bluuebunny/crossref_metadata_2025_split huggingface dataset:
Protocol for a randomised, double-blinded, placebo-controlled, double-dummy 6-week clinical trial comparing the treatment effects of the glucagon-like peptide 1 receptor agonist liraglutide versus the bile acid sequestrant colesevelam on bile acid malabsorption
Authors: Kårhus Martin Lund , Brønden Andreas , Lyng Forman Julie , Haaber Anne , Vilsbøll Tina , Sonne David Peick , Knop Filip Krag 
Published: February 2021

IntroductionBile acid malabsorption (BAM) is a socially debilitating disease characterised by high stool frequency and urgency caused by a spillover of bile acids into the colon. Bile acid sequestrants (BASs) have limited therapeutic effect but represent the only available treatment option. Cases reporting total remission of BAM-related symptoms after treatment with liraglutide, a glucagon-like peptide 1 analogue, prompted us to design a clinical trial investigating the therapeutic effect of this compound in patients with BAM.Methods and analysisFifty adult individuals with moderate or severe BAM as assessed by the75selenium-homotaurocholic acid test (SeHCAT) will, after a run-in period of 10 days with no BAM treatment, be randomised to either treatment with the BAS colesevelam or liraglutide (double blinded) for 6 weeks. Daily symptom diaries and questionnaires will be filled in. Blood and faecal samples will be collected and SeHCAT will be performed at baseline, after week 3 and at end of trial. The primary endpoint is change in daily stool frequency. Secondary endpoints include changes from baseline in questionnaires, biochemistry, SeHCAT and faecal bile acid content and microbial composition.Ethics and disseminationThe study complies with Danish and European Union legislation and is approved by the Danish Medicines Agency, the Regional Scientific Ethics Committee of the Capital Region of Denmark and the Danish Data Protection Agency. The study is monitored by the Capital Region of Denmark’s good clinical practice unit. All results, positive, negative and inconclusive, will be disseminated at national and/or international scientific meetings and in peer-reviewed scientific journals.Trial registration numberEudraCA: 2018-003575-34; Pre-results.
Palliative Medicine Specialist Trainee Research experience, interest and opportunities: a national survey
Authors: Wakefield Donna , Dewhurst Felicity , Koffman Jonathan , Chamberlain Charlotte 
Published: February 2021

ObjectivesDespite the acknowledged benefits of research, Palliative Medicine receives minimal research funding and has few dedicated research training posts. This study investigated the opportunities and barriers to participating in research for the current cohort of UK Palliative Medicine Specialist Trainees (PMSTs), to better understand the opportunities to improve evidence-based practice within the specialty.MethodsTwo surveys, one for PMSTs and a second for training programme directors (TPDs), were developed. Surveys were piloted and then reviewed by the UK Palliative trainee Research Collaborative and the Palliative Medicine Specialty Advisory Committee (SAC) before distribution. All current PMSTs and TPDs representing all of the UK training regions (n=13) were invited to complete the appropriate survey.ResultsOverall, 85% (11/13) and 45% (102/225) of TPDs and PMSTs responded, respectively. Almost all (92%) PMSTs reported that they were either ‘very interested’ or ‘quite interested’ in taking part in clinical research. PMSTs generally felt that educationaland clinical supervisors were supportive of them taking part in research; however, few (35%) believed they had access to personnel with adequate research experience to provide practical support. Opportunity for appropriate research supervision varied considerably by training region. Where research was being conducted, it was often conducted in trainees’ personal time due to the wide regional variation in dedicated research time.ConclusionDespite significant interest in clinical research and support by TPDs and clinical supervisors, access to experienced researchers and equitable protected research time by region needs urgent attention to enhance progress in evidence-based palliative medicine.
Performance of the 2019 EULAR/ACR systemic lupus erythematosus classification criteria in a cohort of patients with biopsy-confirmed lupus nephritis
Authors: Wang Huijing , Gao Yunjie , Ma Yanhong , Cai Fanghao , Huang Xiaohan , Lan Lan , Ren Pingping , Wang Yaomin , Chen Jianghua , Han Fei 
Published: February 2021

ObjectiveTo evaluate the performance of the European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) SLE classification criteria in a cohort of patients with biopsy-confirmed lupus nephritis (LN) and their renal prognosis.MethodsPatients with newly diagnosed SLE attending and followed up for >12 months were included. A retrospective review of all patients with renal biopsy fulfilling a consensus expert opinion during 2014 and 2018. Clinical, serological and pathological data were collected and each patient was assigned a high/low criteria scores (HS/LS) group. Survival curves for flare adjusted for multiplicity on renal flares, was applied to the two groups.ResultsApplying EULAR/ACR criteria in our cohort of 126 patients, 6 (4.76%) did not meet the criterion, resulting in a sensitivity of 95.24%. The EULAR/ACR criteria scores was positively correlated with SLE disease activity index scores. Additionally, we noticed that a significant difference in clinical and immunological manifestations between HS and LS group. We observed a higher proportions of class Ⅲ or Ⅳ LN and lower proportions of class Ⅱ or V LN (p=0.034) and pathological higher activity index in HS group (p=0.007). Compared with LS groups, patients involved more severe renal damage and achieved higher rate of complete remission in the HS group. The Kaplan-Meier exploratory analyses, adjusted for LN classification, estimated glomerular filtration rate, activity index and chronicity index and induction and maintenance treatments, showed that patients in the HS group had a tendency of higher renal flare risk than that in the LS group (HR=0.21, p=0.04).ConclusionsThe EULAR/ACR criteria performed high sensitivity in identifying SLE in this cohort of biopsy-confirmed LN. Patients with LN with high criteria scores had more extrarenal manifestations, and worse renal prognosis in the short and long terms.
Association of asymptomatic hemorrhage after endovascular stroke treatment with outcomes
Authors: Feldman Michael J , Roth Steven , Fusco Matthew R , Mehta Tapan , Arora Niraj , Siegler James E , Schrag Matthew , Mittal Shilpi , Kirshner Howard , Mistry Akshitkumar M. , Yaghi Shadi , Chitale Rohan V , Khatri Pooja , Mistry Eva A 
Published: February 2021

BackgroundIntracerebral hemorrhage (ICH) occurs in ~20%–30% of stroke patients undergoing endovascular therapy (EVT). However, there is conflicting evidence regarding the effect of asymptomatic ICH (aICH) on post-EVT outcomes. We sought to evaluate the effect of aICH on immediate and 90-day post-EVT neurological outcomes.MethodsIn this post-hoc analysis of the multicenter, prospective Blood Pressure after Endovascular Therapy (BEST) study we identified subjects with ICH following EVT. This population was divided into no ICH, aICH, and symptomatic ICH (sICH). Associations with 90-day modified Rankin Scale (mRS) dichotomized by functional independence (0–2 vs 3–6) and early neurological recovery (ENR) were determined using univariate/multivariate logistic regression models.ResultsOf 485 patients enrolled in BEST, 446 had 90-day follow-up data available. 92 (20.6%) developed aICH, and 18 (4%) developed sICH. Compared with those without ICH, aICH was not associated with worse 90-day outcome or lower ENR (OR 0.84 [0.53–1.35], P=0.55, aOR 0.84 [0.48–1.44], P=0.53 for 90-day mRS 0–2; OR 0.77 [0.48–1.23], P=0.34, aOR 0.72 [0.43–1.22] for ENR). aICH was not associated with 90-day outcome or ENR in patients with mTICI ≥2 b (OR 0.78 [0.48–1.26], P=0.33 for 90-day mRS 0–2; OR 0.89 [0.69–1.12], P=0.15 for ENR). A higher proportion of patients with aICH had mTICI ≥2 b than those without ICH (97%vs 87%, P=0.01).ConclusionsaICH was not associated with worse outcomes in patients with large-vessel stroke treated with EVT. aICH was more frequent in patients with successful recanalization. Further validation of our findings in large cohort studies of EVT-treated patients is warranted.
Subgroups, hyperbolicity and cohomological dimension for totally disconnected locally compact groups
Authors: Arora S. , Castellano I. , Cook G. Corob , Martínez-Pedroza E. 
Published: February 2021

This paper is part of the program of studying large-scale geometric properties of totally disconnected locally compact groups, TDLC-groups, by analogy with the theory for discrete groups. We provide a characterization of hyperbolic TDLC-groups, in terms of homological isoperimetric inequalities. This characterization is used to prove the main result of this paper: for hyperbolic TDLC-groups with rational discrete cohomological dimension [Formula: see text], hyperbolicity is inherited by compactly presented closed subgroups. As a consequence, every compactly presented closed subgroup of the automorphism group [Formula: see text] of a negatively curved locally finite [Formula: see text]-dimensional building [Formula: see text] is a hyperbolic TDLC-group, whenever [Formula: see text] acts with finitely many orbits on [Formula: see text]. Examples where this result applies include hyperbolic Bourdon’s buildings. We revisit the construction of small cancellation quotients of amalgamated free products, and verify that it provides examples of hyperbolic TDLC-groups of rational discrete cohomological dimension [Formula: see text] when applied to amalgamated products of profinite groups over open subgroups. We raise the question of whether our main result can be extended to locally compact hyperbolic groups if rational discrete cohomological dimension is replaced by asymptotic dimension. We prove that this is the case for discrete groups and sketch an argument for TDLC-groups.
Preparation of Biocomposite Material with Superhydrophobic Surface by Reinforcing Waste Polypropylene with Sisal (Agave sisalana) Fibers
Authors: Abebayehu Seyoum Getaneh , Engida Adam Mekonnen 
Published: February 2021

Nowadays, eco-friendly, renewable, and biodegradable biocomposites are among the most intensely sought materials of choice. Biocomposites have been widely used as substitutes for plastics due to their biodegradability. However, biocomposite materials absorb water and ultimately loss mechanical properties that affect service life. In this work, a biocomposite material with superhydrophobic surface was prepared by reinforcing waste polypropylene with sisal (Agave sisalana) fibers. The biocomposite was prepared by mixing waste polypropylene and sisal fiber with 5%, 10%, 15%, and 20% fiber loading. Based on characterization results, the composite with 15% fiber content is considered as optimum ratio. Physicochemical properties of composites were evaluated using standard American Society of Testing Materials including biodegradability test and chemical resistance test. The biodegradability of the composite before surface modification was determined by calculating weight loss and found to be 0.11%, 4.62%, 7.15%, and 10.97% for 0%, 5%, 10%, and 15% fiber loadings, and their tensile strength was

10.25
±
0.05

,

14.47
±
0.02

,

14.48
±
0.02

, and

19.90
±
0.09

MPa

for 0%, 5%, 10%, and 15% fiber content, respectively. The surface of the composite was modified for hydrophobicity by etching the surface with chromic acid followed by treating with stearic acid. The FTIR and the SEM images of unmodified and modified (superhydrophobic) surface of composites clearly state the significant difference in chemical composition and surface structure, respectively. The superhydrophobicity of the surface-modified biocomposite was defined by its self-cleaning and low wet ability properties.
The Effectiveness and Safety of Cinobufotalin Injection as an Adjunctive Treatment for Lung Cancer: A Meta-Analysis of Randomized Controlled Trials
Authors: Li Lin-Lu , Su Yi-Xin , Mao Yun , Jiang Peng-Yuan , Chu Xue-Lei , Xue Peng , Jia Bo-Hui , Zhu Shi-Jie 
Published: February 2021

Cinobufotalin injection is a water-soluble preparation extracted from the skin secretion of Bufo bufo gargarizans Cantor or B. melanotictus Schneider, which has been widely used as an adjuvant treatment in lung cancer patients. This study aimed to evaluate the clinical efficacy and safety of cinobufotalin (PubChem CID: 259776) injection as an adjunctive treatment for lung cancer. We designed a meta-analysis that performed following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. We aim to include randomized controlled trials by systematically searching the PubMed, EMBASE, CNKI, Wanfang database, VIP, CBM, the Cochrane Central Register of Controlled Trials, and Chinese Clinical Trial Registry from inception to Mar 1, 2020, comparing the difference between the use of cinobufotalin injection as an adjunctive treatment and a control group without cinobufotalin injection. The objective response rate (ORR) and quality of life (QOL) will be defined as the primary outcomes, and the disease control rate (DCR) and adverse events will be defined as the secondary outcomes. We included 21 articles with 1735 cases of lung cancer patients. Comparison results show that combining with cinobufotalin injection can improve ORR (OR = 1.77, 95% CI [1.43, 2.21],

P

< 0.001), with low heterogeneity (

P

= 0.94, I2 = 0%); DCR (OR = 2.20, 95% CI [1.70, 2.85],

P

< 0.001), with low heterogeneity (

P

= 0.60, I2 = 0%); KPS score (OR = 3.10, 95% CI [2.23, 4.32],

P

< 0.001), with low heterogeneity (

P

= 0.85, I2 = 0%); and the effect of pain relief (OR = 2.68, 95% CI [1.30, 5.55],

P

= 0.008), with low heterogeneity (

P

= 0.72, I2 = 0%). Low-to-moderate evidence shows that cinobufotalin injection combined with chemotherapy can significantly increase ORR, DCR, QOL, and the effect of pain relief. Meanwhile, cinobufotalin injection did not bring additional adverse events such as hematological toxicity, gastrointestinal toxicity, cardiotoxicity, hepatotoxicity, and nephrotoxicity; however, multicenter, large-sample, high-quality clinical research results are still needed to reveal the therapeutic effect of cinobufotalin injection in small-cell lung cancer (PROSPERO registration number: CRD42020170052).
Germline and Somatic Genetic Variants in the p53 Pathway Interact to Affect Cancer Risk, Progression, and Drug Response
Authors: Zhang Ping , Kitchen-Smith Isaac , Xiong Lingyun , Stracquadanio Giovanni , Brown Katherine , Richter Philipp H. , Wallace Marsha D. , Bond Elisabeth , Sahgal Natasha , Moore Samantha , Nornes Svanhild , De Val Sarah , Surakhy Mirvat , Sims David , Wang Xuting , Bell Douglas A. , Zeron-Medina Jorge , Jiang Yanyan , Ryan Anderson J. , Selfe Joanna L. , Shipley Janet , Kar Siddhartha , Pharoah Paul D. , Loveday Chey , Jansen Rick , Grochola Lukasz F. , Palles Claire , Protheroe Andrew , Millar Val , Ebner Daniel V. , Pagadala Meghana , Blagden Sarah P. , Maughan Timothy S. , Domingo Enric , Tomlinson Ian , Turnbull Clare , Carter Hannah , Bond Gareth L. 
Published: February 2021

Abstract

Insights into oncogenesis derived from cancer susceptibility loci (SNP) hold the potential to facilitate better cancer management and treatment through precision oncology. However, therapeutic insights have thus far been limited by our current lack of understanding regarding both interactions of these loci with somatic cancer driver mutations and their influence on tumorigenesis. For example, although both germline and somatic genetic variation to the p53 tumor suppressor pathway are known to promote tumorigenesis, little is known about the extent to which such variants cooperate to alter pathway activity. Here we hypothesize that cancer risk-associated germline variants interact with somatic TP53 mutational status to modify cancer risk, progression, and response to therapy. Focusing on a cancer risk SNP (rs78378222) with a well-documented ability to directly influence p53 activity as well as integration of germline datasets relating to cancer susceptibility with tumor data capturing somatically-acquired genetic variation provided supportive evidence for this hypothesis. Integration of germline and somatic genetic data enabled identification of a novel entry point for therapeutic manipulation of p53 activities. A cluster of cancer risk SNPs resulted in increased expression of prosurvival p53 target gene KITLG and attenuation of p53-mediated responses to genotoxic therapies, which were reversed by pharmacologic inhibition of the prosurvival c-KIT signal. Together, our results offer evidence of how cancer susceptibility SNPs can interact with cancer driver genes to affect cancer progression and identify novel combinatorial therapies.

Significance:
These results offer evidence of how cancer susceptibility SNPs can interact with cancer driver genes to affect cancer progression and present novel therapeutic targets.
Ubiquitin-Specific Protease 6 Functions as a Tumor Suppressor in Ewing Sarcoma through Immune Activation
Authors: Henrich Ian C. , Jain Kanika , Young Robert , Quick Laura , Lindsay Jarrett M. , Park Daniel H. , Oliveira Andre M. , Blobel Gerd A. , Chou Margaret M. 
Published: February 2021

Abstract

Ewing sarcoma is the second most common pediatric bone cancer, with a 5-year survival rate for metastatic disease of only 20%. Recent work indicates that survival is strongly correlated with high levels of tumor-infiltrating lymphocytes (TIL), whose abundance is associated with IFN-inducible chemokines CXCL10 and CCL5. However, the tumor-intrinsic factors that drive chemokine production and TIL recruitment have not been fully elucidated. We previously showed that ubiquitin-specific protease 6 (USP6) directly deubiquitinates and stabilizes Jak1, thereby inducing an IFN signature in Ewing sarcoma cells. Here, we show that this gene set comprises chemokines associated with immunostimulatory, antitumorigenic functions, including CXCL10 and CCL5. USP6 synergistically enhanced chemokine production in response to exogenous IFN by inducing surface upregulation of IFNAR1 and IFNGR1. USP6-expressing Ewing sarcoma cells stimulated migration of primary human monocytes and T lymphocytes and triggered activation of natural killer (NK) cells in vitro. USP6 inhibited Ewing sarcoma xenograft growth in nude but not NSG mice and was accompanied by increased intratumoral chemokine production and infiltration and activation of NK cells, dendritic cells, and macrophages, consistent with a requirement for innate immune cells in mediating the antitumorigenic effects of USP6. High USP6 expression in patients with Ewing sarcoma was associated with chemokine production, immune infiltration, and improved survival. This work reveals a previously unrecognized tumor-suppressive function for USP6, which engenders an immunostimulatory microenvironment through pleiotropic effects on multiple immune lineages. This further raises the possibility that USP6 activity may be harnessed to create a “hot” tumor microenvironment in immunotherapy.

Significance:
This study reveals a novel tumor-suppressive function for USP6 by inducing an immunostimulatory microenvironment, suggesting that USP6 activity may be exploited to enhance immunotherapy regimens.
An Open-label, Multicenter, Single-arm, Phase II Study of Fluzoparib in Patients with Germline BRCA1/2 Mutation and Platinum-sensitive Recurrent Ovarian Cancer
Authors: Li Ning , Bu Hualei , Liu Jihong , Zhu Jianqing , Zhou Qi , Wang Li , Yin Rutie , Wu Xiaohua , Yao Shuzhong , Gu Kangsheng , Zhang Hui , Li Guiling , Pan Hongming , Wu Qiang , An Ruifang , Yang Xinfeng , Zhu Yaping , Wan Xiaoping , Duan Wei , Xiong Jianping , Guo Hongyan , Lou Ge , Wang Jing , Hu Wenjing , Zhang Xin , Meng Yuanguang , Zhang Ben , Wang Yuting , Wang Quanren , Wu Lingying 
Published: February 2021

Abstract

Purpose:
Fluzoparib (PARP inhibitor) showed promising antitumor activity for advanced ovarian cancer in a phase I study. This study aimed to assess the efficacy and safety of fluzoparib in patients with germline BRCA1/2-mutated recurrent ovarian cancer.

Patients and Methods:
This open-label, multicenter, single-arm, phase II study enrolled patients with platinum-sensitive recurrent ovarian cancer and germline BRCA1/2 mutation who had previously received two to four lines of platinum-based chemotherapy. Fluzoparib 150 mg was administered orally twice daily. The primary endpoint was independent review committee (IRC)-assessed objective response rate per RECIST v1.1.

Results:
A total of 113 patients were enrolled and received at least one dose of fluzoparib. As of data cutoff on March 21, 2020, the median follow-up period was 15.9 months (interquartile range, 13.5–18.5). The IRC- and investigator-assessed objective response rates were 69.9% [95% confidence interval (CI), 60.6–78.2] and 70.8% (95% CI, 61.5–79.0), respectively. The objective response rates were similar across all prespecified subgroups. The median IRC- and investigator-assessed progression-free survival was 12.0 months (95% CI, 9.3–13.9) and 10.3 months (95% CI, 9.2–12.0), respectively. The 12-month survival rate was 93.7% (95% CI, 87.2–96.9). Grade ≥3 adverse events occurred in 63.7% (72/113) of the patients, with the most common one being anemia/decreased hemoglobin. Adverse events that led to treatment interruption, dose reduction, and discontinuation occurred in 39.8%, 34.5%, and 0.9% of patients, respectively. One treatment-related death occurred.

Conclusions:
Fluzoparib demonstrated promising antitumor activity and acceptable safety profile in germline BRCA1/2-mutated, platinum-sensitive relapsed ovarian cancer. Thus, fluzoparib might be a novel treatment option for this population.