tbuckley/cabot-search huggingface dataset:
T-cell–Secreted TNFα Induces Emergency Myelopoiesis and Myeloid-Derived Suppressor Cell Differentiation in Cancer
Authors: Mohamad F. Al Sayed, Michael A. Amrein, Elias D. Bührer, Anne-Laure Huguenin, Ramin Radpour, Carsten Riether, Adrian F. Ochsenbein
Journal: Cancer Research (2018)

Hematopoiesis in patients with cancer is characterized by reduced production of red blood cells and an increase in myelopoiesis, which contributes to the immunosuppressive environment in cancer. Some tumors produce growth factors that directly stimulate myelopoiesis such as G-CSF or GM-CSF. However, for a majority of tumors that do not directly secrete hematopoietic growth factors, the mechanisms involved in the activation of myelopoiesis are poorly characterized. In this study, we document in different murine tumor models activated hematopoiesis with increased proliferation of long-term and short-term hematopoietic stem cells and myeloid progenitor cells. As a consequence, the frequency of myeloid-derived suppressor cells and its ratio to CD8+ T cells increased in tumor-bearing mice. Activation of hematopoiesis and myeloid differentiation in tumor-bearing mice was induced by TNFα, which was mainly secreted by activated CD4+ T cells. Therefore, the activated adaptive immune system in cancer induces emergency myelopoiesis and immunosuppression. SIGNIFICANCE: These findings characterize a regulatory circuit linking activated T cells to suppression of tumor-specific immune responses, providing a conceptual advance in the understanding of emergency-hematopoiesis in cancer and opening new targets for therapeutic approaches. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/79/2/346/F1.large.jpg.
Abstract P067: Long-term Exposure to Ambient Air Pollution and Type 2 Diabetes Incidence: A Time Series Analysis
Authors: Guozhang Xu, Donghuui Duan, Dingyun You, Jiaying Xu, Xiaoqi Feng, Thomas Astell-Burt, Tianfeng He, Guodong Xu, Jinshun Zhao, Lina Zhang, Hui Li, Liyuan Han
Journal: Circulation (2018)

Introduction: Epidemiological evidence on long-term exposure to ambient air pollution and type 2 diabetes (T2D) incidence are sparse, and the results are contradictory. Hypothesis: We performed a time-series analysis to investigate potential association between long-term exposure to ambient air pollution and T2D incidence in the Chinese population. Methods: Monthly time-series data between 2008-2015 on ambient air pollutants and incident T2D were obtained from the Environment Monitoring Center of Ningbo and the Chronic Disease Surveillance System of Ningbo. Relative risks (RRs) and 95% confidence intervals (95%CIs) of incident T2D per 10 μg/m 3 increase in ambient air pollutants were estimated from Poisson generalized additive models and adjusted for month, temperature, relative humidity, air pressure and wind speed. This model was combined with a distributed lag non-linear model to determine the relative risks. Main Outcome Measures: The main outcome measure was T2D incidence. Results: Long-term exposure to particulate matter &lt;10 μm (PM10) and Sulphur dioxide (SO2) were associated with increased T2D incidence. The relative risks (RRs) of each increment in 10 μg/m 3 of PM10 and SO2 were 1.62 (95%CI, 1.16 to 2.28) and 1.63 (95%CI, 1.12 to 2.38) for overall participants, 1.56 (95%CI, 1.12 to 2.17) and 1.59 (95%CI, 1.14 to 2.23) for males, 1.68 (95%CI, 1.15 to 2.44) and 1.76 (95%CI, 1.21 to 2.56) for females, respectively. Whereas for ozone (O3) exposure, the RRs were 0.78 (95%CI, 0.68 to 0.90) for overall participants, 0.78 (95%CI, 0.69 to 0.90) for males, and 0.78 (95%CI, 0.67 to 0.91) for females, respectively. Female participants were more prone to develop T2D after long-term exposed to ambient air pollutants than male counterparts. No statistically significant associations were observed for PM2.5, NO2, and CO exposures, nor in the two- and three-pollutant models. Conclusions: Long-term exposure to PM10 and SO2 is positively associated with T2D incidence, whereas O3 is negatively associated with T2D incidence.
Large Paraesophageal Schwannoma With Intense Prostate-Specific Membrane Antigen Expression on 68Ga-PSMA-PET/CT Mimicking Lymph Node Metastasis in a Patient With Prostate Cancer
Authors: Martin Ries, Fadi Khreish, Christian Veith, Joachim von den Hoff, Samer Ezziddin
Journal: Clinical Nuclear Medicine (2018)

Prostate-specific membrane antigen (PSMA)-PET/CT as an emerging modality in molecular imaging will lead to earlier detection and localization of relapse in prostate cancer but will undoubtedly also lead to false-positive findings, as it becomes clear that this new tracer is not as specific as its name would suggest. In this context, we present a case of a large PSMA-expressing schwannoma, a rare nerve sheath tumor mimicking paraesophageal lymph node metastasis in a patient with a history of prostate cancer and biochemical recurrence.
Prenatal particulate matter affects new asthma via airway hyperresponsiveness in schoolchildren
Authors: Song‐I Yang, So‐Yeon Lee, Hyo‐Bin Kim, Hwan‐Cheol Kim, Jong‐Han Leem, Hyeon‐Jong Yang, Hyeok Kwon, Ju‐Hee Seo, Hyun‐Ju Cho, Jisun Yoon, Eun Lee, Young‐Ho Jung, Yeongho Kim, Sungsu Jung, Ho‐Jang Kwon, Soo‐Jong Hong
Journal: Allergy (2018)

Abstract Background The most relevant time of PM 10 exposure to affect airway hyperresponsiveness ( AHR ) and new development of asthma in school‐aged children is unclear. The aims of this study were to investigate the most critical time of PM 10 exposure to affect AHR and new diagnosis of asthma from AHR in school‐aged children. Methods Elementary schoolchildren (n = 3570) have been enrolled in a nationwide prospective 4‐year follow‐up survey in Korea from 2005 to 2006. Individual annual PM 10 exposure was estimated by using an ordinary kriging method from the prenatal period to 7 years of age. AHR at 7 years was defined by a methacholine PC 20 ≤8 mg/mL. Results PM 10 exposure during pregnancy and at 1 year of age showed significant effects on AHR ( aOR : 1.694, 95% CI : 1.298‐2.209; and aOR : 1.750, 95% CI : 1.343‐2.282, respectively). PM 10 exposure during pregnancy was associated with the risk of a new diagnosis of asthma ( aOR : 2.056, 95% CI : 1.240‐3.409), with the highest risk in children with AHR at age 7 ( aOR : 6.080, 95% CI : 2.150‐17.195). PM 10 exposure in the second trimester was associated with the highest risk of a new diagnosis of asthma in children with AHR at age 7 ( aOR : 4.136, 95% CI : 1.657‐10.326). Conclusions Prenatal PM 10 exposure in the second trimester is associated with an increased risk of a new diagnosis of asthma in school‐aged children with AHR at 7 years. This study suggests that PM 10 exposure during a specific trimester in utero may affect the onset of childhood asthma via AHR .
Bayer and Novartis appeal ruling that Avastin for wet AMD is lawful
Authors: Deborah Cohen
Journal: BMJ (2018)

The drug companies Bayer and Novartis plan to appeal against a High Court ruling that gave doctors the right to offer patients off-label bevacizumab to treat wet age related macular degeneration (AMD).

Both claim that the judgment is wrong because it undermines the role of drug regulatory agencies in the UK and Europe and puts public health at risk.

Bayer and Novartis brought legal proceedings against 12 clinical commissioning groups (CCGs) in the north of England for offering bevacizumab (Roche’s Avastin), which is not licensed for treatment of wet AMD, alongside ranibizumab (Lucentis, marketed by Novartis) and aflibercept (Bayer’s Eylea), which are approved by the National Institute for Health and Clinical Excellence for treating the condition. But in September Mrs Justice Whipple backed the CCGs’ policy and dismissed the companies’ application for judicial review.1

The BMJ understands that some trusts are reluctant to change their practices after the ruling, which the CCGs claim could save the NHS millions of pounds.

Greg Fell, director of public health in Sheffield, has …
Abstract 18480: Mortality Risk in Married and Unmarried ICD and CRT-D Patients With Mild Heart Failure: A MADIT-CRT Sub-study
Authors: Mehmet K Aktas, Yitschak Biton, Wojciech Zareba, Slava Polonsky, Scott McNitt, Arthur J Moss, Valentina Kutyifa
Journal: Circulation (2015)

Background: Married patients have been shown to have a lower risk for adverse cardiovascular outcomes. However, the risk of heart failure or death, and death alone in married versus unmarried patients with left ventricular (LV) dysfunction and an implantable cardioverter defibrillator (ICD), and the effect of cardiac resynchronization therapy with defibrillator (CRT-D) are unknown. Methods: In MADIT-CRT, we evaluated the long-term clinical outcomes of all-cause mortality, and heart failure (HF) or death in married and common law patients compared to the unmarried (single/divorced/widowed) with left bundle branch block (LBBB) and CRT-D vs. an ICD-only. Results: There were 937 married patients and 344 unmarried patients with LBBB. Married patients were more likely to be men, white, smokers, and heavier. During a median follow-up of 5.6 years, married/common law ICD patients had a significantly lower incidence of death compared to unmarried patients (p=0.004) (Figure). In multivariate analysis in the ICD-only sub-group, married or common-law patients had a 39% lower risk of all-cause mortality (HR 0.46, 95% CI 0.30 - 0.71, p&lt;0.001) when compared to the unmarried. However, in the CRT-D group, the survival benefit was attenuated in married/common-law patients (HR 0.74, 95% CI 0.51 - 1.06, p=0.10) compared to the unmarried (HR 0.40, 95% CI 0.23 - 0.69, p&lt;0.001, interaction p=0.07). There were no differences in clinical outcomes of HF or death in married and unmarried patients with an implanted CRT-D vs. ICD-only, or in patients with non-LBBB ECG pattern. Conclusions: During long-term follow-up of mild HF patients with LV dysfunction, married/common-law patients were at a significantly lower risk for death compared to those not married. In married patients, CRT-D was associated with an attenuated survival benefit when compared to their unmarried counterparts.
Prevalence and Changes in Preexisting Diabetes and Gestational Diabetes Among Women Who Had a Live Birth — United States, 2012–2016
Authors: Nicholas P. Deputy, Shin Y. Kim, Elizabeth J. Conrey, Kai McKeever Bullard
Journal: MMWR Morbidity and Mortality Weekly Report (2018)

In 2016, the national prevalences of preexisting and gestational diabetes were 0.86% and 5.96%, respectively. Among 40 jurisdictions, the prevalence of age- and race/ethnicity-standardized preexisting diabetes was stable at 0.8% and increased slightly from 5.2% to 5.6% for gestational diabetes.
Polarity Acquisition in Cortical Neurons Is Driven by Synergistic Action of Sox9-Regulated Wwp1 and Wwp2 E3 Ubiquitin Ligases and Intronic miR-140
Authors: Mateusz C. Ambrozkiewicz, Manuela Schwark, Mika Kishimoto-Suga, Ekaterina Borisova, Kei Hori, Andrea Salazar-Lázaro, Alexandra Rusanova, Bekir Altas, Lars Piepkorn, Paraskevi Bessa, Theres Schaub, Xin Zhang, Tamara Rabe, Silvia Ripamonti, Marta Rosário, Haruhiko Akiyama, Olaf Jahn, Tatsuya Kobayashi, Mikio Hoshino, Victor Tarabykin, Hiroshi Kawabe
Journal: Neuron (2018)
High dose iron regimen improves outcomes in dialysis patients, UK study finds
Authors: Jacqui Wise
Journal: BMJ (2018)

Patients undergoing kidney dialysis who were given a high dose regimen of intravenous iron needed fewer blood transfusions and lower doses of erythropoiesis stimulating agent (ESA) to maintain target haemoglobin levels than those in a low dose group, a large UK trial has found.

In addition, a high dose iron regimen seemed to protect against recurrent events, including admission for heart failure. The high dose regimen was also not associated with a greater risk of infection, in the study published in the New England Journal of Medicine .1

Safety concerns have previously arisen about using higher doses of ESAs to elevate haemoglobin levels, as cardiovascular toxic effects have been observed in trials.

In …
THU0051 Tnf receptor 2 plays an immunoregulatory and anti-inflammatory role in arthritis
Authors: W.-Y. Tseng, I.-S. Huang, F. Clanchy, K. Mcnamee, F. Mccann, R.O. Williams
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Despite the overall success of TNFα inhibitors in rheumatoid arthritis (RA), up to half of patients are classified as either primary or secondary non-responders<sup>1</sup>. One hypothesis put forward to explain resistance to anti-TNFα therapy is an ascendant effect of dysregulated regulatory T cells and increased Th17 responses following TNFα blockade. Previous studies have demonstrated that TNFR2 is critical for stabilisation and suppressive function of regulatory T cells<sup>2,3</sup>. However, TNFR2 also activates pro-inflammatory signalling cascades and, to date, the net effect of TNFR2 on the pathogenesis of RA remains unclear. <h3>Objectives</h3> In this study we address this question by assessing the progression of collagen-induced arthritis (CIA) in mice deficient for TNFR1 or TNFR2. <h3>Methods</h3> C57Bl/6N.Q (H-2<sup>q</sup>) mice were immunised with bovine type II collagen emulsified in complete Freund's adjuvant. The mice were monitored daily for arthritis and scored clinically from the day of onset of disease. Mice were culled on day 10 after arthritis onset and spleens, lymph nodes, serum and paws were collected for further analysis. <h3>Results</h3> As expected, TNFR1<sup>-/-</sup> mice were found to be largely resistant to arthritis both clinically and histologically (figure 1). In contrast, there was significantly enhanced disease activity at the clinical and histological levels in TNFR2<sup>-/-</sup> mice (figure 1) and this was accompanied by increased expression of the pro-inflammatory cytokines, TNFα and IL-6, reduced numbers of regulatory T cells, reduced FoxP3 expression and reduced expression of the immune inhibitory molecules, PD-1 and LAG3, in TNFR2<sup>-/-</sup> mice compared to WT mice. <h3>Conclusions</h3> This study has shown that TNFR2 signalling plays immunoregulatory and anti-inflammatory roles in CIA. First, it contributes to promotion of regulatory T cell generation and FoxP3 expression, and second, it limits the expression of pro-inflammatory cytokines. TNFR2 also regulates the expression immune inhibitory molecules during inflammation. The results support the rationale to for development of TNFR1 specific antagonists or TNFR2 agonists for the treatment of RA. <h3>References</h3> [1] Giulia Roda, et al. Loss of Response to Anti-TNFs: Definition, Epidemiology, and Management. Clinical and Translational Gastroenterology2016. [2] Xin Chen, et al. TNFR2 is critical for the stabilization of the CD4+Foxp3+ regulatory T cell phenotype in the inflammatory enviroment. J. Immunol2013. [3] Xin Chen et al. Expression of TNFR2 defines a maximally suppressive subset of mouse CD4 +CD25+FoxP3+T regulatory cells: applicability to tumour infiltrating T regulatory cells. J. Immunology 2008. <h3>Acknowledgements</h3> This work was supported by grants from Chang Gung Memorial Hospital and Ministry of Science and Technology (Taiwan) <h3>Disclosure of Interest</h3> None declared
Verification of Long-Term Genetic Stability of hMSCs during Subculture after Internalization of Sunflower-Type Nanoparticles (SF-NPs)
Authors: Ji Sun Park, Se Won Yi, Hye Jin Kim, Hyun Jyung Oh, Jung Sun Lee, Minyeon Go, Sung Han Shim, Keun-Hong Park
Journal: Theranostics (2018)

Background: For many years, researchers have sought to overcome major challenges in the use of nanoparticles as therapeutics, including issues related to intracellular delivery, biocompatibility, and activation. In particular, the genetic stability of cells treated with nanoparticles has become increasingly important in the context of stem cell therapy. Methods: Functional nanoparticles (Sunflower typed nanoparticles; SF-NPs) were fabricated by coating heparin pluronic F127 gels with quantum dot nanoparticles (QDs), and then bound the SOX9 gene to the QD nanogels. The resultant nanoparticles were transferred into stem cells, and the effect on genetic stability was monitored. To determinate gene delivery efficacy and long-term genomic stability of cells transfected with QD nanogels, hMSCs were transfected with nanogels at passage 4 (T1; Transfected cells 1) and then sub-cultured to passage of (T4). Following transplantation of transfected T1-T4 cells, the cells were monitored by in vivo imaging. The genetic stability of cells treated with nanoparticles was confirmed by chromosomal analysis, copy number variation (CNV) analysis, and mRNA profiling. Results: After 21 days of pellet culture after sub-culture from T1 to T4, hMSCs treated with QD nanogels complexed with SOX9 plasmid DNA (pDNA) significantly increased expression of specific extracellular matrix (ECM) polysaccharides and glycoproteins, as determined by Safranin O and Alcian blue staining. Moreover, the T4 hMSCs expressed higher levels of specific proteins, including collagen type II (COLII) and SOX9, than P4 hMSCs, with no evidence of DNA damage or genomic malfunction. Microarray analysis confirmed expression of genes specific to matured chondrocytes. Stem cells that internalized nanoparticles at the early stage retained genetic stability, even after passage. In in vivo studies in rats, neuronal cartilage formation was observed in damaged lesions 6 weeks after transplantation of T1 and T4 cells. The degree of differentiation into chondrocytes in the cartilage defect area, as determined by mRNA and protein expression of COLII and SOX9, was higher in rats treated with SF-NPs. Conclusion: The QD nanogels used in this study, did not affect genome integrity during long-term subculture, and are thus suitable for multiple theranostic applications.
Measurement of Plasma Cell-Free Mitochondrial Tumor DNA Improves Detection of Glioblastoma in Patient-Derived Orthotopic Xenograft Models
Authors: Richard Mair, Florent Mouliere, Christopher G. Smith, Dineika Chandrananda, Davina Gale, Francesco Marass, Dana W.Y. Tsui, Charles E. Massie, Alan J. Wright, Colin Watts, Nitzan Rosenfeld, Kevin M. Brindle
Journal: Cancer Research (2018)

The factors responsible for the low detection rate of cell-free tumor DNA (ctDNA) in the plasma of patients with glioblastoma (GBM) are currently unknown. In this study, we measured circulating nucleic acids in patient-derived orthotopically implanted xenograft (PDOX) models of GBM (
Identification of TMAO-producer phenotype and host–diet–gut dysbiosis by carnitine challenge test in human and germ-free mice
Authors: Wei-Kai Wu, Chieh-Chang Chen, Po-Yu Liu, Suraphan Panyod, Ben-Yang Liao, Pei-Chen Chen, Hsien-Li Kao, Han-Chun Kuo, Ching-Hua Kuo, Tina H T Chiu, Rou-An Chen, Hsiao-Li Chuang, Yen-Te Huang, Hsin-Bai Zou, Cheng-Chih Hsu, Ting-Yan Chang, Chin-Lon Lin, Chi-Tang Ho, Hon-Tsen Yu, Lee-Yan Sheen, Ming-Shiang Wu
Journal: Gut (2018)

Objective The gut microbiota-derived metabolite, trimethylamine N-oxide (TMAO) plays an important role in cardiovascular disease (CVD). The fasting plasma TMAO was shown as a prognostic indicator of CVD incident in patients and raised the interest of intervention targeting gut microbiota. Here we develop a clinically applicable method called oral carnitine challenge test (OCCT) for TMAO-related therapeutic drug efforts assessment and personalising dietary guidance. Design A pharmacokinetic study was performed to verify the design of OCCT protocol. The OCCT was conducted in 23 vegetarians and 34 omnivores to validate gut microbiota TMAO production capacity. The OCCT survey was integrated with gut microbiome, host genotypes, dietary records and serum biochemistry. A humanised gnotobiotic mice study was performed for translational validation. Results The OCCT showed better efficacy than fasting plasma TMAO to identify TMAO producer phenotype. The omnivores exhibited a 10-fold higher OR to be high TMAO producer than vegetarians. The TMAO-associated taxa found by OCCT in this study were consistent with previous animal studies. The TMAO producer phenotypes were also reproduced in humanised gnotobiotic mice model. Besides, we found the faecal CntA gene was not associated with TMAO production; therefore, other key relevant microbial genes might be involved. Finally, we demonstrated the urine TMAO exhibited a strong positive correlation with plasma TMAO (r=0.92, p&lt;0.0001) and improved the feasibility of OCCT. Conclusion The OCCT can be used to identify TMAO-producer phenotype of gut microbiota and may serve as a personal guidance in CVD prevention and treatment. Trial registration number NCT02838732 ; Results.
Abstract 20619: Platelet Derived Beta-2 Microglobulin Mediates a Monocyte Pro-Inflammatory Phenotype
Authors: Zachary T Hilt, Sara K Ture, Andrew L Johanson, Daphne N Pariser, Craig N Morrell
Journal: Circulation (2017)

Introduction: Platelets are an important part of the immune system. Platelets regulate both innate and adaptive immune responses: platelets activate the acute phase response, release cytokines and ...
Cancer Risk Estimates for Study of Multiple-Gene Testing After Diagnosis of Breast Cancer—Reply
Authors: Allison W. Kurian, Steven J. Katz
Journal: JAMA Oncology (2018)

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