bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting clinical epigenetic reprogramming for chemoprevention of metabolic and viral hepatocellular carcinoma
Authors: Jühling Frank , Hamdane Nourdine , Crouchet Emilie , Li Shen , El Saghire Houssein , Mukherji Atish , Fujiwara Naoto , Oudot Marine A , Thumann Christine , Saviano Antonio , Roca Suarez Armando Andres , Goto Kaku , Masia Ricard , Sojoodi Mozhdeh , Arora Gunisha , Aikata Hiroshi , Ono Atsushi , Tabrizian Parissa , Schwartz Myron , Polyak Stephen J , Davidson Irwin , Schmidl Christian , Bock Christoph , Schuster Catherine , Chayama Kazuaki , Pessaux Patrick , Tanabe Kenneth K , Hoshida Yujin , Zeisel Mirjam B , Duong François HT , Fuchs Bryan C , Baumert Thomas F 
Published: March 2020

ObjectiveHepatocellular carcinoma (HCC) is the fastest-growing cause of cancer-related mortality with chronic viral hepatitis and non-alcoholic steatohepatitis (NASH) as major aetiologies. Treatment options for HCC are unsatisfactory and chemopreventive approaches are absent. Chronic hepatitis C (CHC) results in epigenetic alterations driving HCC risk and persisting following cure. Here, we aimed to investigate epigenetic modifications as targets for liver cancer chemoprevention.DesignLiver tissues from patients with NASH and CHC were analysed by ChIP-Seq (H3K27ac) and RNA-Seq. The liver disease-specific epigenetic and transcriptional reprogramming in patients was modelled in a liver cell culture system. Perturbation studies combined with a targeted small molecule screen followed by in vivoandex vivovalidation were used to identify chromatin modifiers and readers for HCC chemoprevention.ResultsIn patients, CHC and NASH share similar epigenetic and transcriptomic modifications driving cancer risk. Using a cell-based system modelling epigenetic modifications in patients, we identified chromatin readers as targets to revert liver gene transcription driving clinical HCC risk. Proof-of-concept studies in a NASH-HCC mouse model showed that the pharmacological inhibition of chromatin reader bromodomain 4 inhibited liver disease progression and hepatocarcinogenesis by restoring transcriptional reprogramming of the genes that were epigenetically altered in patients.ConclusionOur results unravel the functional relevance of metabolic and virus-induced epigenetic alterations for pathogenesis of HCC development and identify chromatin readers as targets for chemoprevention in patients with chronic liver diseases.
Population impact of direct-acting antiviral treatment on new presentations of hepatitis C-related decompensated cirrhosis: a national record-linkage study
Authors: Hutchinson Sharon J , Valerio Heather , McDonald Scott A , Yeung Alan , Pollock Kevin , Smith Shanley , Barclay Stephen , Dillon John F , Fox Raymond , Bramley Peter , Fraser Andrew , Kennedy Nicholas , Gunson Rory N , Templeton Kate , Innes Hamish , McLeod Allan , Weir Amanda , Hayes Peter C , Goldberg David 
Published: March 2020

ObjectivePopulation-based studies demonstrating the clinical impact of interferon-free direct-acting antiviral (DAA) therapies are lacking. We examined the impact of the introduction of DAAs on HCV-related decompensated cirrhosis (DC) through analysis of population-based data from Scotland.DesignThrough analysis of national surveillance data (involving linkage of HCV diagnosis and clinical databases to hospital and deaths registers), we determined i) the scale-up in the number of patients treated and achieving a sustained viral response (SVR), and ii) the change in the trend of new presentations with HCV-related DC, with the introduction of DAAs.ResultsApproximately 11 000 patients had been treated in Scotland over the 8-year period 2010/11 to 2017/18. The scale-up in the number of patients achieving SVR between the pre-DAA and DAA eras was 2.3-fold overall and 5.9-fold among those with compensated cirrhosis (the group at immediate risk of developing DC). In the pre-DAA era, the annual number of HCV-related DC presentations increased 4.6-fold between 2000 (30) and 2014 (142). In the DAA era, presentations decreased by 51% to 69 in 2018 (and by 67% among those with chronic infection at presentation), representing a significant change in trend (rate ratio 0.88, 95% CI 0.85 to 0.90). With the introduction of DAAs, an estimated 330 DC cases had been averted during 2015–18.ConclusionsNational scale-up in interferon-free DAA treatment is associated with the rapid downturn in presentations of HCV-related DC at the population-level. Major progress in averting HCV-related DC in the short-term is feasible, and thus other countries should strive to achieve the same.
Lactoferrin-containing immunocomplex mediates antitumor effects by resetting tumor-associated macrophages to M1 phenotype
Authors: Dong Hongliang , Yang Yueyao , Gao Chenhui , Sun Hehe , Wang Hongmin , Hong Chao , Wang Jun , Gong Fangyuan , Gao Xiaoming 
Published: March 2020

BackgroundTumor-associated macrophages (TAMs) resemble M2-polarized cells with potent immunosuppressive activity and play a pivotal role in tumor growth and progression. Converting TAMs to proinflammatory M1-like phenotype is thus an attractive strategy for antitumor immunotherapy.MethodsA mouse IgG1(kappa) monoclonal Ab, M-860, specific to human lactoferrin (LTF) was generated by using the traditional hybridoma cell fusion technology. TAMs were generated by culturing human and mouse CD14+monocytes in tumor-conditioned media containing a cytokine cocktail containing recombinant interleukin-4 (IL-4), interleukin-10 (IL-10) and macrophage colony stimulating factor (M-CSF). TAMs after treatment with immunocomplex (IC) between human LTF and M860 (LTF-IC) were phenotypically and functionally characterized by flow cytometry (FACS), ELISA, Q-PCR and killing assays. The antitumor effects of LTF-IC were further analyzed using in vivo experiments employing tumor-bearing human FcγRIIa-transgenic mouse models.ResultsThrough coligation of membrane-bound CD14 and FcγRIIa, LTF-IC rendered TAMs not only M2 to M1 conversion, evidenced by increased tumor necrosis factor α production, down-regulated M2-specific markers (CD206, arginase-1 and vascular endothelial growth factor) and upregulated M1-specific markers (CD86 and HLA-DR) expression, but also potent tumoricidal activity in vitro. LTF-IC administration conferred antitumor protective efficacy and prolonged animal survival in FcγRIIa-transgenic mice, accompanied by accumulation of M1-like macrophages as well as significantly reduced infiltration of immunosuppressive myeloid-derived suppressor cells and regulatory T cells in solid tumor tissues.ConclusionsLTF-IC is a promising cancer therapeutic agent capable of converting TAMs into tumoricidal M1-like cells.
A new oncolyticVacciniavirusaugments antitumor immune responses to prevent tumor recurrence and metastasis after surgery
Authors: Ahmed Jahangir , Chard Louisa S , Yuan Ming , Wang Jiwei , Howells Anwen , Li Yuenan , Li Haoze , Zhang Zhongxian , Lu Shuangshuang , Gao Dongling , Wang Pengju , Chu Yongchao , Al Yaghchi Chadwan , Schwartz Joel , Alusi Ghassan , Lemoine Nicholas , Wang Yaohe 
Published: March 2020

BackgroundLocal recurrence and remote metastasis are major challenges to overcome in order to improve the survival of patients with cancer after surgery. Oncolytic viruses are a particularly attractive option for prevention of postsurgical disease as they offer a non-toxic treatment option that can directly target residual tumor deposits and beneficially modulate the systemic immune environment that is suppressed post surgery and allows residual disease escape from control. Here, we report that a novelVaccinia virus(VV), VVΔTKΔN1L (with deletion of both thymidine kinase (TK) and N1L genes) armed with interleukin 12 (IL-12), can prolong postoperative survival when used as a neoadjuvant treatment in different murine and hamster surgical models of cancer.MethodsA tumor-targeted replicating VV with deletion of TK gene and N1L gene (VVΔTKΔN1L) was created. This virus was armed rationally with IL-12. The effect of VVΔTKΔN1L and VVΔTKΔN1L-IL12 on modulation of the tumor microenvironment and induction of tumor-specific immunity as well the feasibility and safety as a neoadjuvant agent for preventing recurrence and metastasis after surgery were assessed in several clinically relevant models.ResultsVVΔTKΔN1L can significantly prolong postoperative survival when used as a neoadjuvant treatment in three different surgery-induced metastatic models of cancer. Efficacy was critically dependent on elevation of circulating natural killer cells that was achieved by virus-induced cytokine production from cells infected with N1L-deleted, but not N1L-intact VV. This effect was further enhanced by arming VVΔTKΔN1L with IL-12, a potent antitumor cytokine. Five daily treatments with VVΔTKΔN1L-IL12 before surgery dramatically improved postsurgical survival. VVΔTKΔN1L armed with human IL-12 completely prevented tumor recurrence in surgical models of head and neck cancer in Syrian hamsters.ConclusionsThese data provide a proof of concept for translation of the regime into clinical trials. VVΔTKΔN1L-IL12 is a promising agent for use as an adjuvant to surgical treatment of solid tumors.
Identification and validation of dichotomous immune subtypes based on intratumoral immune cells infiltration in clear cell renal cell carcinoma patients
Authors: Xiong Ying , Wang Zewei , Zhou Quan , Zeng Han , Zhang Hongyu , Liu Zhaopei , Huang Qiuren , Wang Jiajun , Chang Yuan , Xia Yu , Wang Yiwei , Liu Li , Zhu Yu , Xu Le , Dai Bo , Bai Qi , Guo Jianming , Xu Jiejie 
Published: March 2020

BackgroundIncreasing evidence has elucidated the clinical significance of tumor infiltrating immune cells in predicting outcomes and therapeutic efficacy. In this study, we comprehensively analyze the tumor microenvironment (TME) immune cell infiltrations in clear cell renal cell carcinoma (ccRCC) and correlated the infiltration patterns with anti-tumor immunity and clinical outcomes.MethodsWe analyzed immune cell infiltrations in four independent cohorts, including the KIRC cohort of 533 patients, the Zhongshan ccRCC cohorts of 259 patients, the Zhongshan fresh tumor sample cohorts of 20 patients and the Zhongshan metastatic ccRCC cohorts of 87 patients. Intrinsic patterns of immune cell infiltrations were evaluated for associations with clinicopathological characteristics, underlying biological pathways, genetic changes, oncological outcomes and treatment responses.ResultsUnsupervised clustering of tumor infiltrating immune cells identified two microenvironment subtypes, TMEcluster-A and TMEcluster-B. Gene markers and biological pathways referring to immune evasion were upregulated in TMEcluster-B. TMEcluster-B associated with poor overall survival (p<0.001; HR 2.629) and recurrence free survival (p=0.012; HR 1.870) in ccRCC validation cohort. TMEcluster-B cases had worse treatment response (p=0.009), overall survival (p<0.001; HR 2.223) and progression free survival (p=0.015; HR 2.7762) in metastatic ccRCC cohort. The predictive accuracy of International Metastatic Database Consortium risk score was improved after incorporation of TME clusters.ConclusionsTMEcluster-A featured increased mast cells infiltration, prolonged survival and better treatment response. TMEcluster-B was a heavily infiltrated but immunosuppressed phenotype enriched for macrophages, CD4+T cells, Tregs, CD8+T cells and B cells. TMEcluster-B predicted dismal survival and worse treatment response in clear cell renal cell carcinoma patients.
Preclinical PET imaging of bispecific antibody ERY974 targeting CD3 and glypican 3 reveals that tumor uptake correlates to T cell infiltrate
Authors: Waaijer Stijn JH , Giesen Danique , Ishiguro Takahiro , Sano Yuji , Sugaya Naofumi , Schröder Carolina P , de Vries Elisabeth GE , Lub-de Hooge Marjolijn N 
Published: March 2020

BackgroundBispecific antibodies redirecting T cells to the tumor obtain increasing interest as potential cancer immunotherapy. ERY974, a full-length bispecific antibody targeting CD3ε on T cells and glypican 3 (GPC3) on tumors, has been in clinical development However, information on the influence of T cells on biodistribution of bispecific antibodies, like ERY974, is scarce. Here, we report the biodistribution and tumor targeting of zirconium-89 (89Zr) labeled ERY974 in mouse models using immuno-positron emission tomography (PET) imaging.MethodsTo study both the role of GPC3 and CD3 on the biodistribution of [89Zr]Zr-N-suc-Df-ERY974,89Zr-labeled control antibodies targeting CD3 and non-mammalian protein keyhole limpet hemocyanin (KLH) or KLH only were used. GPC3 dependent tumor targeting of [89Zr]Zr-N-suc-Df-ERY974 was tested in xenograft models with different levels of GPC3 expression. In addition, CD3 influence on biodistribution of [89Zr]Zr-N-suc-Df-ERY974 was evaluated by comparing biodistribution between tumor-bearing immunodeficient mice and mice reconstituted with human immune cells using microPET imaging and ex vivo biodistribution. Ex vivo autoradiography was used to study deep tissue distribution.ResultsIn tumor-bearing immunodeficient mice, [89Zr]Zr-N-suc-Df-ERY974 tumor uptake was GPC3 dependent and specific over [89Zr]Zr-N-suc-Df-KLH/CD3 and [89Zr]Zr-N-suc-Df-KLH/KLH. In mice engrafted with human immune cells, [89Zr]Zr-N-suc-Df-ERY974 specific tumor uptake was higher than in immunodeficient mice. Ex vivo autoradiography demonstrated a preferential distribution of [89Zr]Zr-N-suc-Df-ERY974 to T cell rich tumor tissue. Next to tumor, highest specific [89Zr]Zr-N-suc-Df-ERY974 uptake was observed in spleen and lymph nodes.Conclusion[89Zr]Zr-N-suc-Df-ERY974 can potentially be used to study ERY974 biodistribution in patients to support drug development.
Comparison of commonly used solid tumor targeted gene sequencing panels for estimating tumor mutation burden shows analytical and prognostic concordance within the cancer genome atlas cohort
Authors: Bevins Nicholas , Sun Shulei , Gaieb Zied , Thorson John A , Murray Sarah S 
Published: March 2020

BackgroundTumor mutation burden (TMB) is a biomarker frequently reported by clinical laboratories, which is derived by quantifying of the number of single nucleotide or indel variants (mutations) identified by next-generation sequencing of tumors. TMB values can inform prognosis or predict the response of a patient’s tumor to immune checkpoint inhibitor therapy. Methods for the calculation of TMB are not standardized between laboratories, with significant variables being the gene content of the panels sequenced and the inclusion or exclusion of synonymous variants in the calculations. The impact of these methodological differences has not been investigated and the concordance of reported TMB values between laboratories is unknown.MethodsSequence variant lists from more than 9000 tumors of various types were downloaded from The Cancer Genome Atlas. Variant lists were filtered to include only appropriate variant types (ie, non-synonymous only or synonymous and non-synonymous variants) within the genes found in five commonly used targeted solid tumor gene panels as well as an in-house gene panel. Calculated TMB was paired with corresponding overall survival (OS) data of each patient.ResultsRegression analysis indicates high concordance of TMB as derived from the examined panels. TMB derived from panels was consistently and significantly lower than that derived from a whole exome. TMB, as derived from whole exome or the examined panels, showed a significant correlation with OS in the examined data.ConclusionsTMB derived from the examined gene panels was analytically equivalent between panels, but not between panels and whole-exome sequencing. Correlation between TMB and OS is significant if TMB method-specific cut-offs are used. These results suggest that TMB values, as derived from the gene panels examined, are analytically and prognostically equivalent.
Social media use by leading US e-cigarette, cigarette, smokeless tobacco, cigar and hookah brands
Authors: O'Brien Erin Keely , Hoffman Leah , Navarro Mario Antonio , Ganz Ollie 
Published: March 2020

BackgroundYouth and young adults frequently use social media and are susceptible to tobacco use. This study is the first to provide a systematic overview of how leading tobacco product brands use popular social media platforms.MethodsWe identified 112 leading brands of e-cigarettes, hookah, cigars, cigarettes and smokeless tobacco based on sales and self-report user data. We searched for each brand on six platforms: Instagram, Facebook, Twitter, YouTube, Pinterest and Tumblr. In early 2019, we conducted a content analysis of each page, coding: age restrictions, warning display, page characteristics and post characteristics.ResultsCigarette brands were generally not present. Most e-cigarettes, hookah and cigar brands had pages on at least two platforms. One-third of smokeless brands had pages on at least one platform. Few brands had pages on Pinterest and Tumblr. Most pages had existed for 3–5 years. Overall, brand pages rarely used age gating, did not display health warnings, generally posted images of a product alone and often used hashtags unrelated to tobacco. Brands commonly used special features like ephemeral posts on Instagram and pop-up chat windows on Facebook. Many pages displayed images of young people and mentioned flavour. Median followers per brand ranged from about 1 000–10 000, and total followers summed across brands reached over 5 million on Facebook and Instagram alone.ConclusionsLeading brands of most tobacco product types use social media extensively. Several findings identify issues related to youth exposure to and appeal of tobacco social media marketing. Findings can inform tobacco education efforts and regulation.
Criterion-referenced mCAFT cut-points to identify metabolically healthy cardiorespiratory fitness among adults aged 18–69 years: an analysis of the Canadian Health Measures Survey
Authors: Wolfe Phillips Emily , Rao Deepa P. , Kaminsky Leonard A. , Tomkinson Grant R. , Ross Robert , Lang Justin J. 
Published: March 2020

This study aimed to develop and validate health-related criterion-referenced cut-points for the modified Canadian Aerobic Fitness Test (mCAFT), a field-based measure to predict cardiorespiratory fitness among adults (18–69 years). Criterion-referenced mCAFT cut-points were developed using nationally representative data from cycles 1 (2007–2009) and 2 (2009–2011) of the Canadian Health Measures Survey (CHMS). Receiver operating characteristic curves were used to identify age- and sex-specific cut-points for measured waist circumference, blood pressure, and high-density lipoprotein. Cut-points were validated against metabolic syndrome using a fasted subsample (n = 1093) from cycle 5 (2016–2017). For the main analyses, 4967 participants (50% women) were retained. The mCAFT cut-points ranged from 28 to 43 mL·kg–1·min–1 (area under the curve (AUC): 0.60–0.87) among men, and 23 to 37 mL·kg–1·min–1 (AUC: 0.61–0.86) among women. The likelihood of meeting the new mCAFT cut-points decreased with an increase in the presence of metabolic risk factors. In total, 54% (95% confidence interval: 42% to 67%) of Canadian adults met the new mCAFT cut-points in 2016–2017. This study developed and validated the first health-related criterion-referenced mCAFT cut-points for metabolic health among Canadian adults aged 18–69 years. These mCAFT cut-points may be useful in health surveillance, clinical, and public health settings. Novelty We developed and validated new criterion-referenced cut-points for the mCAFT to help identify adults at potential risk of poor metabolic health. These new cut-points could help support national health surveillance efforts.
Heat kernel coefficients on the sphere in any dimension
Authors: Kluth Yannick , Litim Daniel F. 
Published: March 2020

AbstractWe derive all heat kernel coefficients for Laplacians acting on scalars, vectors, and tensors on fully symmetric spaces, in any dimension. Final expressions are easy to evaluate and implement, and confirmed independently using spectral sums and the Euler–Maclaurin formula. We also obtain the Green’s function for Laplacians acting on transverse traceless tensors in any dimension, and new integral representations for heat kernels using known eigenvalue spectra of Laplacians. Applications to quantum gravity and the functional renormalisation group, and other, are indicated.
On the resonances near the continua boundaries of the Dirac equation with a short-range interaction
Authors: Krylov K. S. , Mur V. D. , Fedotov A. M. 
Published: March 2020

AbstractUsing the model of a deep spherically symmetric rectangular well as an example, it is shown that resonant scattering near the boundaries of the lower or upper Dirac continua cannot serve as evidence in favor of spontaneous electron-positron pair production in a supercritical domain.
Hyper-Scalable JSQ with Sparse Feedback
Authors: van der Boor Mark , Borst Sem , van Leeuwaarden Johan 
Published: March 2020

Load balancing algorithms play a vital role in enhancing performance in data centers and cloud networks. Due to the massive size of these systems, scalability challenges, and especially the communication overhead associated with load balancing mechanisms, have emerged as major concerns. Motivated by these issues, we introduce and analyze a novel class of load balancing schemes where the various servers provide occasional queue updates to guide the load assignment.
We show that the proposed schemes strongly outperform JSQ( d ) strategies with comparable communication overhead per job, and can achieve a vanishing waiting time in the many-server limit with just one message per job, just like the popular JIQ scheme. The proposed schemes are particularly geared however towards the sparse feedback regime with less than one message per job, where they outperform corresponding sparsified JIQ versions.
We investigate fluid limits for synchronous updates as well as asynchronous exponential update intervals. The fixed point of the fluid limit is identified in the latter case, and used to derive the queue length distribution. We also demonstrate that in the ultra-low feedback regime the mean stationary waiting time tends to a constant in the synchronous case, but grows without bound in the asynchronous case.