bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sex differences in prevalence, treatment and control of cardiovascular risk factors in England
Authors: Pinho-Gomes Ana Catarina , Peters Sanne A E , Thomson Blake , Woodward Mark 
Published: September 2020

ObjectiveTo investigate sex differences in prevalence, treatment and control of major cardiovascular risk factors in England.MethodsData from the Health Survey for England 2012–2017 on non-institutionalised English adults (aged ≥16 years) were used to investigate sex differences in prevalence, treatment and control of major cardiovascular risk factors: body mass index, smoking, systolic blood pressure and hypertension, diabetes, and cholesterol and dyslipidaemia. Physical activity and diet were not assessed in this study.ResultsOverall, 49 415 adults (51% women) were included. Sex differences persisted in prevalence of cardiovascular risk factors, with smoking, hypertension, overweight and dyslipidaemia remaining more common in men than in women in 2017. The proportion of individuals with neither hypertension, dyslipidaemia, diabetes nor smoking increased from 32% to 36% in women and from 28% to 29% in men between 2012 and 2017. Treatment and control of hypertension and diabetes improved over time and were comparable in both sexes in 2017 (66% and 51% for treatment and control of hypertension and 73% and 20% for treatment and control of diabetes). However, women were less likely than men to have treated and controlled dyslipidaemia (21% vs 28% for treatment and 15% vs 24% for control, for women versus men in 2017).ConclusionsImportant sex differences persist in cardiovascular risk factors in England, with an overall higher number of risk factors in men than in women. A combination of public health policy and individually tailored interventions is required to further reduce the burden of cardiovascular disease in England.
Guide to using antibiotics in pet birds
Authors: Baldrey Vicki 
Published: September 2020

BackgroundPet birds are increasingly presented for veterinary treatment. The limited range of licensed antibiotics available for treating avian species, alongside having to comply with additional legislation relating to use of veterinary medicines in food‐producing species, means that treating bacterial infections in pet birds can be challenging. Additionally, antimicrobial resistance is a significant public health issue and so responsible use of antibiotics by the veterinary profession is of vital importance.Aim of the articleThis article outlines the issues affecting antibiotic choice in avian species, the relevant legislation and discusses the approach to antibiotic use for common conditions in avian species.
Update on feline infectious peritonitis
Authors: Barker Emi , Tasker Séverine 
Published: September 2020

BackgroundFeline coronavirus (FCoV) infection in cats is common, usually only causing mild intestinal signs, such as diarrhoea. It is highly infectious and found worldwide. A sequela of FCoV infection, feline infectious peritonitis (FIP), is a common cause of death in young cats, occurring in up to 10 per cent of cats infected with FCoV. Although suspicion of FIP is frequent in sick, particularly young, cats, obtaining a definitive diagnosis using non‐ or minimally‐invasive approaches is difficult.Aim of the articleThis article provides an update regarding diagnosing cases of FIP and guidance on current treatment recommendations.
Tobacco use and access among 13 to 15 year olds in Kuna Yala, an indigenous region of Panama
Authors: Quintana Hedley , Roa Reina 
Published: September 2020

BackgroundPanama has the lowest overall prevalence of tobacco use in the Americas, however rates are almost three times higher in the indigenous territory of Kuna Yala compared with the national average. Most people who smoke started during adolescence, making this a key period for tobacco control efforts.ObjectiveWe aimed to examine tobacco access and use among adolescents (13 to 15 years old) in Kuna Yala compared with nationwide Panama using data from the 2017 Global Youth Tobacco Survey, a standardised international tool for assessing key tobacco control indicators among adolescents.ResultsThe prevalence of current tobacco use among 13 to 15 year olds in Kuna Yala was 14.0% (95% CI: 11.6% to 16.9%)—almost twice the national average of 7.8% (95% CI: 6.3% to 9.4%). Half of all adolescents in Kuna Yala estimated the cost of a 20-cigarette pack as less than US$0.75, compared with 16.2% of adolescents across of Panama (p value <0.01).ConclusionsKuna Yala is one of the few indigenous territories in Spanish-speaking countries where key tobacco control indicators have recently been assessed. Higher tobacco use and lower reported cigarette prices in that region may be linked with the presence of barter economy which may give adolescents more ready access to cigarettes than in other parts of Panama. There is a need for more indigenous-specific data to help build the evidence base to improve tobacco control and reduce commercial tobacco use among indigenous peoples.
Stop search in SUSY SO(10) GUTs with nonuniversal Gaugino masses
Authors: Altın Zafer , Kırca Zerrin , Tanımak Tug̃çe , Salih Ün Cem 
Published: September 2020

AbstractWe explore the stop mass and its possible probe through a set of three different signal processes within a class of SUSY GUTs with non-universal gaugino masses. The stop mass can be realized in a wide range (0.4–8 TeV) consistent with the current experimental constraints. We consider the decay processes;$$\tilde{t}_{1}\rightarrow t\tilde{\chi }_{1}^{0}$$t~1→tχ~10,$$\tilde{t}_{1}\rightarrow b W^{\pm }\tilde{\chi }_{1}^{0}$$t~1→bW±χ~10and$$\tilde{t}_{1}\rightarrow b q{\bar{q}}^{\prime }\tilde{\chi }_{1}^{0}$$t~1→bqq¯′χ~10to be possible signals, and explore the impact of the current experimental results as well as the possible mass scales of stop, which can be probed in the future collider experiments. We find that the first and third signal processes can be tested in the current experiments, and significantly probed in future, while the second signal process is not available for the current experiments in this class of SUSY GUTs. We also comment that the second signal process can be available to be tested when the collider experiments are conducted at high center of mass energies and luminosity.
Revealing Every Story of Data in Blockchain Systems
Authors: Ruan Pingcheng , Anh Dinh Tien Tuan , Lin Qian , Zhang Meihui , Chen Gang , Chin Ooi Beng 
Published: September 2020

The success of Bitcoin and other cryptocurrencies bring enormous interest to blockchains. A blockchain system implements a tamper-evident ledger for recording transactions that modify some global states. The system captures the entire evolution history of the states. The management of that history, also known as data provenance or lineage, has been studied extensively in database systems. However, querying data history in existing blockchains can only be done by replaying all transactions. This approach is feasible for large-scale, offline analysis, but is not suitable for online transaction processing.
We present LineageChain, a fine-grained, secure, and efficient provenance system for blockchains. LineageChain exposes provenance information to smart contracts via simple interfaces, thereby enabling a new class of blockchain applications whose execution logics depend on provenance information at runtime. LineageChain captures provenance during contract execution and stores it in a Merkle tree. LineageChain provides a novel skip list index that supports efficient provenance queries. We have implemented LineageChain on top of Hyperledger Fabric and a blockchainoptimized storage system called ForkBase. We conduct extensive evaluation, demonstrating benefits of LineageChain, its efficient querying, and its small storage overhead.
Safety and Clinical Activity of MEDI1873, a Novel GITR Agonist, in Advanced Solid Tumors
Authors: Balmanoukian Ani S. , Infante Jeffrey R. , Aljumaily Raid , Naing Aung , Chintakuntlawar Ashish V. , Rizvi Naiyer A. , Ross Helen J. , Gordon Michael , Mallinder Philip R. , Elgeioushi Nairouz , González-García Ignacio , Standifer Nathan , Cann Jennifer , Durham Nicholas , Rahimian Shahram , Kumar Rakesh , Denlinger Crystal S. 
Published: September 2020

Abstract

Purpose:
The safety and preliminary efficacy of MEDI1873, an agonistic IgG1 fusion protein targeting glucocorticoid-induced TNF receptor–related protein (GITR), were evaluated in an open-label, first-in-human, phase I, dose escalation study in previously treated patients with advanced solid tumors.

Patients and Methods:
Two single-patient cohorts at 1.5 and 3 mg i.v. were followed by 3+3 dose escalation in six cohorts at 7.5, 25, 75, 250, 500, and 750 mg, all every 2 weeks, for up to 52 weeks. Primary endpoints were safety and tolerability, dose-limiting toxicities (DLT), and MTD. Secondary endpoints included antitumor activity, pharmacokinetics, immunogenicity, and pharmacodynamics.

Results:
Forty patients received MEDI1873. Three experienced DLTs: grade 3 worsening tumor pain (250 mg); grade 3 nausea, vomiting, and headache (500 mg); and grade 3 non-ST segment elevation myocardial infarction (750 mg). An MTD was not reached and treatment was well tolerated up to 500 mg. Most common treatment-related adverse events were headache (25%), infusion-related reaction (17.5%), and decreased appetite (17.5%). MEDI1873 exposure was dose proportional. Antidrug–antibody incidence was low. MEDI1873 increased peripheral CD4+ effector memory T-cell proliferation as well as cytokines associated with effector T-cell activation at dose levels ≥75 mg. The best response was stable disease (SD) in 17 patients (42.5%), including 1 unconfirmed partial response. Eight patients (20.0%) had SD ≥24 weeks.

Conclusions:
MEDI1873 showed acceptable safety up to 500 mg i.v. every 2 weeks with pharmacodynamics activity, and prolonged SD in some patients. However, further development is not planned because of lack of demonstrated tumor response.
Phase Ib Study of Ribociclib plus Fulvestrant and Ribociclib plus Fulvestrant plus PI3K Inhibitor (Alpelisib or Buparlisib) for HR+ Advanced Breast Cancer
Authors: Tolaney Sara M. , Im Young-Hyuck , Calvo Emiliano , Lu Yen-Shen , Hamilton Erika , Forero-Torres Andres , Bachelot Thomas , Maur Michela , Fasolo Angelica , Tiedt Ralph , Nardi Lisa , Stammberger Uz , Abdelhady Ahmed M. , Ruan Shiling , Lee Soo Chin 
Published: September 2020

Abstract

Purpose:
Resistance to treatment with endocrine therapy in patients with HR+, HER2− advanced breast cancer (ABC) is common and dual inhibition of CDK4/6 and PI3K pathways may delay the development of resistance. This phase Ib trial evaluates the safety and tolerability of triple and double regimens containing the CDK4/6 inhibitor ribociclib.

Patients and Methods:
In this open-label, multicenter, phase Ib study, 70 postmenopausal women with HR+, HER2− ABC were enrolled into one of four treatment combinations: ribociclib (once daily, 3 weeks on, 1 week off) plus fulvestrant; ribociclib (continuous dosing) plus fulvestrant; ribociclib plus alpelisib plus fulvestrant; or ribociclib plus buparlisib plus fulvestrant.

Results:
The recommended phase II dose (RP2D) of ribociclib was confirmed to be 600 mg (3 weeks on, 1 week off) and 400 mg (continuous dosing) plus fulvestrant 500 mg. For the triple combination with buparlisib, the RP2D was ribociclib 400 mg plus buparlisib 30 mg plus fulvestrant 500 mg. Enrollment for the triple combinations was stopped due to unexpected toxicity. No RP2D was determined for the alpelisib combination. The safety profiles of the ribociclib plus fulvestrant combinations were consistent with those in previous studies. There was no marked difference in ribociclib exposure in the presence of triple-combination partners. The highest overall response rate was seen in the buparlisib triple combination (25.0%; 95% confidence interval, 9.8–46.7).

Conclusions:
Ribociclib plus fulvestrant demonstrated safety in the treatment of patients with HR+, HER2− ABC. Triple combinations with alpelisib or buparlisib plus fulvestrant are not recommended for phase II investigation.
See related commentary by Clark et al., p. 371
Circulating T-cell Immunosenescence in Patients with Advanced Non–small Cell Lung Cancer Treated with Single-agent PD-1/PD-L1 Inhibitors or Platinum-based Chemotherapy
Authors: Ferrara Roberto , Naigeon Marie , Auclin Edouard , Duchemann Boris , Cassard Lydie , Jouniaux Jean-Mehdi , Boselli Lisa , Grivel Jonathan , Desnoyer Aude , Mezquita Laura , Texier Matthieu , Caramella Caroline , Hendriks Lizza , Planchard David , Remon Jordi , Sangaletti Sabina , Proto Claudia , Garassino Marina C. , Soria Jean-Charles , Marabelle Aurelien , Voisin Anne-Laure , Farhane Siham , Besse Benjamin , Chaput Nathalie 
Published: September 2020

Abstract

Purpose:
CD28, CD57, and KLRG1 have been previously identified as markers of T-cell immunosenescence. The impact of immunosenescence on anti-PD(L)-1 (ICI) or platinum-based chemotherapy (PCT) in patients with advanced non–small cell lung cancer (aNSCLC) is unknown.

Experimental Design:
The percentage of CD28−, CD57+, KLRG1+ among CD8+ T cells [senescent immune phenotype (SIP)] was assessed by flow cytometry on blood from patients with aNSCLC before single-agent ICI (discovery cohort). A SIP cut-off was identified by log-rank maximization method and patients with aNSCLC treated with ICI (validation cohort) or PCT were classified accordingly. Proliferation and functional properties of SIP+ CD8+ T cells were assessed in vitro.

Results:
In the ICI discovery cohort (N = 37), SIP cut-off was 39.5%, 27% of patients were SIP+. In the ICI validation cohort (N = 46), SIP+ status was found in 28% of patients and significantly correlated with worse objective response rate (ORR; 0% vs. 30%, P = 0.04), median progression-free survival (PFS) [1.8 (95% confidence interval (CI), 1.3-NR) vs. 6.4 (95% CI, 2–19) months, P = 0.009] and median overall survival, OS [2.8 (95% CI, 2.0-NR) vs. 20.8 (95% CI, 6.0-NR) months, P = 0.02]. SIP+ status was significantly associated with circulating specific immunephenotypes, in vitro lower CD8+ T cells proliferation, lower IL2 and higher TNFα and IFNγ production. In the ICI-pooled population (N = 83), SIP+ status did not correlate with any clinical characteristics and it was associated with significantly worse ORR, PFS, and OS. In PCT cohort (N = 61), 11% of patients were SIP+. SIP status did not correlate with outcomes upon PCT.

Conclusions:
Circulating T-cell immunosenescence is observed in up to 28% of patients with aNSCLC and correlates with lack of benefit from ICI but not from PCT.
See related commentary by Salas-Benito et al., p. 374
Abstract 1020: Anti-oxidant amino acid L-ergothioneine exhibits immunomodulatory effect by regulating immunosuppressive cytokine production of tumor cells
Authors: Kato Kazunori , Kuroki Katsuhiro , Shimizu Yui 
Published: September 2020

Abstract
Ergothioneine (ERG) is a natural antioxidant nutrient containing in edible golden oyster mushroom, Pleurotus cornucopiae (Tamogitake). In previous AACR meeting, we reported that administration of ERG rich water extracts of p. cornucopiae to tumor-bearing mice could suppress the growth of subcutaneous tumors and reduce the number of regulatory T cells (Treg) in lymph node and spleen. However, the molecular events inducing antitumor and immunomodulatory effects are still unknown. Our aim is to identify the mechanism of ERG in tumor cells which secrete various immunomodulatory cytokines. We cocultured human tumor cell lines with ERG and tested cytokine concentration in culture supernatants and expression of immune checkpoint molecules on tumors. ERG could significantly inhibit the production of VEGF, CCL2 and TGF-β1 which are important in not only angiogenesis and tumor invasion but also Treg induction. Importantly, ERG also reduced the expression of some immune checkpoint molecules on tumor cells and prolonged the survival of IL-2-activated lymphocytes in vitro. Overall, ERG rich water extract of p. citrinopileatus might inhibit the induction of Treg in tumor-bearing host via suppression of VEGF and TGF-β1, indicating a novel immunomodulatory antioxidant nutrient in mushrooms
Citation Format: Kazunori Kato, Katsuhiro Kuroki, Yui Shimizu. Anti-oxidant amino acid L-ergothioneine exhibits immunomodulatory effect by regulating immunosuppressive cytokine production of tumor cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1020.
Abstract 1027: Inhibition of c-MET upregulates PD-L1 related immune escape in lung adenocarcinoma
Authors: Sun Xian , Li Chia-Wei , Wang Wei-Jan , Hung Mien-Chie 
Published: September 2020

Abstract
Non-small cell lung cancer (NSCLC) patients with c-MET dysregulation may benefit from c-MET inhibitors therapy as inhibition of c-MET activity has emerged as a therapeutic approach against this disease. Although several c-MET inhibitors have been evaluated in phase III clinical trials in lung cancer, their benefits so far have been modest. Thus, furthering our understanding of the mechanisms contributing to the lack of success of c-MET inhibitors in clinical trials is essential toward the development of rational and effective combination strategies. Here we show that exposure of NCSLC cell lines to c-MET inhibitor tivantinib increases their expression of PD-L1, which in turn causes cells to become more resistant to T-cell killing. Tivantinib upregulates PD-L1 in NSCLC cells in dose and time-dependent manner. Mechanistically, inhibition of c-MET suppresses p-GSK3-beta, leading to the stabilization of PD-L1. Collectively, our findings suggest a potential crosstalk between c-Met inhibition and immune escape and provide a rationale for the combination therapy of c-Met inhibitors and immune checkpoint blockade in NSCLC.
Citation Format: Xian Sun, Chia-Wei Li, Wei-Jan Wang, Mien-Chie Hung. Inhibition of c-MET upregulates PD-L1 related immune escape in lung adenocarcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1027.
Abstract 1033: NANOG-HSP90A axis confers immunotherapeutic resistance by blocking anti-tumor immunity cycle
Authors: Oh Se Jin , Kim Tae Woo , Song Kwon-Ho , Kim Suyeon 
Published: September 2020

Abstract
T cell-based immunotherapy has shifted the paradigm for cancer treatment. However, the majority of patients lack effective responses due to presence of immune-refractory tumor cells that limits its clinical success by blocking amplification of anti-tumor immunity cycle. Previously, we found that immune selection by T-cell based immunotherapy drives the evolution of tumors toward immunotherapeutic refractoriness including multimodal resistant and stem-like phenotype via activation of NANOG-TCL1A-AKT axis. Here, we report a crucial role of HSP90A at the crossroads between NANOG-TCL1A axis and the refractoriness of immune-edited tumor cells by identifying HSP90AA1 as a novel NANOG transcriptional target. Furthermore, we found that TCL1A is a novel client of HSP90A, and demonstrated that HSP90A potentiates AKT activation through TCL1A stabilization and thereby contributes to refractoriness in NANOGhigh immune-edited tumor cells. Importantly, inhibition of HSP90A sensitizes immune-refractory tumor cells to T cell-based immunotherapy and elicits effective anti-tumor response by re-invigorating anti-tumor immune cycle of tumor-reactive T cells. Our findings implicate that the NANOG-HSP90A pathway is a central molecular axis and a potential target for immune-refractory tumor.
Citation Format: Se Jin Oh, Tae Woo Kim, Kwon-Ho Song, Suyeon Kim. NANOG-HSP90A axis confers immunotherapeutic resistance by blocking anti-tumor immunity cycle [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1033.
Abstract 1057: Targeting MTHFD2 using first-in-class inhibitors kills haematological and solid cancer through thymineless-induced replication stress
Authors: Helleday Thomas 
Published: September 2020

Abstract
Summary
Thymidine synthesis pathways are upregulated pathways in cancer. Since the 1940s, targeting nucleotide and folate metabolism to induce thymineless death has remained first-line anti-cancer treatment. Recent discoveries that showing cancer cells have rewired networks and exploit unique enzymes for proliferation, have renewed interest in metabolic pathways. The cancer-specific expression of MTHFD2 has gained wide-spread attention and here we describe an emerging role for MTHFD2 in the DNA damage response (DDR). The folate metabolism enzyme MTHFD2 is one of the most consistently overexpressed metabolic enzymes in cancer and an emerging anticancer target. We show a novel role for MTHFD2 being essential for DNA replication and genomic stability in cancer cells. We describe first-in-class nanomolar MTHFD2 inhibitors (MTHFD2i), with protein co-crystal structures demonstrating binding in the active site of MTHFD2 and engaging with the target in cells and tumours. We show MTHFD2i reduce replication fork speed and induce replication stress, followed by S phase arrest, apoptosis and killing of a range of haematological and solid cancer cells in vitro and in vivo, with a therapeutic window spanning up to four orders of magnitude compared to non-transformed cells. Mechanistically, MTHFD2i prevent thymidine production leading to mis-incorporation of uracil into DNA and replication stress. As MTHFD2 expression is cancer specific there is a potential of MTHFD2i to synergize with other treatments. Here, we show MTHFD2i synergize with dUTPase inhibitors as well as other DDR inhibitors and demonstrate the mechanism of action. These results demonstrate a new link between MTHFD2-dependent cancer metabolism and replication stress that can be exploited therapeutically.
Keywords
MTHFD2, one-carbon metabolism, folate metabolism, DNA replication, replication stress, synthetic lethal, thymineless death, small-molecule inhibitor, DNA damage response
Citation Format: Thomas Helleday. Targeting MTHFD2 using first-in-class inhibitors kills haematological and solid cancer through thymineless-induced replication stress [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1057.