: Hongli Hu, Daming Gao
Journal: Hepatology (2017)

Potential conflict of interest: Nothing to report. D.G. is supported by grant from Ministry of Science and Technology of China (2015CB964502) and grants from National Natural Science foundation of China to D.G. (81372602and 81422033). Author names in bold designate shared co‐first authorship. Reply: In our recent report,1 we demonstrated the oncogenic role of glycolytic enzyme PGK1 in liver cancer and characterized K323 acetylation as an important posttranslational modification for its oncogenic function. A mechanistic study revealed PCAF and SIRT7 as the enzymes regulating K323 acetylation. Briefly, we detected the endogenous interaction of PGK1 with PCAF (Fig. 4B of Hu et al.,1 the same below) and SIRT7 (Fig. 5B) in HepG2 cells. Depletion of endogenous PCAF significantly decreased K323 acetylation of both endogenous PGK1 (Fig. 4C) in HepG2 cells and ectopically expressed PGK1 (Supporting Fig. S3C) in 293T cells. On the other hand, depletion of endogenous SIRT7 caused an increase of K323 acetylation of both endogenous (Fig. 5D) and ectopically expressed PGK1 (Supporting Fig. S4D) in HepG2 cells. Furthermore, cotransfected SIRT7 reduced the increase of K323 acetylation caused by cotransfected PCAF in Huh7 cells (Fig. 5F). We also performed in vitro assays with recombinant proteins to demonstrate that PCAF acetylates PGK1 (Fig. 4F) whereas SIRT7 deacetylates PGK1 at the K323 site (Fig. 5E). Therefore, our experimental evidences strongly support that PCAF and SIRT7 are important regulators for PGK1 K323 acetylation in liver cancer cells, which is consistent with PCAF's role in promoting cancer cell metabolism reported by others.2 In keeping with its stronger enzymatic activity and more oncogenic function (Fig. 6), we detected higher levels of acetylated PGK1 in liver tumor tissues compared to adjacent nontumor tissues (Fig. 3E). In some cases (sample pair 1,3,4 of Fig. 3E), much higher PGK1 total protein levels were observed in tumor tissues, indicating that the higher PGK1 K323 acetylation levels may be caused by more PGK1 protein without alteration of acetylase/deacetylase balance. On the other hand, there are also cases (such as sample pair 2,5 of Fig. 3E) in which higher PGK1 K323 acetylation levels were observed in tumor tissues without overexpression of PGK1 total protein, and that may be caused by the off‐balance acetylase/deacetylase activity regulating PGK1. Thus, the reason for higher PGK1 K323 acetylation levels in liver cancer samples could be very complex. Furthermore, given that posttranslational modifications often regulate protein enzymatic activity, subcellular localization, and stability, differential PCAF/SIRT7 transcripts may not correlate with functional PCAF/SIRT7 proteins available to regulate PGK1 in original samples. Certainly, we totally agree that more efforts are warranted to fully understand the physiological expression, function, and regulation of PCAF/SIRT7 proteins in liver cancer occurrence and progression, which is beyond our current research scope.
Minimal access necrosectomy: the newest advance of many in the treatment of necrotising pancreatitis
Authors: Michael G Sarr
Journal: Gut (2017)

This study by van Brunschott and international colleagues1 has shown that when possible in high-risk patients with severe acute necrotising pancreatitis, a minimal access approach for drainage combined with a necrosectomy, either via an operative (ie, laparoscopic like) or an endoscopic transgastric or transduodenal approach, decreases mortality of this horrible disease when compared with the classic open operation (laparotomy). These data are convincing and support the use of such minimal access approaches whenever feasible. This study reviews the data on another huge advance in our treatment and understanding of this horrific disease.

In this commentary, I want to use this study as an example of the marked changes in our thinking of pancreatitis over the last 40 years. Our current approach to the treatment of necrotising pancreatitis really had its origin in the 1970s with the introduction of the new concept of an operative ‘necrosectomy’ rather than just peripancreatic drainage which at that time was designed to remove the bad humours believed to be the cause of the systemic aspects of the disease. Through the pioneering work of Beger and colleagues2 in Ulm, Germany and that of Bradley (and Stone) in Atlanta, Georgia, USA,3 a new era emerged with our thinking of this systemic inflammatory disease originating from endogenous pancreatic parenchymal necrosis and later, its superinfection. Indeed, the introduction of the importance of removing the infected necrotic tissues (necrosectomy) combined with drainage of the peripancreatic region immediately decreased the mortality of this disease …
Traitement de l’obésité par ballon intra-gastrique: résultats préliminaires de l’étude de la vidange gastrique
Authors: F Mion, B Napoléon, S Roman, C Nascimento, B Pujol, R Bory
Journal: Endoscopy (2004)

Objectif: Le traitement de l’obésité par l’utilisation de ballons intra gastriques a été proposé. Cependant, la tolérance et l’efficacité du ballon semblent très variables selon les patients. Le but de cette étude prospective était d’évaluer l’utilité d’un test de vidange gastrique pour prédire la tolérance et/ou l’efficacité d’un ballon intra-gastrique pour le traitement de l’obésité non morbide et d’apprécier l’impact du ballon sur la vidange gastrique. Patients et Méthodes: De septembre 2002 à juin 2003, 15 patients (12 femmes et 3 hommes, d’âge moyen 35 ans (19 à 55 ans)), avec un IMC moyen de 34,4 ± 0,8 (30,1 à 40,0) ont été inclus. Tous ont eu un ballon (Inamed Health) placé dans l’estomac sous contrôle endoscopique, rempli avec 600 mL de sérum salé. L’ablation per endoscopique du ballon était prévue 6 mois plus tard. La vidange gastrique (VG) des solides était étudiée par le test respiratoire à l’acide octanoïque-13C, réalisé avant l’insertion du ballon, 1 et 4 mois plus tard, et 1 mois après l’ablation du ballon. La perte pondérale était mesurée à chaque visite, ainsi que la qualité de vie (QDV) par le questionnaire IWQOL-Lite [1]. Les résultats préliminaires présentés sont ceux obtenus 1 mois après la mise en place du ballon. Résultats: Avant insertion du ballon, la vidange était normale chez 11 patients, et ralentie (t1/2 > 110 min) chez 4 (26,7%). La tolérance initiale du ballon (nausées et vomissements pour la majorité des patients pendant 2 à 14 jours avec retour à la normale ensuite) n’était pas différente en fonction dutest de VG. La perte pondérale était significative pour l’ensemble du groupe à 1 mois (IMC M1:32,4 ± 0,8 vs 34,4 ± 0,8 à M0, –(5,7%, p < 0,0001), mais plus marquée pour ceux avec une VG initiale normale (– 6,2 ± 0,5% vs – 4,3 ± 1,2%, p = 0,11). Il existait une corrélation significative entre le tlag de la VG initiale et la perte pondérale à M1 (r = – 0,576, p = 0,023). A M1, la VG était significativement ralentie chez les patients avec VG initiale normale, mais pas chez ceux à VG initiale lente (p < 0,05). Le score de QDV était amélioré à M1 par rapport à M0 (72 ± 6 vs 85 ± 6 à M0, p = 0,0032); cette amélioration était plus nette mais non significative dans le groupe à VG normale (– 17 ± 5 vs – 4 ± 6 pour VG lente, p = 0,16). Conclusion: La VG des solides semble ralentie chez 1/4 des obèses. Le ballon intra-gastrique ralentit la VG uniquement chez les obèses à VG normale. La perte pondérale à 1 mois est corrélée à la rapidité de la VG initiale. L’efficacité du ballon pourrait être liée en partie à son effet sur la VG. La tolérance précoce du ballon ne dépend pas des résultats de la VG initiale.
Challenges in the implementation of <scp>EAACI</scp> guidelines on allergen immunotherapy: A global perspective on the regulation of allergen products
Authors: A. Bonertz, G. C. Roberts, M. Hoefnagel, M. Timon, J. E. Slater, R. L. Rabin, J. Bridgewater, C. Pini, O. Pfaar, C. Akdis, J. Goldstein, L. K. Poulsen, R. van Ree, C. Rhyner, D. Barber, O. Palomares, A. Sheikh, R. Pawankar, D. Hamerlijnk, L. Klimek, I. Agache, E. Angier, T. Casale, M. Fernandez‐Rivas, S. Halken, M. Jutel, S. Lau, G. Pajno, G. Sturm, E. M. Varga, R. Gerth van Wijk, S. Bonini, A. Muraro, S. Vieths
Journal: Allergy (2017)

Regulatory approaches for allergen immunotherapy (AIT) products and the availability of high-quality AIT products are inherently linked to each other. While allergen products are available in many countries across the globe, their regulation is very heterogeneous. First, we describe the regulatory systems applicable for AIT products in the European Union (EU) and in the United States (US). For Europe, a depiction of the different types of relevant procedures, as well as the committees involved, is provided and the fundamental role of national agencies of the EU member states in this complex and unique network is highlighted. Furthermore, the regulatory agencies from Australia, Canada, Japan, Russia, and Switzerland provided information on the system implemented in their countries for the regulation of allergen products. While AIT products are commonly classified as biological medicinal products, they are made available by varying types of procedures, most commonly either by obtaining a marketing authorization or by being distributed as named patient products. Exemptions from marketing authorizations in exceptional cases, as well as import of allergen products from other countries, are additional tools applied by countries to ensure availability of needed AIT products. Several challenges for AIT products are apparent from this analysis and will require further consideration.
NHS agrees to fund baby’s heart surgery in US
Authors: Jacqui Wise
Journal: BMJ (2017)

NHS England has agreed to pay for a baby to be sent to the United States for surgery to remove a cardiac fibroma, saying that the United Kingdom did not have a surgical service with the relevant experience.

The decision came in the wake of the lengthy legal battle over the baby Charlie Gard. The High Court refused permission for the terminally ill child to leave London’s Great Ormond Street Hospital for Children for …
JCAD Promotes Progression of Nonalcoholic Steatohepatitis to Liver Cancer by Inhibiting LATS2 Kinase Activity
Authors: Juan Ye, Tian-Sheng Li, Gang Xu, Yi-Ming Zhao, Ning-Ping Zhang, Jia Fan, Jian Wu
Journal: Cancer Research (2017)

Abstract Nonalcoholic steatohepatitis-associated hepatocellular carcinoma (NASH-HCC) is a malignancy whose incidents are rapidly increasing. However, the mechanisms that drive development of HCC in a steatotic microenvironment remain unknown. Here we report that the obesity-associated protein JCAD is expressed at significantly higher levels in human NASH-HCC specimens compared with pericarcinoma specimens. High JCAD expression was verified in multiple hepatoma cell lines. Forced overexpression of JCAD in hepatoma cells promoted tumor growth and proliferation, whereas JCAD silencing yielded opposite effects. JCAD interacted with the kinase domain of the tumor suppressor kinase LATS2, a core component of the Hippo signaling pathway. JCAD overexpression inhibited the ability of LATS2 to phosphorylate YAP in this pathway, in turn upregulating CCND1 and GLI2 to promote hepatoma cell proliferation. JCAD was induced by fatty acid overload in hepatic cells and was highly expressed in a mouse model of NASH-precarcinoma lesions, where the ratio of phospho-YAP to YAP was decreased. In human NASH-HCC specimens, JCAD expression and YAP phosphorylation patterns paralleled with the mouse model. Our findings illuminate a new role for JCAD and its critical interplay in the Hippo signaling cascade during the transition of NASH to HCC, with potential implications for therapeutic development in this setting. Cancer Res; 77(19); 5287–300. ©2017 AACR.
Bone SPECT/CT Localizes Increased Bone Metabolism and Subsequent Bone Resorption in Reflex Sympathetic Dystrophy
Authors: Hidetoshi Narimatsu, Tadaki Nakahara, Sayuri Kodama, Hiromi Hisazumi, Shinichi Tominaga, Kiyoshi Ohkuma, Masahiro Jinzaki
Journal: Clinical Nuclear Medicine (2017)

A 64-year-old man with lung cancer with a history of revascularization of the occluded right femoral artery underwent bone scintigraphy, which showed intense uptake in the distal side of the right leg. The additional SPECT/CT clarified that the uptake was predominantly increased in the epiphyses of the right ankle and foot with possible osteopenia. One month later, follow-up SPECT/CT showed the manifestation of periosteal resorption in the hypermetabolic sites with slight decrease in bone metabolism. Radiological correlation between bone metabolism and subsequent bone resorption in addition to clinical symptoms in this patient suggested the diagnosis of reflex sympathetic dystrophy.
02.18 Can rankl serum levels predict future progression to rheumatoid arthritis in early arthritis clinic patients?
Authors: Agata N Burska, Jehan J El-Jawhari, Ai L Tan, Richard J Wakefield, Helena Marzo-Ortega, Philip G Conaghan, Paul Emery, Frederique Ponchel, Jane E Freeston
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background/objectives</h3> The earliest diagnosis of rheumatoid arthritis (RA) is crucial to initiate treatment and prevent further disease progression and the accumulation of irreversible damages to the joints. Despite recent advances with the discovery and integration of anti–citrullinated protein antibody (ACPA) in diagnostic criteria, there is still an unmet need for new diagnostic biomarkers, notably for ACPA-negative disease. The receptor-activator-nuclear-factor-κB axis (RANK/RANKL) is known to regulate bone homeostasis. The aim of this pilot study is to establish whether serum RANKL levels in people with early inflammatory arthritis, are associated with RA diagnosis at follow-up and to evaluate the added value of RANKL for early RA diagnosis. <h3>Materials/methods</h3> Serum from 298 subjects (95/204 Male/Female) was collected at the baseline participant visit to the Leeds early arthritis clinic. Demographic (age, symptom duration) and clinical data (joint counts swollen and tender (SJC, TJC), CRP, DAS28, rheumatoid factor (RF) and ACPA, shared epitope (SE)) were collected. A commercial ELISA (BioVENDOR) was used to measure RANKL. Ultrasound of 26 joints (bilateral elbows, wrists, MCP 2–3, PIP 2–3, knees, ankles and MTP 1–5) was performed at baseline recording summative scores for power Doppler (PD), grey scale hypertrophy (GS) and synovitis (SYN). <h3>Results</h3> At follow-up, 151 patients had a confirmed diagnosis of RA (EULAR-2010 criteria) and 147 were classified as non-RA (undifferentiated arthritis, other inflammatory or non-inflammatory diagnosis). All routinely-used biomarkers were associated with RA diagnosis (ACPA, RF, SE, TJC, SJC, CRP, DAS28, p&lt;0.0001), similarly to imaging biomarkers (PD, GS, SYN, p&lt;0.001). RANKL levels were significantly higher in RA (RA 1002.4±1053.2 pmol/L, non-RA 339.2±451.5 pmol/L, p&lt;0.0001). A regression analysis suggested that four parameters were sufficient to account for all associations with RA: RANKL, age, SJC, PD with 75.3% accurate prediction. An AUROC analysis suggested cut-off for each parameter and a score was calculated adding 1 point for each of factors (RANKL &gt;700, age &gt;62, TPD &gt;3, SJC&gt;4). This score predicted RA with an AUROC of 0.782 ((0.23–0.840), p&lt;0.0001). <h3>Conclusions</h3> A score including RANKL, age, SJC and PD showed good predictive value for non-RA when low and for RA when high. Furthermore, the regression redone in ACPA-negative only patients performed particularly well for (77.4% accurate).
Analysis of Plasma Epstein–Barr Virus DNA to Screen for Nasopharyngeal Cancer
Authors: K.C. Allen Chan, John K.S. Woo, Ann King, Benny C.Y. Zee, W.K. Jacky Lam, Stephen L. Chan, Sam W.I. Chu, Constance Mak, Irene O.L. Tse, Samantha Y.M. Leung, Gloria Chan, Edwin P. Hui, Brigette B.Y. Ma, Rossa W.K. Chiu, Sing-Fai Leung, Andrew C. van Hasselt, Anthony T.C. Chan, Y.M. Dennis Lo
Journal: New England Journal of Medicine (2017)

Circulating cell-free Epstein-Barr virus (EBV) DNA is a biomarker for nasopharyngeal carcinoma. We conducted a prospective study to investigate whether EBV DNA in plasma samples would be useful to screen for early nasopharyngeal carcinoma in asymptomatic persons.We analyzed EBV DNA in plasma specimens to screen participants who did not have symptoms of nasopharyngeal carcinoma. Participants with initially positive results were retested approximately 4 weeks later, and those with persistently positive EBV DNA in plasma underwent nasal endoscopic examination and magnetic resonance imaging (MRI).A total of 20,174 participants underwent screening. EBV DNA was detectable in plasma samples obtained from 1112 participants (5.5%), and 309 (1.5% of all participants and 27.8% of those who initially tested positive) had persistently positive results on the repeated sample. Among these 309 participants, 300 underwent endoscopic examination, and 275 underwent both endoscopic examination and MRI; of these participants, 34 had nasopharyngeal carcinoma. A significantly higher proportion of participants with nasopharyngeal carcinoma that was identified by screening had stage I or II disease than in a historical cohort (71% vs. 20%, P<0.001 by the chi-square test) and had superior 3-year progression-free survival (97% vs. 70%; hazard ratio, 0.10; 95% confidence interval, 0.05 to 0.18). Nine participants declined to undergo further testing, and 1 of them presented with advanced nasopharyngeal carcinoma 32 months after enrollment. Nasopharyngeal carcinoma developed in only 1 participant with negative EBV DNA in plasma samples within 1 year after testing. The sensitivity and specificity of EBV DNA in plasma samples in screening for nasopharyngeal carcinoma were 97.1% and 98.6%, respectively.Analysis of EBV DNA in plasma samples was useful in screening for early asymptomatic nasopharyngeal carcinoma. Nasopharyngeal carcinoma was detected significantly earlier and outcomes were better in participants who were identified by screening than in those in a historical cohort. (Funded by the Kadoorie Charitable Foundation and the Research Grants Council of the Hong Kong government; ClinicalTrials.gov number, NCT02063399 .).