bluuebunny/crossref_metadata_2025_split huggingface dataset:
Promotion of ubiquitination-dependent survivin destruction contributes to xanthohumol-mediated tumor suppression and overcomes radioresistance in human oral squamous cell carcinoma
Authors: Li Ming , Gao Feng , Yu Xinfang , Zhao Qing , Zhou Li , Liu Wenbin , Li Wei 
Published: May 2020

Abstract
Background
Overexpression of survivin plays a crucial role in tumorigenesis and correlates with poor prognosis in human malignancies. Thus, survivin has been proposed as an attractive target for new anti-tumor interventions.

Methods
A natural product library was used for natural compound screening through MTS assay. The expression of survivin in oral squamous cell carcinoma (OSCC) and the inhibitory effect of xanthohumol (XN) on OSCC were examined by anchorage-dependent and -independent growth assays, immunoblot, immunofluorescence, immunohistochemical staining, ubiquitination analysis, co-immunoprecipitation assay, CRISPR-Cas9-based gene knockout, and xenograft experiment.

Results
Survivin is highly expressed in OSCC patient-derived tissues and cell lines. Knockout of survivin reduced the tumorigenic properties of OSCC cells in vitro and in vivo. With a natural compound screening, we identified that xanthohumol inhibited OSCC cells by reducing survivin protein level and activating mitochondrial apoptotic signaling. Xanthohumol inhibited the Akt-Wee1-CDK1 signaling, which in turn decreased survivin phosphorylation on Thr34, and facilitated E3 ligase Fbxl7-mediated survivin ubiquitination and degradation. Xanthohumol alone or in combination with radiation overcame radioresistance in OSCC xenograft tumors.

Conclusion
Our findings indicate that targeting survivin for degradation might a promising strategy for OSCC treatment.
Association of TILs with clinical parameters, Recurrence Score® results, and prognosis in patients with early HER2-negative breast cancer (BC)—a translational analysis of the prospective WSG PlanB trial
Authors: Kolberg-Liedtke Cornelia , Gluz Oleg , Heinisch Fred , Feuerhake Friedrich , Kreipe Hans , Clemens Michael , Nuding Benno , Malter Wolfram , Reimer Toralf , Wuerstlein Rachel , Graeser Monika , Shak Steve , Nitz Ulrike , Kates Ronald , Christgen Matthias , Harbeck Nadia 
Published: May 2020

Abstract
Background
The presence of tumor-infiltrating lymphocytes has been associated with prognosis and chemotherapy response, particularly in high-risk breast cancer subtypes. There is limited data so far as to (i) how tumor-infiltrating lymphocyte (TIL) measurements correlate with genomic measurements such as the Oncotype DX Recurrence Score® and (ii) whether the survival impact of TIL measurements varies according to different adjuvant systemic therapies.

Methods
The WSG PlanB trial compared an anthracycline-free chemotherapy regimen (6x docetaxel/cyclophosphamide, TC) to an anthracycline-taxane sequence (4xEC followed by 4x docetaxel) in patients with intermediate-risk, HER2-negative early breast cancer (EBC). Patients with HR-positive HER2-negative EBC were further stratified to receive endocrine therapy alone vs. chemotherapy followed by endocrine therapy based on Recurrence Score results and nodal status. In this analysis, three independent observers quantified and categorized the presence of TILs among tumor samples from patients in PlanB. TIL measurements were correlated with clinical/pathological parameters and treatment outcome overall and according to the treatment arm.

Results
Disease-free survival (DFS) rates were significantly better (p = .04) in HR-negative patients with high vs. intermediate TIL levels and were higher in low vs. intermediate TIL patients, however with borderline significance only (p = .06). There were no significant differences among TIL categories in HR+ patients. High RS categories, HR-negative status, and high KI67 were independently and significantly associated with high TIL categories. There was no significant impact of TIL category on DFS in patients treated by endocrine therapy only; however, in patients receiving chemotherapy, DFS in the intermediate TIL category was lower than that in the other categories.

Conclusion
Although the presence of high TILs is associated with negative prognostic parameters such as high KI67 and HR-negative status among patients with HR-positive HER2-negative EBC, patients with high TILs show a favorable 5-year DFS in both HR-positive/HER2-negative and triple-negative breast cancer.
Comparison of the clinical and cost effectiveness of two management strategies (rehabilitation versus surgical reconstruction) for non-acute anterior cruciate ligament (ACL) injury: study protocol for the ACL SNNAP randomised controlled trial
Authors: Davies Loretta , Cook Jonathan , Leal Jose , Areia Carlos Morgado , Shirkey Beverly , Jackson William , Campbell Helen , Fletcher Heidi , Carr Andrew , Barker Karen , Lamb Sarah E. , Monk Paul , O’Leary Sean , Haddad Fares , Wilson Chris , Price Andrew , Beard David 
Published: May 2020

AbstractBackgroundAnterior cruciate ligament (ACL) rupture is a common knee injury that can lead to poor quality of life, decreased activity and increased risk of secondary osteoarthritis of the knee. Management of patients with a non-acute ACL injury can include a non-surgical (rehabilitation) or surgical (reconstruction) approach. However, insufficient evidence to guide treatment selection has led to high variation in treatment choice for patients with non-acute presentation of ACL injury.The objective of the ACL SNNAP trial is to determine in patients with non-acute anterior cruciate ligament deficiency (ACLD) whether a strategy of non-surgical management (rehabilitation) (with option for later ACL reconstruction only if required) is more clinically effective and cost effective than a strategy of surgical management (reconstruction) without prior rehabilitation with all patients followed up at 18 months.MethodsThe study is a pragmatic, multi-centre, superiority, randomised controlled trial with two-arm parallel groups and 1:1 allocation. Patients with a symptomatic non-acute ACL deficient knee will be randomised to either non-surgical management (rehabilitation) or surgical management (reconstruction). We aim to recruit 320 patients from approximately 30 secondary care orthopaedic units from across the United Kingdom. Randomisation will occur using a web-based randomisation system. Blinding of patients and clinicians to treatment allocation will not be possible because of the nature of the interventions. Participants will be followed up via self-reported questionnaires at 6, 12 and 18 months. The primary outcome is the Knee injury and Osteoarthritis Outcome Score (KOOS) at 18 months post randomisation. Secondary outcomes will include a return to sport/activity, intervention-related complications, patient satisfaction, expectations of activity, generic health quality of life, knee specific quality of life and resource usage.DiscussionAt present, no evidence-based treatment of non-acute ACL deficiency exists, particularly in the NHS. Moreover, little consensus exists on the management approach for these patients. The proposed trial will address this gap in knowledge regarding the clinical and cost effectiveness of ACL treatment and inform future standards of care for this condition.Trial registrationISRCTN:10110685. Registered on 16 November 2016. ClinicalTrials.gov:NCT02980367. Registered in December 2016.
Xiaochaihu decorction relieves liver fibrosis caused by Schistosoma japonicum infection via the HSP47/TGF-β pathway
Authors: Huang Yuzheng , Lu Jin , Xu Yongliang , Xiong Chunrong , Tong Deshen , Hu Nannan , Yang Haitao 
Published: May 2020

Abstract
Background
Hepatic fibrosis caused by chronic infection with Schistosoma japonica remains a serious public health problem in the world. Symptoms include inflammation, liver granuloma and fibrosis, whilst treatment options are still limited. This study aims to investigate whether and how traditional Chinese medicine Xiaochaihu decoction (XCH) could mitigate liver fibrosis caused by S. japonicum infection.

Methods
BALB/c mice were infected with S. japonicum cercariae and treated with XCH for 16 weeks. Liver pathological changes were assessed by H&E and Masson staining. NIH3T3 and Raw264.7 cells were treated with S. japonicum egg antigens with or without XCH treatment. Quantitative real-time PCR, western blot, immunfluorescence and ELISA were performed to determine the changes of levels of fibrogenic markers.

Results
XCH protected mouse liver from injuries and fibrosis caused by S. japonicum infection and considerably reduced egg burden in a dose-dependent manner. Infection with S. japonicum caused elevation of serum ALT, AST, ALP, HA and PIIINP levels and reduction of ALB and GLOB levels, which was markedly suppressed by XCH. The upregulation of TGF-β1, Hsp47, α-SMA, Col1A1 and Col3A1 in S. japonicum-infected mouse liver was also significantly inhibited by XCH. Schistosoma japonicum egg antigens promoted the expression of Hsp47, TGF-β1, Timp-1, α-SMA, Col1A1 and Col3A1 in NIH3T3 cells, and TGF-β1, CTGF, IL-13, IL-17 and IL-6 in Raw264.7 cells, which was inhibited by XCH, LY2157299 and shRNA-Hsp47.

Conclusions
These results demonstrated that the hepatic protective effects of Xiaochaihu decoction were mediated by HSP47/TGF-β axis.
Slight temperature changes cause rapid transcriptomic responses in Trypanosoma cruzi metacyclic trypomastigotes
Authors: Cruz-Saavedra Lissa , Muñoz Marina , Patiño Luz Helena , Vallejo Gustavo A. , Guhl Felipe , Ramírez Juan David 
Published: May 2020

Abstract
Background
Severe changes in temperature can affect the behavior and ecology of some infectious agents. Trypanosoma cruzi is a protozoan that causes Chagas disease. This parasite has high genetic variability and can be divided into six discrete typing units (DTUs). Trypanosoma cruzi also has a complex life-cycle, which includes the process of metacyclogenesis when non-infective epimastigote forms are differentiated into infective metacyclic trypomastigotes (MT). Studies in triatomines have shown that changes in temperature also affect the number and viability of MT.

Methods
The objective of this study was to evaluate how temperature affects the transcriptional profiles of T. cruzi I and II (TcI and TcII) MT by exposing parasites to two temperatures (27 °C and 28 °C) and comparing those to normal culture conditions at 26 °C. Subsequently, RNA-seq was conducted and differentially expressed genes were quantified and associated to metabolic pathways.

Results
A statistically significant difference was observed in the number of MT between the temperatures evaluated and the control, TcII DTU was not strongly affected to exposure to high temperatures compared to TcI. Similar results were found when we analyzed gene expression in this DTU, with the greatest number of differentially expressed genes being observed at 28 °C, which could indicate a dysregulation of different signaling pathways under this temperature. Chromosome analysis indicated that chromosome 1 harbored the highest number of changes for both DTUs for all thermal treatments. Finally, gene ontology (GO) analyses showed a decrease in the coding RNAs involved in the regulation of processes related to the metabolism of lipids and carbohydrates, the evasion of oxidative stress, and proteolysis and phosphorylation processes, and a decrease in RNAs coding to ribosomal proteins in TcI and TcII, along with an increase in the expression of surface metalloprotease GP63 in TcII.

Conclusions
Slight temperature shifts lead to increased cell death of metacyclic trypomastigotes because of the deregulation of gene expression of different processes essential for the TcI and TcII DTUs of T. cruzi.
Toxoplasma gondii and Neospora caninum infections in South American camelids in Switzerland and assessment of serological tests for diagnosis
Authors: Basso Walter , Sollberger Elena , Schares Gereon , Küker Susanne , Ardüser Flurin , Moore-Jones Gaia , Zanolari Patrik 
Published: May 2020

Abstract
Background
Little is known about the epidemiology of Toxoplasma gondii and Neospora caninum infections in alpacas (Vicugna pacos) and llamas (Lama glama) outside South America. The study aimed to estimate the seroprevalence of T. gondii and N. caninum infections in South American camelids (SAC) in Switzerland, to optimize serological tests for SAC and to identify risk factors, which may favour infection.

Methods
A total of 571 sera from 132 Swiss farms (374 alpacas and 197 llamas, mean 4.3 animals/farm) were obtained. Four commercial enzyme-linked immunosorbent assays (ELISA) for detecting antibodies against T. gondii (ID Screen® Toxoplasmosis Indirect (TOXO-MS)) or N. caninum (i.e. ID Screen® Neospora caninum Indirect Multi-species (NCS-MS); ID Screen® Neospora caninum Competition (NCC) and ID Screen® Neospora caninum Indirect (NCS)) were first assessed for their use on SAC comparing their results with those in immunoblot, and optimizing cut-offs. Subsequently, two kits (TOXO-MS and NCS-MS) were selected for seroprevalence estimation. Additionally, a risk factor analysis for infection was performed on 41 farms, which agreed to participate in a web-based survey.

Results
Three kits (TOXO-MS, NCS-MS and NCC) showed almost perfect agreement (kappa > 0.901) with immunoblot results when the cut-offs were optimized, and one kit (NCS) proved not to be useful for detecting N. caninum seropositive SAC. By TOXO-MS ELISA, 82.3% (308/374) of the alpacas and 84.8% (167/197) of the llamas were seropositive for T. gondii, and 131/132 (99.2%) farms had seropositive animals. By NCS-MS ELISA, 3.5% (13/374) of the alpacas and 2.5% (5/197) of the llamas evidenced antibodies against N. caninum, and 9.1% (12/132) of the farms had seropositive animals. The variables “age” and “female sex” were identified as risk factors for T. gondii infection and “absence of cats in the farm during the last two years” as a protective factor. No risk or protective factors for N. caninum infection could be identified.

Conclusions
This nationwide cross-sectional study demonstrated for the first time the presence of antibodies against T. gondii and N. caninum in the Swiss SAC population, highlighting a high seroprevalence for T. gondii, the presence of cats as a risk factor and suggesting that SAC meat might represent an additional infection source for humans.
Targeting a cysteine protease from a pathobiont alleviates experimental arthritis
Authors: Peng Hsin-Yi , Chen Shih-Yao , Siao Shih-Hong , Chang Jinghua Tsai , Xue Ting-Yin , Lee Yi-Hsuan , Jan Ming-Shiou , Tsay Gregory J. , Zouali Moncef 
Published: May 2020

Abstract
Background
Several lines of evidence suggest that the pathobiont Porphyromonas gingivalis is involved in the development and/or progression of auto-inflammatory diseases. This bacterium produces cysteine proteases, such as gingipain RgpA, endowed with the potential to induce significant bone loss in model systems and in patients.

Objective
We sought to gain further insight into the role of this pathobiont in rheumatoid arthritis (RA) and to identify novel therapeutic targets for auto-inflammatory diseases.

Methods
We profiled the antibody response to RgPA-specific domains in patient sera. We also tested the potential protective effects of RgpA domains in an experimental arthritis model.

Results
Pre-immunization of rats with purified recombinant RgpA domains alleviated arthritis in the joints of the rodents and reduced bone erosion. Using a functional genomics approach at both the mRNA and protein levels, we report that the pre-immunizations reduced arthritis severity by impacting a matrix metalloprotease characteristic of articular injury, a chemokine known to be involved in recruiting inflammatory cells, and three inflammatory cytokines. Finally, we identified an amino acid motif in the RgpA catalytic domain of P. gingivalis that shares sequence homology with type II collagen.

Conclusion
We conclude that pre-immunization against gingipain domains can reduce the severity of experimentally induced arthritis. We suggest that targeting gingipain domains by pre-immunization, or, possibly, by small-molecule inhibitors, could reduce the potential of P. gingivalis to translocate to remote tissues and instigate and/or exacerbate pathology in RA, but also in other chronic inflammatory diseases.
Type IV secretion of Helicobacter pylori CagA into oral epithelial cells is prevented by the absence of CEACAM receptor expression
Authors: Tegtmeyer Nicole , Ghete Tabita Denisia , Schmitt Verena , Remmerbach Torsten , Cortes Maria Celeste C. , Bondoc Edgardo M. , Graf Hans-Ludwig , Singer Bernhard B. , Hirsch Christian , Backert Steffen 
Published: May 2020

Abstract
Background
Helicobacter pylori typically colonizes the human stomach, but it can occasionally be detected in the oral cavity of infected persons. Clinical outcome as a result of gastric colonization depends on presence of the pathogenicity island cagPAI that encodes a type-IV secretion system (T4SS) for translocation of the effector protein CagA and ADP-heptose. Upon injection into target cells, CagA is phosphorylated, which can be demonstrated by in vitro infection of the gastric epithelial cell line AGS, resulting in cell elongation. Here we investigated whether H. pylori can exert these responses during interaction with cells from the oral epithelium. To this purpose, three oral epithelial cell lines, HN, CAL-27 and BHY, were infected with various virulent wild-type H. pylori strains, and CagA delivery and ADP-heptose-mediated pro-inflammatory responses were monitored.

Results
All three oral cell lines were resistant to elongation upon infection, despite similar bacterial binding capabilities. Moreover, T4SS-dependent CagA injection was absent. Resistance to CagA delivery was shown to be due to absence of CEACAM expression in these cell lines, while these surface molecules have recently been recognized as H. pylori T4SS receptors. Lack of CEACAM expression in HN, CAL-27 and BHY cells was overcome by genetic introduction of either CEACAM1, CEACAM5, or CEACAM6, which in each of the cell lines was proven sufficient to facilitate CagA delivery and phosphorylation upon H. pylori infection to levels similar to those observed with the gastric AGS cells. Pro-inflammatory responses, as measured by interleukin-8 ELISA, were induced to high levels in each cell line and CEACAM-independent.

Conclusions
These results show that lack of CEACAM receptors on the surface of the oral epithelial cells was responsible for resistance to H. pylori CagA-dependent pathogenic activities, and confirms the important role for the T4SS-dependent interaction of these receptors with H. pylori in the gastric epithelium.
Adaptive middleware in go - a software architecture-based approach
Authors: Rosa Nelson , Cavalcanti David , Campos Gláucia , Silva André 
Published: May 2020

AbstractAdaptive middleware is essential for developing distributed systems in several applications domains. The design and implementation of this kind of middleware, however, it is still a challenge due to general adaptation issues, such as When to adapt? Where to include the adaptation code? What to adapt?, and How to guarantee safe adaptations?. Current solutions commonly face these challenges at the implementation level and do not focus on the safety aspects of the adaptation. This paper proposes a holistic solution implemented in Go programming language for developing adaptive middleware centred on the adoption of software architecture principles combined with lightweight use of formalisms. Software architecture concepts work as an enabling approach for structuring and adapting the middleware. Meanwhile, the formalisation helps in providing some guarantees before and during the middleware execution. The proposed solution is evaluated by implementing an adaptive middleware and comparing its performance against existing middleware systems. As shown in the experimental evaluation, the proposed solution enables us to design and implement safe adaptive middleware systems without compromising their performance.
Long-term safety and tolerability of atabecestat (JNJ-54861911), an oral BACE1 inhibitor, in early Alzheimer’s disease spectrum patients: a randomized, double-blind, placebo-controlled study and a two-period extension study
Authors: Novak Gerald , Streffer Johannes Rolf , Timmers Maarten , Henley David , Brashear H. Robert , Bogert Jennifer , Russu Alberto , Janssens Luc , Tesseur Ina , Tritsmans Luc , Van Nueten Luc , Engelborghs Sebastiaan 
Published: May 2020

Abstract
Background
Atabecestat, a potent brain-penetrable inhibitor of BACE1 activity that reduces CSF amyloid beta (Aβ), was developed for oral treatment for Alzheimer’s disease (AD).
The long-term safety and effect of atabecestat on cognitive performance in participants with predementia AD in two phase 2 studies were assessed.

Methods
In the placebo-controlled double-blind parent ALZ2002 study, participants aged 50 to 85 years were randomized (1:1:1) to placebo or atabecestat 10 or 50 mg once daily (later reduced to 5 and 25 mg) for 6 months. Participants entered ALZ2004, a 12-month treatment extension with placebo or atabecestat 10 or 25 mg, followed by an open-label phase. Safety, changes in CSF biomarker levels, brain volume, and effects on cognitive performance were assessed.

Results
Of 114 participants randomized in ALZ2002, 99 (87%) completed, 90 entered the ALZ2004 double-blind phase, and 77 progressed to the open-label phase. CSF Aβ fragments and sAPPβ were reduced dose-proportionately. Decreases in whole brain and hippocampal volumes were greater in participants with mild cognitive impairment (MCI) due to AD than in preclinical AD, but were not affected by treatment. In ALZ2004, change from baseline in RBANS trended toward worse scores for atabecestat versus placebo. Elevated liver enzyme adverse events reported in 12 participants on atabecestat resulted in dosage modification and increased frequency of safety monitoring. Treatment discontinuation normalized ALT or AST in all except one with pretreatment elevation, which remained mildly elevated. No case met ALT/AST > 3× ULN and total bilirubin > 2× ULN (Hy’s law).

Conclusion
Atabecestat was associated with trend toward declines in cognition, and elevation of liver enzymes.

Trial registration
ALZ2002: ClinicalTrials.gov, NCT02260674, registered October 9, 2014; ALZ2004: ClinicalTrials.gov, NCT02406027, registered April 1, 2015.
The meta-memory ratio: a new cohort-independent way to measure cognitive awareness in asymptomatic individuals at risk for Alzheimer’s disease
Authors:   for ADNI; for the INSIGHT-preAD study group, Gagliardi Geoffroy , Houot Marion , Cacciamani Federica , Habert Marie-Odile , Dubois Bruno , Epelbaum Stéphane 
Published: May 2020

Abstract
Background
Lack of awareness of cognitive decline (ACD) has been described at the preclinical and prodromal stages of Alzheimer’s disease (AD). In this study, we introduced a meta-memory ratio (MMR) and explored how it is associated with neuroimaging AD biomarkers in asymptomatic individuals at risk for AD.

Method
Four hundred forty-eight cognitively healthy participants from two cohorts of subjective memory complainers (INSIGHT-PreAD and ADNI) were included. Regression models were used to assess the impact of AD biomarkers on the MMR.

Result
In both cohorts, there was a significant quadratic effect of cerebral amyloidosis on the MMR value. In particular, participants had a high ACD up to the amyloid positivity threshold, above which a decrease of ACD was eventually observed as the amyloid load increased.

Conclusion
This nonlinear evolution of ACD in very early AD must be taken into account in clinical care and for trial enrollment as well.