tbuckley/cabot-search huggingface dataset:
Addressing Financial Barriers to Enrollment in Clinical Trials
Authors: Emily A. Largent, Holly Fernandez Lynch
Journal: JAMA Oncology (2018)

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Inhibition of UGT8 suppresses basal-like breast cancer progression by attenuating sulfatide–αVβ5 axis
Authors: Qianhua Cao, Xingyu Chen, Xuebiao Wu, Ruocen Liao, Panpan Huang, Yanjia Tan, Li Wang, Guoping Ren, Jian Huang, Chenfang Dong
Journal: The Journal of Experimental Medicine (2018)

Basal-like breast cancer (BLBC) is associated with a poor clinical outcome as a result of the few treatment options and poor therapeutic response. Here, we report that elevated expression of urine diphosphate–galactose ceramide galactosyltransferase (UGT8) specifically occurs in BLBC and predicts poor prognosis in breast cancer patients. UGT8 expression is transcriptionally up-regulated by Sox10, triggering the sulfatide biosynthetic pathway; increased sulfatide activates integrin αVβ5-mediated signaling that contributes to BLBC progression. UGT8 expression promotes, whereas UGT8 knockdown suppresses tumorigenicity and metastasis. Importantly, we identify that zoledronic acid (ZA), a marketed drug for treating osteoporosis and bone metastasis, is a direct inhibitor of UGT8, which blocks the sulfatide biosynthetic pathway. Significantly, a clinically achievable dosage of ZA exhibits apparent inhibitory effect on migration, invasion, and lung metastasis of BLBC cells. Together, our study suggests that UGT8 is a potential prognostic indicator and druggable target of BLBC and that pharmacologic inhibition of UGT8 by ZA offers a promising opportunity for treating this challenging disease.
Cost-effectiveness of a New Opportunistic Screening Strategy for Walk-in Fingertip HbA1c Testing at Community Pharmacies in Japan
Authors: Aiko Shono, Masahide Kondo, Shu-ling Hoshi, Reiko Okubo, Naoya Yahagi
Journal: Diabetes Care (2018)

OBJECTIVE A new opportunistic community-based strategy was launched in Japan in April 2014 to detect lifestyle-related diseases, including diabetes, by creating Specimen Measurement Offices (SMOs). SMOs offer walk-in fingertip HbA1c testing. This article aimed to assess the value-for-money of HbA1c testing services at SMOs by conducting a cost-effectiveness analysis. RESEARCH DESIGN AND METHODS We compared two scenarios: 1) status quo, defined as HbA1c testing that is available only through conventional screening, and 2) HbA1c testing available at SMOs as a complement to the status quo scenario. The model consisted of a screening module with a decision tree and a disease progression module with a Markov model. We calculated incremental cost-effectiveness ratios (i.e., cost per quality-adjusted life-years [QALYs]) over the lifetime analytic horizon as the primary end point of the cost-effectiveness analysis. In this model, we assumed the participant cohort to be people 40–74 years of age who sought walk-in fingertip HbA1c testing at SMOs on the premises of community pharmacies. Costs and outcomes were discounted at a rate of 3%. The cost-effectiveness was analyzed from a societal perspective. RESULTS The incremental cost per individual for those 40–74 years of age was estimated to be −527 U.S. dollars (USD) (−52,722 Japanese yen [JPY]) for HbA1c testing at SMOs compared with the status quo. Incremental effectiveness was estimated to be 0.0203 QALYs for HbA1c testing at SMOs compared with the status quo. Therefore, this cost-effectiveness analysis showed that compared with the status quo, HbA1c testing at SMOs was more effective and had lower cost for the population studied. CONCLUSIONS We consider our results to be robust because most simulations were under the threshold of USD 50,000 (JPY 5,000,000) per QALYs gained, by sensitivity analysis. These results will be useful to managers of pharmacies or other health institutions and/or policy makers in local government.
240Mesenchymal stem cells transfected with minicircle-HIF-1a decreases LV adverse remodelling via release of cardioprotective miRNAs and pro-angiogenic factors
Authors: E Gara, S G Ong, J Winkler, K Zlabinger, D Lukovic, A Jakab, B Merkely, J C Wu, M Gyongyosi, N Pavo
Journal: Cardiovascular Research (2018)
Long non-coding RNAs AC026904.1 and UCA1: a “one-two punch” for TGF-β-induced SNAI2 activation and epithelial-mesenchymal transition in breast cancer
Authors: Guo-Yin Li, Wei Wang, Jian-Yong Sun, Bo Xin, Xiang Zhang, Ting Wang, Qian-Feng Zhang, Li-Bo Yao, Hua Han, Dai-Ming Fan, An-Gang Yang, Lin-Tao Jia, Lei Wang
Journal: Theranostics (2018)

Transforming growth factor-β (TGF-β) has received much attention as a major inducer of epithelial-mesenchymal transition (EMT) during cancer progression, mainly by activating a set of pleiotropic transcription factors including SNAI2/Slug.However, the involvement of long non-coding RNAs (lncRNAs) in TGF-β-induced Slug activation and EMT remains largely unknown.Methods: In this study, we used microarray analysis to compare lncRNA expression profiles between TGF-β treated and untreated breast cancer cells.Then, the clinical significance of lncRNAs in breast cancer was investigated by qPCR and Kaplan-Meier survival analysis.The molecular mechanisms and EMT-promoting effects in vitro were analyzed by confocal laser microscopy, Western blotting, chromosome conformation capture (3C), chromatin isolation by RNA purification (ChIRP), ChIP, luciferase reporter assay and transwell migration assay.Lastly, the pro-metastatic effects in vivo were evaluated by bioluminescent imaging and hematoxylin and eosin (H&E) staining. Results:We observed that TGF-β induced genome-wide changes in lncRNA levels in breast cancer cells, among which AC026904.1 and UCA1 were highly expressed in metastatic breast cancer and closely associated with poor prognosis.Mechanistic study revealed that AC026904.1 and UCA1 were upregulated by non-canonical and canonical TGF-β pathways, respectively.Further analysis showed that AC026904.1 functions as an enhancer RNA in the nucleus, whereas UCA1 exerts a competitive endogenous RNA (ceRNA) activity in the cytoplasm.In addition, the biological functions of these two lncRNAs converged on the activation and maintenance of Slug, constituting a one-two punch in promoting EMT and tumor metastasis. Conclusion:These findings uncover for the first time that AC026904.1 and UCA1 could cooperatively upregulate Slug expression at both transcriptional and post-transcriptional levels, exerting critical roles in TGF-β-induced EMT.The present work provides new evidence that lncRNAs function as key regulators of EMT and hold great promise to be used as novel biomarkers and therapeutic targets for metastatic breast cancer.
Utilization of elbasvir/grazoprevir (EBR/GZR) and adoption of resistance associated substitutions (RAS) testing in real-world treatment of HCV genotype 1 (GT1) infection: results from the German Hepatitis C Registry (DHC-R)
Authors: H. Hinrichsen, H. Klinker, A. Stoehr, C. John, R. Heyne, G. Klausen, K.-G. Simon, M. Cornberg, M. Kuhn, U. Naumann, M. Bilzer, K. Bayer, V. Witte, S. Zeuzem
Journal: Journal of Hepatology (2018)
Clinicopathological Risk Factors for an Invasive Breast Cancer Recurrence after Ductal Carcinoma<i>In Situ</i>—A Nested Case–Control Study
Authors: Lindy L. Visser, Lotte E. Elshof, Michael Schaapveld, Koen van de Vijver, Emma J. Groen, Mathilde M. Almekinders, Carolien Bierman, Flora E. van Leeuwen, Emiel J. Rutgers, Marjanka K. Schmidt, Esther H. Lips, Jelle Wesseling
Journal: Clinical Cancer Research (2018)

Abstract Purpose: Ductal carcinoma in situ (DCIS) is treated to prevent progression to invasive breast cancer. Yet, most lesions will never progress, implying that overtreatment exists. Therefore, we aimed to identify factors distinguishing harmless from potentially hazardous DCIS using a nested case–control study. Experimental Design: We conducted a case–control study nested in a population-based cohort of patients with DCIS treated with breast-conserving surgery (BCS) alone (N = 2,658) between 1989 and 2005. We compared clinical, pathologic, and IHC DCIS characteristics of 200 women who subsequently developed ipsilateral invasive breast cancer (iIBC; cases) and 474 women who did not (controls), in a matched setting. Median follow-up time was 12.0 years (interquartile range, 9.0–15.3). Conditional logistic regression models were used to assess associations of various factors with subsequent iIBC risk after primary DCIS. Results: High COX-2 protein expression showed the strongest association with subsequent iIBC [OR = 2.97; 95% confidence interval (95% CI), 1.72–5.10]. In addition, HER2 overexpression (OR = 1.56; 95% CI, 1.05–2.31) and presence of periductal fibrosis (OR = 1.44; 95% CI, 1.01–2.06) were associated with subsequent iIBC risk. Patients with HER2+/COX-2high DCIS had a 4-fold higher risk of subsequent iIBC (vs. HER2−/COX-2low DCIS), and an estimated 22.8% cumulative risk of developing subsequent iIBC at 15 years. Conclusions: With this unbiased study design and representative group of patients with DCIS treated by BCS alone, COX-2, HER2, and periductal fibrosis were revealed as promising markers predicting progression of DCIS into iIBC. Validation will be done in independent datasets. Ultimately, this will aid individual risk stratification of women with primary DCIS. Clin Cancer Res; 24(15); 3593–601. ©2018 AACR.
Abstract 17152: Mesenchymal Stem Cell-derived Angiopoietin-like 4 Directs Alternative Activation of Macrophages to Induce the Resolution of Inflammation
Authors: Dong Im Cho, Yong Sook Kim, Youngkeun Ahn
Journal: Circulation (2017)

Introduction:  Mesenchymal stem cells (MSCs) are extensively challenged for regenerative therapy for inflammation-related diseases, and known to suppress pathological inflammation.   Hypothesis:  The critical messenger released from MSC might be responsible for anti-inflammatory effect against macrophages.   Methods:  In this study, immortalized human bone marrow-derived MSC and differentiated THP-1 macrophage cells were cocultured. We used CXCL10 and CXCL11 as markers of the inflammatory macrophages. Gene expression patterns of MSC were analyzed by microarray, and candidate factors were selected. The anti-inflammation activity was validated in a mouse peritonitis model.   Results:  The expression levels of CXCL10 and CXCL11 in stimulated macrophages were markedly reduced by coculture with MSC, and angiopoietin like 4 (ANGPTL4) was one of the selected functional mediators of MSC. The levels of mRNA, cellular protein, and released protein of Factor A were dramatically upregulated in MSC by coculture with macrophages ANGPTL4 knockdown MSC failed to reduce the inductions of CXCL10 and CXCL11 in stimulated macrophages. From these results, ANGPTL4 is suggested as a responsible mediator of MSC to suppress the inflammatory phenotype of macrophages. To identify the mechanism of ANGPTL4 induction in MSC, we analyzed the ANGPTL4 promoter binding sites, and found that retinoic acid-related orphan receptor (ROR) was involved in the induction of ANGPTL4 in MSC. Besides, we found integrin β5 subunit on the macrophage was essential for ANGPTL4-mediated suppression of inductions of CXCL10 and CXCL11 by using blocking antibody and knockdown experiments. To perform the  in vivo  assay of MSC-released ANGPTL4 in a mouse peritonitis model, we injected intraperitoneally MSC-cultured media (MSC-CM) or ANGPTL4 knockdown MSC-CM. Peritoneal macrophages isolated from MSC-CM treated mice showed higher levels of anti-inflammatory genes such as CD206, arginase 1, and interleukin-10, and lower levels of pro-inflammatory genes such as interleukin-1β and interleukin 10 compared with the ANGPTL4 knockdown MSC-CM treated mice.   Conclusions:  In this study, we identified ANGPTL4 as an immunomoulatory factor of MSC that control the pathological inflammation.
Effects of Neonicotinoid Pesticides on Promoter-Specific Aromatase (CYP19) Expression in Hs578t Breast Cancer Cells and the Role of the VEGF Pathway
Authors: Élyse Caron-Beaudoin, Rachel Viau, J. Thomas Sanderson
Journal: Environmental Health Perspectives (2018)

Background: Aromatase (CYP19) is a key enzyme in estrogens biosynthesis. In the mammary gland, CYP19 gene is expressed at low levels under the regulation of its I.4 promoter. In hormone-dependent breast cancer, fibroblast cells surrounding the tumor express increased levels of CYP19 mRNA due to a decrease of I.4 promoter activity and an increase of PII, I.3, and I.7 promoter activity. Little is known about the effects of environmental chemicals on the promoter-specific CYP19 expression. Objective: We aimed to determine the effects of two neonicotinoids (thiacloprid and imidacloprid) on promoter-specific CYP19 expression in Hs578t breast cancer cells and understand the signaling pathways involved. Methods: Hs578t cells were exposed to various signaling pathway stimulants or neonicotinoids for 24 h. Promoter-specific expression of CYP19 was determined by real-time quantitative polymerase chain reaction and catalytic activity of aromatase by tritiated water release assay. Results: To our knowledge, we are the first to demonstrate that the normal I.4 promoter and the breast cancer-relevant PII, I.3, and I.7 promoters of CYP19 are active in these cells. We found that the expression of CYP19 via promoters PII, I.3, and I.7 in Hs578t cells was, in part, dependent on the activation of two VEGF signaling pathways: mitogen-activated protein kinase (MAPK) 1/3 and phospholipase C (PLC). Exposure of Hs578t cells to environmental concentrations of imidacloprid and thiacloprid resulted in a switch in CYP19 promoter usage, involving inhibition of I.4 promoter activity and an increase of PII, I.3, and I.7 promoter-mediated CYP19 expression and aromatase catalytic activity. Greater effects were seen at lower concentrations. Our results suggest that thiacloprid and imidacloprid exert their effects at least partially by inducing the MAPK 1/3 and/or PLC pathways. Conclusions: We demonstrated in vitro that neonicotinoids may stimulate a change in CYP19 promoter usage similar to that observed in patients with hormone-dependent breast cancer. https://doi.org/10.1289/EHP2698
Interleukin-1β Activates a MYC-Dependent Metabolic Switch in Kidney Stromal Cells Necessary for Progressive Tubulointerstitial Fibrosis
Authors: Dario R. Lemos, Michael McMurdo, Gamze Karaca, Julia Wilflingseder, Irina A. Leaf, Navin Gupta, Tomoya Miyoshi, Koichiro Susa, Bryce G. Johnson, Kirolous Soliman, Guanghai Wang, Ryuji Morizane, Joseph V. Bonventre, Jeremy S. Duffield
Journal: Journal of the American Society of Nephrology (2018)

Background Kidney injury is characterized by persisting inflammation and fibrosis, yet mechanisms by which inflammatory signals drive fibrogenesis remain poorly defined. Methods RNA sequencing of fibrotic kidneys from patients with CKD identified a metabolic gene signature comprising loss of mitochondrial and oxidative phosphorylation gene expression with a concomitant increase in regulators and enzymes of glycolysis under the control of PGC1 α and MYC transcription factors, respectively. We modeled this metabolic switch in vivo , in experimental murine models of kidney injury, and in vitro in human kidney stromal cells (SCs) and human kidney organoids. Results In mice, MYC and the target genes thereof became activated in resident SCs early after kidney injury, suggesting that acute innate immune signals regulate this transcriptional switch. In vitro , stimulation of purified human kidney SCs and human kidney organoids with IL-1 β recapitulated the molecular events observed in vivo , inducing functional metabolic derangement characterized by increased MYC-dependent glycolysis, the latter proving necessary to drive proliferation and matrix production. MYC interacted directly with sequestosome 1/p62, which is involved in proteasomal degradation, and modulation of p62 expression caused inverse effects on MYC expression. IL-1 β stimulated autophagy flux, causing degradation of p62 and accumulation of MYC. Inhibition of the IL-1R signal transducer kinase IRAK4 in vivo or inhibition of MYC in vivo as well as in human kidney organoids in vitro abrogated fibrosis and reduced tubular injury. Conclusions Our findings define a connection between IL-1 β and metabolic switch in fibrosis initiation and progression and highlight IL-1 β and MYC as potential therapeutic targets in tubulointerstitial diseases.
Increased vessel perfusion predicts the efficacy of immune checkpoint blockade
Authors: Xichen Zheng, Zhaoxu Fang, Xiaomei Liu, Shengming Deng, Pei Zhou, Xuexiang Wang, Chenglin Zhang, Rongping Yin, Haitian Hu, Xiaolan Chen, Yijie Han, Yun Zhao, Steven H. Lin, Songbing Qin, Xiaohua Wang, Betty Y.S. Kim, Penghui Zhou, Wen Jiang, Qingyu Wu, Yuhui Huang
Journal: Journal of Clinical Investigation (2018)

Immune checkpoint blockade (ICB) has demonstrated curative potential in several types of cancer, but only for a small number of patients. Thus, the identification of reliable and noninvasive biomarkers for predicting ICB responsiveness is an urgent unmet need. Here, we show that ICB increased tumor vessel perfusion in treatment-sensitive EO771 and MMTV-PyVT breast tumor as well as CT26 and MCA38 colon tumor models, but not in treatment-resistant MCaP0008 and 4T1 breast tumor models. In the sensitive tumor models, the ability of anti–cytotoxic T lymphocyte–associated protein 4 or anti–programmed cell death 1 therapy to increase vessel perfusion strongly correlated with its antitumor efficacy. Moreover, globally enhanced tumor vessel perfusion could be detected by Doppler ultrasonography before changes in tumor size, which predicted final therapeutic efficacy with more than 90% sensitivity and specificity. Mechanistically, CD8+ T cell depletion, IFN-γ neutralization, or implantation of tumors in IFN-γ receptor knockout mice abrogated the vessel perfusion enhancement and antitumor effects of ICB. These results demonstrated that ICB increased vessel perfusion by promoting CD8+ T cell accumulation and IFN-γ production, indicating that increased vessel perfusion reflects the successful activation of antitumor T cell immunity by ICB. Our findings suggest that vessel perfusion can be used as a novel noninvasive indicator for predicting ICB responsiveness.
Junior doctors lose legal test case over right to have breaks every four hours
Authors: Clare Dyer
Journal: BMJ (2018)

Junior doctors have lost a High Court test case backed by the BMA over their right to have a 30 minute break every four hours or be paid at a higher rate.1

The group of 21 doctors, led by Sarah Hallett, argued that Derby Teaching Hospitals NHS Foundation Trust breached their employment contracts by using an incorrect system to monitor rotas to check whether doctors took their breaks.2

Hallett brought the case on behalf of herself and another 20 doctors training at the trust between August 2013 and August 2014, when she was in her foundation year. She is now a paediatric trainee and deputy chair for education and training of the BMA’s Junior Doctors Committee.

The junior doctors argued that Department …
Eya3 promotes breast tumor–associated immune suppression via threonine phosphatase–mediated PD-L1 upregulation
Authors: Rebecca L. Vartuli, Hengbo Zhou, Lingdi Zhang, Rani K. Powers, Jared Klarquist, Pratyaydipta Rudra, Melanie Y. Vincent, Debashis Ghosh, James C. Costello, Ross M. Kedl, Jill E. Slansky, Rui Zhao, Heide L. Ford
Journal: Journal of Clinical Investigation (2018)

Eya proteins are critical developmental regulators that are highly expressed in embryogenesis but downregulated after development. Amplification and/or re-expression of Eyas occurs in many tumor types. In breast cancer, Eyas regulate tumor progression by acting as transcriptional cofactors and tyrosine phosphatases. Intriguingly, Eyas harbor a separate threonine (Thr) phosphatase activity, which was previously implicated in innate immunity. Here we describe what we believe to be a novel role for Eya3 in mediating triple-negative breast cancer-associated immune suppression. Eya3 loss decreases tumor growth in immune-competent mice and is associated with increased numbers of infiltrated CD8+ T cells, which, when depleted, reverse the effects of Eya3 knockdown. Mechanistically, Eya3 utilizes its Thr phosphatase activity to dephosphorylate Myc at pT58, resulting in a stabilized form. We show that Myc is required for Eya3-mediated increases in PD-L1, and that rescue of PD-L1 in Eya3-knockdown cells restores tumor progression. Finally, we demonstrate that Eya3 significantly correlates with PD-L1 in human breast tumors, and that tumors expressing high levels of Eya3 have a decreased CD8+ T cell signature. Our data uncover a role for Eya3 in mediating tumor-associated immune suppression, and suggest that its inhibition may enhance checkpoint therapies.
Estimation of Future Cancer Burden Among Rescue and Recovery Workers Exposed to the World Trade Center Disaster
Authors: Ankura Singh, Rachel Zeig-Owens, William Moir, Charles B. Hall, Theresa Schwartz, Madeline Vossbrinck, Nadia Jaber, Mayris P. Webber, Kerry J. Kelly, Viola Ortiz, Ellen Koffler, David J. Prezant
Journal: JAMA Oncology (2018)

Elevated rates of cancer have been reported in individuals exposed to the World Trade Center (WTC) disaster, including Fire Department of the City of New York (FDNY) rescue and recovery workers.
Proton pump inhibitors and risk of gastric cancer in a case–control study
Authors: Shih-Wei Lai, Hsueh-Chou Lai, Cheng-Li Lin, Kuan-Fu Liao
Journal: Gut (2018)

We read four manuscripts published in Gut about the relationship between proton pump inhibitors use and gastric cancer.1–4 Proton pump inhibitors are widely used for the management of peptic ulcer disease, gastroesophageal reflux disease and eradication of Helicobacter pylori infection.5 However, its safety for long-term use has raised pubic concern.6 In order to clarify the relationship between proton pump inhibitors use and gastric cancer, we used the 2000–2013 database of Taiwan National Health Insurance Program to conduct a population-based case–control study. The study design and data source were adapted from previous studies.7 8 Subjects aged 20–84 years with newly diagnosed gastric cancer were selected as the cases. Subjects without gastric cancer were randomly selected from the same database as the matched controls. The index date was defined as the date of each case being diagnosed with gastric cancer. Both cases with gastric cancer and matched controls were matched with sex, age (every five years) and the year of index date. In order to reduce the latency bias, subjects whose first-time prescriptions for proton pump …
Modeling HBV infections and immune responses in humanized mouse models
Authors: M. Dusseaux, G. Masse-Ranson, S. Darche, J. Ahodantin, Y. Li, E. Beaumont, P. Moreau, C. Neuveut, P. Soussan, P. Roingeard, D. Kremsdorf, J.D. Santo, H. Strick-Marchand
Journal: Journal of Hepatology (2018)