bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of preterm birth on brain development and long-term outcome: protocol for a cohort study in Scotland
Authors: Boardman James P , Hall Jill , Thrippleton Michael J , Reynolds Rebecca M , Bogaert Debby , Davidson Donald J , Schwarze Jurgen , Drake Amanda J , Chandran Siddharthan , Bastin Mark E , Fletcher-Watson Sue 
Published: March 2020

IntroductionPreterm birth is closely associated with altered brain development and is a leading cause of neurodevelopmental, cognitive and behavioural impairments across the life course. We aimed to investigate neuroanatomic variation and adverse outcomes associated with preterm birth by studying a cohort of preterm infants and controls born at term using brain MRI linked to biosamples and clinical, environmental and neuropsychological data.Methods and analysisTheirworld Edinburgh Birth Cohort is a prospective longitudinal cohort study at the University of Edinburgh. We plan to recruit 300 infants born at <33 weeks of gestational age (GA) and 100 healthy control infants born after 37 weeks of GA. Multiple domains are assessed: maternal and infant clinical and demographic information; placental histology; immunoregulatory and trophic proteins in umbilical cord and neonatal blood; brain macrostructure and microstructure from structural and diffusion MRI (dMRI); DNA methylation; hypothalamic–pituitary–adrenal axis activity; social cognition, attention and processing speed from eye tracking during infancy and childhood; neurodevelopment; gut and respiratory microbiota; susceptibility to viral infections; and participant experience. Main analyses include creation of novel methods for extracting information from neonatal structural and dMRI, regression analyses of predictors of brain maldevelopment and neurocognitive outcome associated with preterm birth, and determination of the quantitative predictive performance of MRI and other early life factors for childhood outcome.Ethics and disseminationEthical approval has been obtained from the National Research Ethics Service (NRES), South East Scotland Research Ethics Committee (NRES numbers 11/55/0061 and 13/SS/0143 (phase I) and 16/SS/0154 (phase II)), and NHS Lothian Research and Development (2016/0255). Results are disseminated through open access journals, scientific meetings, social media, newsletters anda study website (www.tebc.ed.ac.uk), and we engage with the University of Edinburgh public relations and media office to ensure maximum publicity and benefit.
Associations between earplug use and hearing loss in ROK military personnel
Authors: Kim Hwi Jun , Oh S Y , Won S Y , Kim H J , Kim T K , Ko B C , Woo S Y , Park E-C 
Published: March 2020

IntroductionThe easiest way to prevent noise-induced hearing loss (NIHL) is to wear earplugs. The Republic of Korea (ROK) Ministry of National Defense (MND) is supplying earplugs to prevent NIHL, but many patients still suffer from this. We speculated that earplugs would have a high NIHL rate, depending on the rate of use of earplugs, regardless of the rate of supply. Therefore, we conducted this study to investigate the relationship between the use of earplugs and hearing loss by ROK military personnel.MethodsThe study used data from the Military Health Survey conducted in 2014–2015, which included 13 470 questionnaires completed by ROK military personnel. Hearing loss and earplug use were self-reported. Logistic regression analysis was used to assess associations between earplug use and hearing loss.ResultsThe study sample included 13 470 ROK military personnel (response rate of 71.2%) (Army, 8330 (61.8%); Navy/Marines, 2236 (16.6%); and Air Force, 2904 (21.6%)). Overall, 18.8% of Korean military personnel reported that they always wore earplugs, and 2.8% reported hearing loss. In logistic regression analysis, there were significant differences in the rates of hearing loss associated with wearing earplugs sometimes (OR=1.48, 95% CI 1.07 to 2.05) and never wearing earplugs (OR=1.53, 95% CI 1.12 to 2.10). In subgroup analysis, in Air Force, non-combat branch, forward area and long-term military service personnel increased hearing loss was associated with not wearing earplugs.ConclusionOur study confirmed that within the ROK military, there is an association between hearing loss and lack of earplug use. In the ROK MND, Army, Navy/Marines and Air Force headquarters must provide guidelines for the use of earplugs during field training to protect military personnel’s hearings and, if necessary, need to be regulated or institutionalised.
Body mass index trajectories among the Canadian workforce and their association with work environment trajectories over 17 years
Authors: Dobson Kathleen G , Gilbert-Ouimet Mahée , Mustard Cameron , Smith Peter M 
Published: March 2020

ObjectiveTo determine the number of latent body mass index (BMI) trajectories from 1994 to 2010 among working Canadians and their association with concurrent trajectories in work environment exposures.MethodsData of employed individuals from the longitudinal CanadianNational Population Health Surveywere used. Group-based trajectory modelling was used to determine the number of latent BMI trajectories and concurrent psychosocial work environment trajectories. A multinomial logistic regression of BMI trajectory membership on trajectories in work environment dimensions (skill discretion, decision latitude, psychological demands, job insecurity, social support, physical exertion) was then explored.ResultsFour latent BMI trajectories corresponding to normal, overweight, obese and very obese BMI values were found. Each trajectory saw an increase in BMI (~2–4 kg/m2) over the 17-year period. A higher decision authority trajectory was associated with lower odds of belonging to the overweight and obese trajectories when compared with the normal weight trajectory. A decreasing physical exertion trajectory was associated with higher odds of belonging to the very obese trajectory when compared with the normal weight trajectory.ConclusionsFour BMI trajectories are present in the Canadian workforce; all trajectories saw increased body weight over time. Declining physical exertion and lower decision authority in the work environment over time is associated with increased likelihood of being in overweight and obese trajectories.
Leading two-loop corrections to the Higgs boson self-couplings in models with extended scalar sectors
Authors: Braathen Johannes , Kanemura Shinya 
Published: March 2020

AbstractWe compute the dominant two-loop corrections to the Higgs trilinear coupling $$\lambda _{hhh}$$λhhh and to the Higgs quartic coupling $$\lambda _{hhhh}$$λhhhh in models with extended Higgs sectors, using the effective-potential approximation. We provide in this paper all necessary details about our calculations, and present general $$\overline{{\mathrm{MS}}}$$MS¯ expressions for derivatives of the integrals appearing in the effective potential at two loops. We also consider three particular Beyond-the-Standard-Model (BSM) scenarios – namely a typical scenario of an Inert Doublet Model (IDM), and scenarios of a Two-Higgs-Doublet Model (2HDM) and of a Higgs Singlet Model (HSM) without scalar mixing – and we include all the necessary finite counterterms to obtain (in addition to $$\overline{{\mathrm{MS}}}$$MS¯ results) on-shell scheme expressions for the corrections to the Higgs self-couplings. With these analytic results, we investigate the possible magnitude of two-loop BSM contributions to the Higgs self-couplings and the fate of the non-decoupling effects that are known to appear at one loop. We find that, at least as long as pertubative unitarity conditions are fulfilled, the size of two-loop corrections remains well below that of one-loop corrections. Typically, two-loop contributions to $$\lambda _{hhh}$$λhhh amount to approximately 20% of those at one loop, implying that the non-decoupling effects observed at one loop are not significantly modified, but also meaning that higher-order corrections need to be taken into account for the future perspective of precise measurements of the Higgs trilinear coupling.
Study of the magnetic properties and magnetocaloric effects in (Ho0.85RE0.15)3Pd2 (RE=Y and Gd) compounds
Authors: Wu X. F. , Guo C. , Du Y. S. , Wang J. , Ma L. , Rao G. H. , Du Z. 
Published: March 2020

The crystal structure, magnetic and magnetocaloric properties of the [Formula: see text] (RE=Y and Gd) compounds were investigated. Both of the compounds crystallize in a single phase with a tetragonal [Formula: see text]-type structure (space group [Formula: see text]/mbm) and undergo a second-order transition from ferromagnetic (FM) state to paramagnetic (PM) state. In the PM region, the reciprocal susceptibilities both obey the Curie–Weiss law. The paramagnetic Curie temperatures [Formula: see text] for [Formula: see text] and [Formula: see text] were determined to be 4.9 K and 3.2 K, and the corresponding effective magnetic moments [Formula: see text] are 10.3 [Formula: see text]/RE and 10.5 [Formula: see text]/RE, respectively. Under a field change from 0 T to 5 T, the maximum values of [Formula: see text] for the [Formula: see text] and [Formula: see text] compounds are determined to be [Formula: see text] and [Formula: see text], with the corresponding RC values of [Formula: see text] and [Formula: see text], respectively.
Targeting Glycosylated PD-1 Induces Potent Antitumor Immunity
Authors: Sun Linlin , Li Chia-Wei , Chung Ezra M. , Yang Riyao , Kim Yong-Soo , Park Andrew H. , Lai Yun-Ju , Yang Yi , Wang Yu-Han , Liu Jielin , Qiu Yufan , Khoo Kay-Hooi , Yao Jun , Hsu Jennifer L. , Cha Jong-Ho , Chan Li-Chuan , Hsu Jung-Mao , Lee Heng-Huan , Yoo Stephen S. , Hung Mien-Chie 
Published: March 2020

Abstract

Immunotherapies targeting programmed cell death protein 1 (PD-1) and programmed cell death 1 ligand 1 (PD-L1) immune checkpoints represent a major breakthrough in cancer treatment. PD-1 is an inhibitory receptor expressed on the surface of activated T cells that dampens T-cell receptor (TCR)/CD28 signaling by engaging with its ligand PD-L1 expressed on cancer cells. Despite the clinical success of PD-1 blockade using mAbs, most patients do not respond to the treatment, and the underlying regulatory mechanisms of PD-1 remain incompletely defined. Here we show that PD-1 is extensively N-glycosylated in T cells and the intensities of its specific glycoforms are altered upon TCR activation. Glycosylation was critical for maintaining PD-1 protein stability and cell surface localization. Glycosylation of PD-1, especially at the N58 site, was essential for mediating its interaction with PD-L1. The mAb STM418 specifically targeted glycosylated PD-1, exhibiting higher binding affinity to PD-1 than FDA-approved PD-1 antibodies, potently inhibiting PD-L1/PD-1 binding, and enhancing antitumor immunity. Together, these findings provide novel insights into the functional significance of PD-1 glycosylation and offer a rationale for targeting glycosylated PD-1 as a potential strategy for immunotherapy.

Significance:
These findings demonstrate that glycosylation of PD-1 is functionally significant and targeting glycosylated PD-1 may serve as a means to improve immunotherapy response.
ICOS Is an Indicator of T-cell–Mediated Response to Cancer Immunotherapy
Authors: Xiao Zunyu , Mayer Aaron T. , Nobashi Tomomi W. , Gambhir Sanjiv S. 
Published: March 2020

Abstract

Immunotherapy is innovating clinical cancer management. Nevertheless, only a small fraction of patient's benefit from current immunotherapies. To improve clinical management of cancer immunotherapy, it is critical to develop strategies for response monitoring and prediction. In this study, we describe inducible T-cell costimulator (ICOS) as a conserved mediator of immune response across multiple therapy strategies. ICOS expression was evaluated by flow cytometry, 89Zr-DFO-ICOS mAb PET/CT imaging was performed on Lewis lung cancer models treated with different immunotherapy strategies, and the change in tumor volume was used as a read-out for therapeutic response. ImmunoPET imaging of ICOS enabled sensitive and specific detection of activated T cells and early benchmarking of immune response. A STING (stimulator of interferon genes) agonist was identified as a promising therapeutic approach in this manner. The STING agonist generated significantly stronger immune responses as measured by ICOS ImmunoPET and delayed tumor growth compared with programmed death-1 checkpoint blockade. More importantly, ICOS ImmunoPET enabled early and robust prediction of therapeutic response across multiple treatment regimens. These data show that ICOS is an indicator of T-cell–mediated immune response and suggests ICOS ImmunoPET as a promising strategy for monitoring, comparing, and predicting immunotherapy success in cancer.

Significance:
ICOS ImmunoPET is a promising strategy to noninvasively predict and monitor immunotherapy response.
See related commentary by Choyke, p. 2975
RUNX1 Is a Driver of Renal Cell Carcinoma Correlating with Clinical Outcome
Authors: Rooney Nicholas , Mason Susan M. , McDonald Laura , Däbritz J. Henry M. , Campbell Kirsteen J. , Hedley Ann , Howard Steven , Athineos Dimitris , Nixon Colin , Clark William , Leach Joshua D.G. , Sansom Owen J. , Edwards Joanne , Cameron Ewan R. , Blyth Karen 
Published: March 2020

AbstractThe recurring association of specific genetic lesions with particular types of cancer is a fascinating and largely unexplained area of cancer biology. This is particularly true of clear cell renal cell carcinoma (ccRCC) where, although key mutations such as loss of VHL is an almost ubiquitous finding, there remains a conspicuous lack of targetable genetic drivers. In this study, we have identified a previously unknown protumorigenic role for the RUNX genes in this disease setting. Analysis of patient tumor biopsies together with loss-of-function studies in preclinical models established the importance of RUNX1 and RUNX2 in ccRCC. Patients with high RUNX1 (and RUNX2) expression exhibited significantly poorer clinical survival compared with patients with low expression. This was functionally relevant, as deletion of RUNX1 in ccRCC cell lines reduced tumor cell growth and viability in vitro and in vivo. Transcriptional profiling of RUNX1-CRISPR–deleted cells revealed a gene signature dominated by extracellular matrix remodeling, notably affecting STMN3, SERPINH1, and EPHRIN signaling. Finally, RUNX1 deletion in a genetic mouse model of kidney cancer improved overall survival and reduced tumor cell proliferation. In summary, these data attest to the validity of targeting a RUNX1-transcriptional program in ccRCC.Significance:These data reveal a novel unexplored oncogenic role for RUNX genes in kidney cancer and indicate that targeting the effects of RUNX transcriptional activity could be relevant for clinical intervention in ccRCC.
Evaluation of p16/Ki-67 Dual-Stained Cytology in Triaging HPV-Positive Women during Cervical Cancer Screening
Authors: Hu Yuan , Hong Zubei , Gu Liying , Xie Li , Yang Binlie , Dai Haiyan , Chen Hua , Zhang Baohua , Huang Lixia , Liu Zhou , Cheng Jingxin , Zhang Yu , Zhang Yu , Lin Jianhua , Qiu Lihua , Di Wen 
Published: March 2020

Abstract

Background:
We aimed to evaluate the utility of p16/Ki-67 dual-stained cytology for triaging human papillomavirus (HPV)-positive women.

Methods:
HPV-positive women ages ≥ 21 years were recruited in a multicenter prospective observational study between May 2016 and May 2017. The clinical performance of dual-stained cytology, with or without HPV16/18 genotyping, was evaluated for all HPV-positive women to detect cervical intraepithelial neoplasia grade 2 or worse (CIN2+).

Results:
846 HPV-positive women ages ≥ 21 years with valid cervical biopsies were enrolled for this study. For CIN2+ detection, dual-stained cytology showed statistically higher specificity (85.28%) than Pap cytology (80.00%, P &lt; 0.001) and HPV16/18 genotyping (72.36%, P &lt; 0.001), while the sensitivity of dual-stained cytology (63.49%) remained comparable with that of Pap cytology (61.90%, P = 0.832) and HPV16/18 genotyping (61.90%, P = 0.897). HPV16/18 genotyping in combination with dual-stained cytology was more specific (62.50% vs. 58.06%, P &lt; 0.001), while it showed similar sensitivity (86.51% vs. 85.71%, P = 1.000), as compared with HPV16/18 genotyping in combination with Pap cytology. Similar patterns were also observed for CIN3+.

Conclusions:
p16/Ki-67 dual-stained cytology, either alone or in combination with HPV16/18 genotyping, showed a good stratification with high specificity and comparable sensitivity for HPV-positive women.

Impact:
This is one of the few studies that has evaluated the performance of dual-stained cytology for triaging HPV-positive women in China. The higher specificity and comparable sensitivity of dual-stained cytology in comparison with Pap cytology in the detection of CIN2+ or CIN3+ is of vital importance to developing countries, where Pap cytology faces many challenges.
Phase Ib Study of Tirabrutinib in Combination with Idelalisib or Entospletinib in Previously Treated Chronic Lymphocytic Leukemia
Authors: Danilov Alexey V. , Herbaux Charles , Walter Harriet S. , Hillmen Peter , Rule Simon A. , Kio Ebenezer A. , Karlin Lionel , Dyer Martin J.S. , Mitra Siddhartha S. , Yi Ping Cheng , Humeniuk Rita , Huang Xi , Zhou Ziqian , Bhargava Pankaj , Jürgensmeier Juliane M. , Fegan Christopher D. 
Published: March 2020

Abstract

Purpose:
Bruton tyrosine kinase (BTK) inhibition alone leads to incomplete responses in chronic lymphocytic leukemia (CLL). Combination therapy may reduce activation of escape pathways and deepen responses. This open-label, phase Ib, sequential dose-escalation and dose-expansion study evaluated the safety, tolerability, pharmacokinetics, and preliminary efficacy of the selective BTK inhibitor tirabrutinib alone, in combination with the PI3K delta (PI3Kδ) inhibitor idelalisib, or with the spleen tyrosine kinase (SYK) inhibitor entospletinib in patients with relapsed/refractory CLL.

Patients and Methods:
Patients received either tirabrutinib monotherapy (80 mg every day) or tirabrutinib 20–150 mg every day in combination with either idelalisib (50 mg twice a day or 100 mg every day) or entospletinib (200 mg or 400 mg every day).

Results:
Fifty-three patients were included. Systemic tirabrutinib exposure was comparable between monotherapy and combination therapy. No MTD was identified. Across all treatment groups, the most common adverse event was diarrhea (43%, 1 patient grade ≥3); discontinuation due to adverse events was uncommon (13%). Objective response rates were 83%, 93%, and 100%, and complete responses were 7%, 7%, and 10% in patients receiving tirabrutinib, tirabrutinib/idelalisib, and tirabrutinib/entospletinib, respectively. As of February 21, 2019, 46 of 53 patients continue to receive treatment on study.

Conclusions:
Tirabrutinib in combination with idelalisib or entospletinib was well tolerated in patients with CLL, establishing an acceptable safety profile for concurrent selective inhibition of BTK with either PI3Kδ or SYK. This small study did not establish a superior efficacy of the combinations over tirabrutinib alone. This trial is registered at www.clinicaltrials.gov (NCT02457598).
GATA6 Expression Distinguishes Classical and Basal-like Subtypes in Advanced Pancreatic Cancer
Authors: O’Kane Grainne M. , Grünwald Barbara T. , Jang Gun-Ho , Masoomian Mehdi , Picardo Sarah , Grant Robert C. , Denroche Robert E. , Zhang Amy , Wang Yifan , Miller Jessica K. , Lam Bernard , Krzyzanowski Paul M. , Lungu Ilinca M. , Bartlett John M.S. , Peralta Melanie , Vyas Foram , Khokha Rama , Biagi James , Chadwick Dianne , Ramotar Stephanie , Hutchinson Shawn , Dodd Anna , Wilson Julie M. , Notta Faiyaz , Zogopoulos George , Gallinger Steven , Knox Jennifer J. , Fischer Sandra E. 
Published: March 2020

AbstractPurpose:To determine the impact of basal-like and classical subtypes in advanced pancreatic ductal adenocarcinoma (PDAC) and to explore GATA6 expression as a surrogate biomarker.Experimental Design:Within the COMPASS trial, patients proceeding to chemotherapy for advanced PDAC undergo tumor biopsy for RNA-sequencing (RNA-seq). Overall response rate (ORR) and overall survival (OS) were stratified by subtypes and according to chemotherapy received. Correlation of GATA6 with the subtypes using gene expression profiling, in situ hybridization (ISH) was explored.Results:Between December 2015 and May 2019, 195 patients (95%) had enough tissue for RNA-seq; 39 (20%) were classified as basal-like and 156 (80%) as classical. RECIST response data were available for 157 patients; 29 basal-like and 128 classical where the ORR was 10% versus 33%, respectively (P = 0.02). In patients with basal-like tumors treated with modified FOLFIRINOX (n = 22), the progression rate was 60% compared with 15% in classical PDAC (P = 0.0002). Median OS in the intention-to-treat population (n = 195) was 9.3 months for classical versus 5.9 months for basal-like PDAC (HR, 0.47; 95% confidence interval, 0.32–0.69; P = 0.0001). GATA6 expression by RNA-seq highly correlated with the classifier (P &lt; 0.001) and ISH predicted the subtypes with sensitivity of 89% and specificity of 83%. In a multivariate analysis, GATA6 expression was prognostic (P = 0.02). In exploratory analyses, basal-like tumors, could be identified by keratin 5, were more hypoxic and enriched for a T-cell–inflamed gene expression signature.Conclusions:The basal-like subtype is chemoresistant and can be distinguished from classical PDAC by GATA6 expression.See related commentary by Collisson, p. 4715
Inhibition of Importin β1 Augments the Anticancer Effect of Agonistic Anti-Death Receptor 5 Antibody in TRAIL-resistant Tumor Cells
Authors: Kojima Yuko , Nishina Takashi , Nakano Hiroyasu , Okumura Ko , Takeda Kazuyoshi 
Published: March 2020

Abstract
TNF-related apoptosis-inducing ligand (TRAIL) and an agonistic antibody against the death-inducing TRAIL receptor 5, DR5, are thought to selectively induce tumor cell death and therefore, have gained attention as potential therapeutics currently under investigation in several clinical trials. However, some tumor cells are resistant to TRAIL/DR5–induced cell death, even though they express DR5. Previously, we reported that DR5 is transported into the nucleus by importin β1, and knockdown of importin β1 upregulates cell surface expression of DR5 resulting in increased TRAIL sensitivity in vitro. Here, we examined the impact of importin β1 knockdown on agonistic anti-human DR5 (hDR5) antibody therapy. Drug-inducible importin β1 knockdown sensitizes HeLa cells to TRAIL-induced cell death in vitro, and exerts an antitumor effect when combined with agonistic anti-hDR5 antibody administration in vivo. Therapeutic importin β1 knockdown, administered via the atelocollagen delivery system, as well as treatment with the importin β inhibitor, importazole, induced regression and/or eradication of two human TRAIL-resistant tumor cells when combined with agonistic anti-hDR5 antibody treatment. Thus, these findings suggest that the inhibition of importin β1 would be useful to improve the therapeutic effects of agonistic anti-hDR5 antibody against TRAIL-resistant cancers.