tbuckley/cabot-search huggingface dataset:
Bacterial Dissemination to the Brain in Sepsis
Authors: Benjamin H. Singer, Robert P. Dickson, Scott J. Denstaedt, Michael W. Newstead, Kwi Kim, Nicole R. Falkowski, John R. Erb-Downward, Thomas M. Schmidt, Gary B. Huffnagle, Theodore J. Standiford
Journal: American Journal of Respiratory and Critical Care Medicine (2017)

Sepsis causes brain dysfunction and neuroinflammation. It is unknown whether neuroinflammation in sepsis is initiated by dissemination of bacteria to the brain and sustained by persistent infection, or whether neuroinflammation is a sterile process resulting solely from circulating inflammatory mediators.
Erratum to: Functional implications of microbial and viral gut metagenome changes in early stage L-DOPA-naive Parkinson's disease patients (vol 9, pg 39, 2017)
Authors: Janis R. Bedarf, Falk Hildebrand, Luis P. Coelho, Shinichi Sunagawa, Mohammad Bahram, Felix Goeser, Peer Bork, Ullrich Wüllner
Journal: Genome Medicine (2017)
Firearms Policy and Suicide Prevention
Authors: Jeffrey C. Sung
Journal: American Journal of Psychiatry (2017)

The recent article by Olfson and colleagues (1), published in the August 2017 issue of the Journal, confirms markedly elevated suicide rates following nonfatal selfharm.An accompanying editorial (2) recommends removing firearms from the home of a person who has attempted suicide in order to mitigate this risk.The legality of this recommendation, however, might depend on state laws regulating firearm transfers.For example, universal background check laws might present legal obstacles to temporary firearm transfers during a suicidal crisis unless specific exceptions to the universal background check exist in case law or statute (3).Here, I describe the collaborative approach taken in Washington State to amend an existing universal background check law with exceptions to facilitate temporary firearm transfers during periods of elevated suicide risk.In 2016, a work group with representation from the Alliance for Gun Responsibility, Forefront Suicide Prevention, the National Rifle Association, the Second Amendment Foundation, the Washington State Office of the Attorney General, Washington State Patrol, and the Washington State Psychiatric Association was formed to discuss amending the universal background check law (RCW 9.41.113).Together with a state legislator, the group reached unanimous agreement on language allowing for an exception to the need for a background check if all the following criteria were met:
Estimates of global seasonal influenza-associated respiratory mortality: a modelling study
Authors: A Danielle Iuliano, Katherine M Roguski, Howard H Chang, David J Muscatello, Rakhee Palekar, Stefano Tempia, Cheryl Cohen, Jon Michael Gran, Dena Schanzer, Benjamin J Cowling, Peng Wu, Jan Kyncl, Li Wei Ang, Minah Park, Monika Redlberger-Fritz, Hongjie Yu, Laura Espenhain, Anand Krishnan, Gideon Emukule, Liselotte van Asten, Susana Pereira da Silva, Suchunya Aungkulanon, Udo Buchholz, Marc-Alain Widdowson, Joseph S Bresee, Eduardo Azziz-Baumgartner, Po-Yung Cheng, Fatimah Dawood, Ivo Foppa, Sonja Olsen, Michael Haber, Caprichia Jeffers, C Raina MacIntyre, Anthony T Newall, James G Wood, Michael Kundi, Therese Popow-Kraupp, Makhdum Ahmed, Mahmudur Rahman, Fatima Marinho, C Viviana Sotomayor Proschle, Natalia Vergara Mallegas, Feng Luzhao, Li Sa, Juliana Barbosa-Ramírez, Diana Malo Sanchez, Leandra Abarca Gomez, Xiomara Badilla Vargas, aBetsy Acosta Herrera, María Josefa Llanés, Thea Kølsen Fischer, Tyra Grove Krause, Kåre Mølbak, Jens Nielsen, Ramona Trebbien, Alfredo Bruno, Jenny Ojeda, Hector Ramos, Matthias an der Heiden, Leticia del Carmen Castillo Signor, Carlos Enrique Serrano, Rohit Bhardwaj, Mandeep Chadha, Venkatesh Narayan, Soewarta Kosen, Michal Bromberg, Aharona Glatman-Freedman, Zalman Kaufman, Yuzo Arima, Kazunori Oishi, Sandra Chaves, Bryan Nyawanda, Reem Abdullah Al-Jarallah, Pablo A Kuri-Morales, Cuitláhuac Ruiz Matus, Maria Eugenia Jimenez Corona, Alexander Burmaa, Oyungerel Darmaa, Majdouline Obtel, Imad Cherkaoui, Cees C van den Wijngaard, Wim van der Hoek, Michael Baker, Don Bandaranayake, Ange Bissielo, Sue Huang, Liza Lopez, Claire Newbern, Elmira Flem, Gry M Grøneng, Siri Hauge, Federico G de Cosío, Yadira de Moltó, Lourdes Moreno Castillo, Maria Agueda Cabello, Marta von Horoch, Jose Medina Osis, Ausenda Machado, Baltazar Nunes, Ana Paula Rodrigues, Emanuel Rodrigues, Cristian Calomfirescu, Emilia Lupulescu, Rodica Popescu, Odette Popovici, Dragan Bogdanovic, Marina Kostic, Konstansa Lazarevic, Zoran Milosevic, Branislav Tiodorovic, Mark Chen, Jeffery Cutter, Vernon Lee, Raymond Lin, Stefan Ma, Adam L Cohen, Florette Treurnicht, Woo Joo Kim, Concha Delgado-Sanz, Salvador de mateo Ontañón, Amparo Larrauri, Inmaculada León León, Fernando Vallejo, Rita Born, Christoph Junker, Daniel Koch, Jen-Hsiang Chuang, Wan-Ting Huang, Hung-Wei Kuo, Yi-Chen Tsai, Kanitta Bundhamcharoen, Malinee Chittaganpitch, Helen K Green, Richard Pebody, Natalia Goñi, Hector Chiparelli, Lynnette Brammer, Desiree Mustaquim
Journal: The Lancet (2017)
Phase 2 Trial of Gemcitabine, Cisplatin, plus Ipilimumab in Patients with Metastatic Urothelial Cancer and Impact of DNA Damage Response Gene Mutations on Outcomes
Authors: Matthew D. Galsky, Huan Wang, Noah M. Hahn, Przemyslaw Twardowski, Sumanta K. Pal, Costantine Albany, Mark T. Fleming, Alexander Starodub, Ralph J. Hauke, Menggang Yu, Qianqian Zhao, Guru Sonpavde, Michael J. Donovan, Vaibhav G. Patel, John P. Sfakianos, Josep Domingo-Domenech, William K. Oh, Nicholas Akers, Bojan Losic, Sacha Gnjatic, Eric E. Schadt, Rong Chen, Seunghee Kim-Schulze, Nina Bhardwaj, Andrew V. Uzilov
Journal: European Urology (2017)
Abstract 35: Enhanced Reprogramming of Human Fibroblasts into Cardiomyocytes Using Minimal Transcription Factors
Authors: Yang Zhou, Sahar Alimohamadi, Jiandong Liu, Li Qian
Journal: Circulation Research (2016)

The adult human heart has limited regenerative capacity and is thus an important target for novel regenerative approaches to replenish lost cardiomyocytes after cardiac injury. Cardiac reprogramming that converts fibroblasts to contractile induced cardiomyocytes (iCMs) by overexpressing cardiac lineage specific transcription factors holds great promise as an alternative approach for cardiac regeneration and disease modeling. Significant advance has been made to generate mouse iCMs; however, human iCM (hiCM) generation remains challenging and the yield is low for clinical applications. Here, we leveraged the knowledge that we learned from studying mouse iCM reprogramming to define the optimal condition for hiCM induction. We titrated the dosage of the human reprogramming factors systematically and surprisingly found the minimal core components GATA4, MEF2C and TBX5 were sufficient to induce cardiac fate in human primary fibroblasts. This is in sharp contrast to what has been reported in the literature. Subsequently, we cloned these three factors into a polycistronic vector separated by 2A peptides for defined ratio of protein expression. By optimizing the growth condition, we further improved the efficiency of hiCM reprogramming. Mechanistically, we found the balanced expression of this minimal combination of transcription factors with tailored microenvironment enhanced the establishment of cardiac program in non-myocytes. In sum, our study demonstrates that the use of a single vector with only three transcription factors simplifies generation and improves the yield of hiCMs for potential future clinical applications.
Physiotherapy breathing retraining for asthma: a randomised controlled trial
Authors: Anne Bruton, Amanda Lee, Lucy Yardley, James Raftery, Emily Arden-Close, Sarah Kirby, Shihua Zhu, Manimekalai Thiruvothiyur, Frances Webley, Lyn Taylor, Denise Gibson, Guiqing Yao, Mark Stafford-Watson, Jenny Versnel, Michael Moore, Steve George, Paul Little, Ratko Djukanovic, David Price, Ian D Pavord, Stephen T Holgate, Mike Thomas
Journal: The Lancet Respiratory Medicine (2017)

Despite effective pharmacotherapy, asthma continues to impair quality of life for most patients. Non-pharmacological approaches, including breathing retraining, are therefore of great interest to patients. However, clinicians rarely advocate breathing retraining and access to this intervention is restricted for most patients due to the limited availability of suitable physiotherapists and poor integration of breathing retraining into standard care. We aimed to assess the effectiveness of a digital self-guided breathing retraining intervention.
Stochasticity enables BCR-independent germinal center initiation and antibody affinity maturation
Authors: Jared Silver, Teng Zuo, Neha Chaudhary, Rupa Kumari, Pei Tong, Sophie Giguere, Alessandra Granato, Rakesh Donthula, Colby Devereaux, Duane R. Wesemann
Journal: The Journal of Experimental Medicine (2017)

Two immunoglobulin (Ig) diversification mechanisms collaborate to provide protective humoral immunity. Combinatorial assembly of IgH and IgL V region exons from gene segments generates preimmune Ig repertoires, expressed as B cell receptors (BCRs). Secondary diversification occurs when Ig V regions undergo somatic hypermutation (SHM) and affinity-based selection toward antigen in activated germinal center (GC) B cells. Secondary diversification is thought to only ripen the antigen-binding affinity of Igs that already exist (i.e., cognate Igs) because of chance generation during preimmune Ig diversification. However, whether stochastic activation of noncognate B cells can generate new affinity to antigen in GCs is unclear. Using a mouse model whose knock-in BCR does not functionally engage with immunizing antigen, we found that chronic immunization induced antigen-specific serological responses with diverse SHM-mediated antibody affinity maturation pathways and divergent epitope targeting. Thus, intrinsic GC B cell flexibility allows for somatic, noncognate B cell evolution, permitting de novo antigen recognition and subsequent antibody affinity maturation without initial preimmune BCR engagement.
Local Control of Soft Tissue and Bone Sarcomas
Authors: Joseph G. Crompton, Koichi Ogura, Nicholas M. Bernthal, Akira Kawai, Fritz C. Eilber
Journal: Journal of Clinical Oncology (2017)

Sarcomas of soft tissue and bone are mesenchymal malignancies that can arise in any anatomic location, most commonly the extremity, retroperitoneum, and trunk. Even for lower grade histologic subtypes, local recurrence can cause significant morbidity and even disease-related death. Although surgery remains the cornerstone of local control, perioperative radiation and systemic therapy are often important adjuvants. This review will summarize the current therapeutic approaches for local control of soft tissue and bone sarcomas.
LNMICC Promotes Nodal Metastasis of Cervical Cancer by Reprogramming Fatty Acid Metabolism
Authors: Chunliang Shang, Wei Wang, Yuandong Liao, Yili Chen, Tianyu Liu, Qiqiao Du, Jiaming Huang, Yanchun Liang, Junxiu Liu, Yunhe Zhao, Luyan Guo, Zheng Hu, Shuzhong Yao
Journal: Cancer Research (2017)

Abstract Cancer spread to lymph nodes predicts poor survival but underlying mechanisms remain little understood. In this study, we show that overexpression of the long noncoding RNA LNMICC associates with lymph node metastasis of primary cervical cancer, where it serves as an independent high-risk factor in patient survival. Functional investigations demonstrated that LNMICC promoted lymph node metastasis by reprogramming fatty acid metabolism, by recruiting the nuclear factor NPM1 to the promoter of the fatty acid binding protein FABP5. We also found that the prometastatic effects of LNMICC were directly targeted and suppressed by miR-190. Our results establish a new mechanism of lymph node metastasis and highlight LNMICC as a candidate prognostic biomarker and therapeutic target in cervical cancer. Significance: These results establish the role of a novel long noncoding RNA in lymph node metastasis, with implications as a candidate prognostic biomarker and therapeutic target in cervical cancer. Cancer Res; 78(4); 877–90. ©2017 AACR.
Abstract 17502: Left Atrial Size and Functional Indices Measured by Three Dimensional Speckle Tracking Analysis have Higher Prognostic Values than Indices by Two dimensional Echocardiography
Authors: Miki Tsujiuchi
Journal: Circulation (2016)

Background: Left atrial volume and functional indices calculated by two dimensional echocardiography (2DE) are strong predictors of future cardiac events. Prognostic values of left atrial maximum a...
Anti-Inflammatory Effects of Omega-3 Fatty Acids in the Brain: Physiological Mechanisms and Relevance to Pharmacology
Authors: Sophie Layé, Agnès Nadjar, Corinne Joffre, Richard P. Bazinet
Journal: Pharmacological Reviews (2017)

Classically, polyunsaturated fatty acids (PUFA) were largely thought to be relatively inert structural components of brain, largely important for the formation of cellular membranes. Over the past 10 years, a host of bioactive lipid mediators that are enzymatically derived from arachidonic acid, the main n-6 PUFA, and docosahexaenoic acid, the main n-3 PUFA in the brain, known to regulate peripheral immune function, have been detected in the brain and shown to regulate microglia activation. Recent advances have focused on how PUFA regulate the molecular signaling of microglia, especially in the context of neuroinflammation and behavior. Several active drugs regulate brain lipid signaling and provide proof of concept for targeting the brain. Because brain lipid metabolism relies on a complex integration of diet, peripheral metabolism, including the liver and blood, which supply the brain with PUFAs that can be altered by genetics, sex, and aging, there are many pathways that can be disrupted, leading to altered brain lipid homeostasis. Brain lipid signaling pathways are altered in neurologic disorders and may be viable targets for the development of novel therapeutics. In this study, we discuss in particular how n-3 PUFAs and their metabolites regulate microglia phenotype and function to exert their anti-inflammatory and proresolving activities in the brain.
Viruses causing lower respiratory symptoms in young children: findings from the ORChID birth cohort
Authors: Mohinder Sarna, Stephen B Lambert, Theo P Sloots, David M Whiley, Asma Alsaleh, Lebogang Mhango, Seweryn Bialasiewicz, David Wang, Michael D Nissen, Keith Grimwood, Robert S Ware
Journal: Thorax (2017)

Viral acute respiratory infections (ARIs) cause substantial child morbidity. Sensitive molecular-based assays aid virus detection, but the clinical significance of positive tests remains uncertain as some viruses may be found in both acutely ill and healthy children. We describe disease-pathogen associations of respiratory viruses and quantify virus-specific attributable risk of ARIs in healthy children during the first 2 years of life.One hundred fifty-eight term newborn babies in Brisbane, Australia, were recruited progressively into a longitudinal, community-based, birth cohort study conducted between September 2010 and October 2014. A daily tick-box diary captured predefined respiratory symptoms from birth until their second birthday. Weekly parent-collected nasal swabs were batch-tested for 17 respiratory viruses by PCR assays, allowing calculation of virus-specific attributable fractions in the exposed (AFE) to determine the proportion of virus-positive children whose ARI symptoms could be attributed to that particular virus.Of 8100 nasal swabs analysed, 2646 (32.7%) were virus-positive (275 virus codetections, 3.4%), with human rhinoviruses accounting for 2058/2646 (77.8%) positive swabs. Viruses were detected in 1154/1530 (75.4%) ARI episodes and in 984/4308 (22.8%) swabs from asymptomatic periods. Respiratory syncytial virus (AFE: 68% (95% CI 45% to 82%)) and human metapneumovirus (AFE: 69% (95% CI 43% to 83%)) were strongly associated with higher risk of lower respiratory symptoms.The strong association of respiratory syncytial virus and human metapneumovirus with ARIs and lower respiratory symptoms in young children managed within the community indicates successful development of vaccines against these two viruses should provide substantial health benefits.
Identification of patterns of factors preceding severe or life‐threatening asthma exacerbations in a nationwide study
Authors: H. Tanaka, E. Nakatani, Y. Fukutomi, K. Sekiya, H. Kaneda, M. Iikura, M. Yoshida, K. Takahashi, K. Tomii, M. Nishikawa, N. Kaneko, Y. Sugino, M. Shinkai, T. Ueda, Y. Tanikawa, T. Shirai, M. Hirabayashi, T. Aoki, T. Kato, K. Iizuka, M. Fujii, M. Taniguchi
Journal: Allergy (2017)

Reducing near-fatal asthma exacerbations is a critical problem in asthma management.To determine patterns of factors preceding asthma exacerbations in a real-world setting.In a nationwide prospective study of 190 patients who had experienced near-fatal asthma exacerbation, cluster analysis was performed using asthma symptoms over the 2-week period before admission.Three distinct clusters of symptoms were defined employing the self-reporting of a visual analogue scale. Cluster A (42.1%): rapid worsening within 7.4 hours from moderate attack to admission, young to middle-aged patients with low Body mass index and tendency to depression who had stopped anti-asthma medications, smoked, and hypersensitive to environmental triggers and furred pets. Cluster B (40.0%): fairly rapid worsening within 48 hours, mostly middle-aged and older, relatively good inhaled corticosteroid (ICS) or ICS/long-acting beta-agonist (LABA) compliance, and low perception of dyspnea. Cluster C (17.9%): slow worsening over 10 days before admission, high perception of dyspnea, smokers, and chronic daily mild-moderate symptoms. There were no differences in overuse of short-acting beta-agonists, baseline asthma severity, or outcomes after admission for patients in these 3 clusters.To reduce severe or life-threatening asthma exacerbation, personalized asthma management plans should be considered for each cluster. Improvement of ICS and ICS/LABA compliance and cessation of smoking are important in cluster A. To compensate for low perception of dyspnea, asthma monitoring of peak expiratory flow rate and/or exhaled nitric oxide would be useful for patients in cluster B. Avoidance of environmental triggers, increase usual therapy, or new anti-type 2 response-targeted therapies should be considered for cluster C.
Radiofrequency Denervation for Chronic Low Back Pain
Authors: Varun Rimmalapudi, Jeff Buchalter, Aaron Calodney
Journal: JAMA (2017)

To the Editor The study by Dr Juch and colleagues1 investigated the effect of radiofrequency denervation plus an exercise program compared with the exercise program alone for patients with chronic low back pain. We note several flaws in the design of the study.
NMDA and AMPA glutamate receptor antagonists in the treatment of human malignant glioma xenografts
Authors: Ranjit K. Goudar, Stephen T. Keir, Darell D. Bigner, Henry S. Friedman
Journal: Cancer Research (2004)

4562  Human glioma cell lines secrete high levels of the excitatory neurotransmitter glutamate (Glu); early published work has shown that glutamate stimulates glioma cell growth, and both NMDA and AMPA glutamate receptor antagonists decreased the proliferation of human glioma cells in vitro. Glu-releasing strains of rat glioma have been shown to form larger and more invasive xenografts, and NMDA receptor antagonists slowed the growth of orthotopic rat glioma xenografts. However, these compounds have not been well evaluated against human malignant glioma xenografts. We used heterotopic and orthotopic models of human glioma in immunocompromised mice to evaluate the efficacy of GYKI-53773 (talampanel, IVAX), an AMPA-subtype Glu receptor antagonist, and memantine, an NMDA-subtype antagonist. When tested against a panel of four subcutaneous human glioma xenografts, one-day gavage dosing regimens of talampanel did not result in statistically-significant tumor growth delay or regressions in tumor volume. Chronic intraperitoneal dosing of talampanel in six glioma lines and one ependymoma line led to a small number of regressions in D212MG (11.1% of samples), D245MG (10%), D245MG (PR) (procarbazine resistant, 8.3%), and D612EP (22.2%) xenografts without statistically-significant growth delays. The reported inhibition of glioma expansion by Glu receptor antagonists may be due to blockade of tumor cell receptors or to inhibition of the excitotoxic death of adjacent normal neurons. Therefore, we hypothesized that these agents may inhibit the expansion of neuron-encased intracranial glioma xenografts more than that of subcutaneous tumors. D54MG and D245MG, human glioma lines that express high levels of AMPA and NMDA receptors, were used in intracranial xenograft trials. Talampanel caused a 9.1% increase (p = 0.5) and memantine caused a 13.0% increase (p = 0.342) in median lifespan of mice bearing orthotopic D245MG xenografts. These preliminary results indicated that NMDA blockade might be more effective than AMPA blockade. In an orthotopic D54MG xenograft model, memantine (30 mg/kg IP BID) produced significant increases in median host animal lifespan of 16.5% (p = 0.016) and 11.9% (p = 0.018), in duplicate experiments. Studies currently underway will determine if higher doses of memantine will result in dose-dependent increases in the lifespan of animals bearing intracranial glioma xenografts.
Abstract IA14: Targeting human endogenous retroviruses for epigenetic therapy
Authors: Peter A. Jones
Journal: Cancer Research (2017)

Abstract Vitamin C deficiency is found in patients with cancer and might complicate various therapy paradigms. Here we show how this deficiency may influence the use of DNA methyltransferase inhibitors (DNMTis) for treatment of hematological neoplasias. In vitro, when vitamin C is added at physiological levels to low doses of the DNMTi 5-aza-2'-deoxycytidine (5-aza-CdR), there is a synergistic inhibition of cancer-cell proliferation and increased apoptosis. These effects are associated with enhanced immune signals including increased expression of bidirectionally transcribed endogenous retrovirus (ERV) transcripts, increased cytosolic dsRNA, and activation of an IFN-inducing cellular response. This synergistic effect is likely the result of both passive DNA demethylation by DNMTi and active conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) by ten-eleven translocation (TET) enzymes at LTR regions of ERVs, because vitamin C acts as a cofactor for TET proteins. In addition, TET2 knockout reduces the synergy between the two compounds. Furthermore, we show that many patients with hematological neoplasia are markedly vitamin C deficient. Thus, our data suggest that correction of vitamin C deficiency in patients with hematological and other cancers may improve responses to epigenetic therapy with DNMTis. Citation Format: Peter A. Jones. Targeting human endogenous retroviruses for epigenetic therapy [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr IA14.
Adapting QOF to focus on wellbeing and health
Authors: James Close, Jose M Valderas, Richard Byng, Nicky Britten, Helen Lloyd
Journal: BMJ (2017)

We welcome Marshall and Roland’s editorial on the Quality and Outcomes Framework (QOF) and propose some future directions.1

QOF (or its replacement) needs an expanded notion of quality of care that accounts for fundamental features of general practice that are not currently captured. This would focus on wellbeing and …