bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immune checkpoint inhibitor-related colitis assessment and prognosis: can IBD scoring point the way?
Authors: Cheung Vincent Ting Fung , Gupta Tarun , Olsson-Brown Anna , Subramanian Sreedhar , Sasson Sarah Christina , Heseltine Jonathan , Fryer Eve , Collantes Elena , Sacco Joseph J. , Pirmohamed Munir , Simmons Alison , Klenerman Paul , Tuthill Mark , Protheroe Andrew S. , Chitnis Meenali , Fairfax Benjamin Peter , Payne Miranda Jane , Middleton Mark Ross , Brain Oliver 
Published: May 2020

Abstract
Background
Immune checkpoint inhibitors (ICI) improve survival but cause immune-related adverse events (irAE). We sought to determine if CTCAE classification, IBD biomarkers/endoscopic/histological scores correlate with irAE colitis outcomes.

Methods
A dual-centre retrospective study was performed on patients receiving ICI for melanoma, NSCLC or urothelial cancer from 2012 to 2018. Demographics, clinical data, endoscopies (reanalysed using Mayo/Ulcerative Colitis Endoscopic Index of Severity (UCEIS) scores), histology (scored with Nancy Index) and treatment outcomes were analysed.

Results
In all, 1074 patients were analysed. Twelve percent (134) developed irAE colitis. Median patient age was 66, 59% were male. CTCAE diarrhoea grade does not correlate with steroid/ infliximab use. G3/4 colitis patients are more likely to need infliximab (p < 0.0001) but colitis grade does not correlate with steroid duration. CRP, albumin and haemoglobin do not correlate with severity. The UCEIS (p = 0.008) and Mayo (p = 0.016) scores correlate with severity/infliximab requirement. Patients with higher Nancy indices (3/4) are more likely to require infliximab (p = 0.03).

Conclusions
CTCAE assessment does not accurately reflect colitis severity and our data do not support its use in isolation, as this may negatively impact timely management. Our data support utilising endoscopic scoring for patients with >grade 1 CTCAE disease, and demonstrate the potential prognostic utility of objective histologic scoring.
UGT2B17 modifies drug response in chronic lymphocytic leukaemia
Authors: Allain Eric P. , Rouleau Michèle , Vanura Katrina , Tremblay Sophie , Vaillancourt Joanie , Bat Vincent , Caron Patrick , Villeneuve Lyne , Labriet Adrien , Turcotte Véronique , Le Trang , Shehata Medhat , Schnabl Susanne , Demirtas Dita , Hubmann Rainer , Joly-Beauparlant Charles , Droit Arnaud , Jäger Ulrich , Staber Philipp B. , Lévesque Eric , Guillemette Chantal 
Published: May 2020

Abstract
Background
High UGT2B17 is associated with poor prognosis in untreated chronic lymphocytic leukaemia (CLL) patients and its expression is induced in non-responders to fludarabine-containing regimens. We examined whether UGT2B17, the predominant lymphoid glucuronosyltransferase, affects leukaemic drug response and is involved in the metabolic inactivation of anti-leukaemic agents.

Methods
Functional enzymatic assays and patients’ plasma samples were analysed by mass-spectrometry to evaluate drug inactivation by UGT2B17. Cytotoxicity assays and RNA sequencing were used to assess drug response and transcriptome changes associated with high UGT2B17 levels.

Results
High UGT2B17 in B-cell models led to reduced sensitivity to fludarabine, ibrutinib and idelalisib. UGT2B17 expression in leukaemic cells involved a non-canonical promoter and was induced by short-term treatment with these anti-leukaemics. Glucuronides of both fludarabine and ibrutinib were detected in CLL patients on respective treatment, however UGT2B17 conjugated fludarabine but not ibrutinib. AMP-activated protein kinase emerges as a pathway associated with high UGT2B17 in fludarabine-treated patients and drug-treated cell models. The expression changes linked to UGT2B17 exposed nuclear factor kappa B as a key regulatory hub.

Conclusions
Data imply that UGT2B17 represents a mechanism altering drug response in CLL through direct inactivation but would also involve additional mechanisms for drugs not inactivated by UGT2B17.
CDK4/6 inhibition presents as a therapeutic option for paediatric and adult germ cell tumours and induces cell cycle arrest and apoptosis via canonical and non-canonical mechanisms
Authors: Skowron Margaretha A. , Vermeulen Marieke , Winkelhausen Anna , Becker Teresa K. , Bremmer Felix , Petzsch Patrick , Schönberger Stefan , Calaminus Gabriele , Köhrer Karl , Albers Peter , Nettersheim Daniel 
Published: May 2020

Abstract
Background
Germ cell tumours (GCTs) are the most common solid malignancies in young men. Although high cure rates can be achieved, metastases, resistance to cisplatin-based therapy and late toxicities still represent a lethal threat, arguing for the need of new therapeutic options. In this study, we analysed the potential of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors palbociclib and ribociclib (PaRi) as molecular drugs to treat cisplatin-resistant and -sensitive paediatric and adult GCTs.

Methods
Ten GCT cell lines, including cisplatin-resistant subclones and non-malignant controls, were treated with PaRi and screened for changes in viability (triphenyl tetrazolium chloride (XTT) assay), apoptosis rates (flow cytometry, caspase assay), the cell cycle (flow cytometry), the transcriptome (RNA-sequencing, quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) and on protein level (western blot). Expression profiling was performed on paediatric and adult GCT tissues (expression microarrays, qRT-PCR, immunohistochemistry, ‘The Cancer Genome Atlas’ database).

Results
We demonstrate that adult GCTs highly express CDK4, while paediatric GCTs strongly express CDK6 instead. Thus, both GCT types are potentially treatable by PaRi. GCTs presented as highly sensitive towards PaRi, which caused a decrease in viability, cell cycle arrest and apoptosis. Although GCTs mainly arrested in the G1/G0 phase, some embryonal carcinoma cell lines were able to bypass the G1/S checkpoint and progressed to the G2/M phase. We found that upregulation of CDK3 and downregulation of many mitosis regulation factors, like the HAUS genes, might be responsible for bypassing the G1/S checkpoint and termination of mitosis, respectively. We postulate that GCT cells do not tolerate these alterations in the cell cycle and eventually induce apoptosis.

Conclusion
Our study highlights PaRi as therapeutic options for cisplatin-resistant and -sensitive paediatric and adult GCTs.
Setting the photoelectron clock through molecular alignment
Authors: Trabattoni Andrea , Wiese Joss , De Giovannini Umberto , Olivieri Jean-François , Mullins Terry , Onvlee Jolijn , Son Sang-Kil , Frusteri Biagio , Rubio Angel , Trippel Sebastian , Küpper Jochen 
Published: May 2020

AbstractThe interaction of strong laser fields with matter intrinsically provides a powerful tool for imaging transient dynamics with an extremely high spatiotemporal resolution. Here, we study strong-field ionisation of laser-aligned molecules, and show a full real-time picture of the photoelectron dynamics in the combined action of the laser field and the molecular interaction. We demonstrate that the molecule has a dramatic impact on the overall strong-field dynamics: it sets the clock for the emission of electrons with a given rescattering kinetic energy. This result represents a benchmark for the seminal statements of molecular-frame strong-field physics and has strong impact on the interpretation of self-diffraction experiments. Furthermore, the resulting encoding of the time-energy relation in molecular-frame photoelectron momentum distributions shows the way of probing the molecular potential in real-time, and accessing a deeper understanding of electron transport during strong-field interactions.
A randomized trial evaluating virus-specific effects of a combination probiotic in children with acute gastroenteritis
Authors: Freedman Stephen B. , Xie Jianling , Nettel-Aguirre Alberto , Pang Xiao-Li , Chui Linda , Williamson-Urquhart Sarah , Schnadower David , Schuh Suzanne , Sherman Philip M. , Lee Bonita E. , Gouin Serge , Farion Ken J. , Poonai Naveen , Hurley Katrina F. , Qiu Yuanyuan , Ghandi Binal , Lloyd Colin , Finkelstein Yaron ,   the Pediatric Emergency Research Canada Probiotic (PERC) Regimen for Outpatient Gastroenteritis Utility of Treatment (PROGUT) Trial Group, Freedman Stephen B. , Xie Jianling , Nettel-Aguirre Alberto , Pang Xiao-Li , Chui Linda , Williamson-Urquhart Sarah , Schnadower David , Schuh Suzanne , Sherman Philip M. , Lee Bonita , Gouin Serge , Farion Ken J. , Poonai Naveen , Hurley Katrina F. , Qiu Yuanyuan , Ghandi Binal , Lloyd Colin , Finkelstein Yaron , Willan Andrew R. , Goeree Ron , Johnson David W. , Black Karen , Gorelick Marc H. 
Published: May 2020

AbstractGastroenteritis accounts for nearly 500,000 deaths in children younger than 5 years annually. Although probiotics have been touted as having the potential to expedite diarrhea resolution, recent clinical trials question their effectiveness. A potential explanation is a shift in pathogens following the introduction of a rotavirus vaccine. Here, we report the results of a multi-center, double-blind trial of 816 children with acute gastroenteritis who completed follow-up and provided multiple stool specimens. Participants were randomized to receive a probiotic containing Lactobacillus rhamnosus and Lactobacillushelveticus or placebo. We report no virus-specific beneficial effects attributable to the probiotic, either in reducing clinical symptoms or viral nucleic acid clearance from stool specimens collected up to 28 days following enrollment. We provide pathophysiological and microbiologic evidence to support the clinical findings and conclude that our data do not support routine probiotic administration to children with acute gastroenteritis, regardless of the infecting virus.
Mitochondrial phosphatase PGAM5 modulates cellular senescence by regulating mitochondrial dynamics
Authors: Yu Bo , Ma Jing , Li Jing , Wang Dazhi , Wang Zhigao , Wang Shusheng 
Published: May 2020

AbstractMitochondria undergo dynamic fusion/fission, biogenesis and mitophagy in response to stimuli or stresses. Disruption of mitochondrial homeostasis could lead to cell senescence, although the underlying mechanism remains unclear. We show that deletion of mitochondrial phosphatase PGAM5 leads to accelerated retinal pigment epithelial (RPE) senescence in vitro and in vivo. Mechanistically, PGAM5 is required for mitochondrial fission through dephosphorylating DRP1. PGAM5 deletion leads to increased mitochondrial fusion and decreased mitochondrial turnover. As results, cellular ATP and reactive oxygen species (ROS) levels are elevated, mTOR and IRF/IFN-β signaling pathways are enhanced, leading to cellular senescence. Overexpression of Drp1 K38A or S637A mutant phenocopies or rescues mTOR activation and senescence in PGAM5−/− cells, respectively. Young but not aging Pgam5−/− mice are resistant to sodium iodate-induced RPE cell death. Our studies establish a link between defective mitochondrial fission, cellular senescence and age-dependent oxidative stress response, which have implications in age-related diseases.
FoxO1–Dio2 signaling axis governs cardiomyocyte thyroid hormone metabolism and hypertrophic growth
Authors: Ferdous Anwarul , Wang Zhao V. , Luo Yuxuan , Li Dan L. , Luo Xiang , Schiattarella Gabriele G. , Altamirano Francisco , May Herman I. , Battiprolu Pavan K. , Nguyen Annie , Rothermel Beverly A. , Lavandero Sergio , Gillette Thomas G. , Hill Joseph A. 
Published: May 2020

AbstractForkhead box O (FoxO) proteins and thyroid hormone (TH) have well established roles in cardiovascular morphogenesis and remodeling. However, specific role(s) of individual FoxO family members in stress-induced growth and remodeling of cardiomyocytes remains unknown. Here, we report that FoxO1, but not FoxO3, activity is essential for reciprocal regulation of types II and III iodothyronine deiodinases (Dio2 and Dio3, respectively), key enzymes involved in intracellular TH metabolism. We further show thatDio2is a direct transcriptional target of FoxO1, and the FoxO1–Dio2 axis governs TH-induced hypertrophic growth of neonatal cardiomyocytes in vitro and in vivo. Utilizing transverse aortic constriction as a model of hemodynamic stress in wild-type and cardiomyocyte-restrictedFoxO1knockout mice, we unveil an essential role for the FoxO1–Dio2 axis in afterload-induced pathological cardiac remodeling and activation of TRα1. These findings demonstrate a previously unrecognized FoxO1–Dio2 signaling axis in stress-induced cardiomyocyte growth and remodeling and intracellular TH homeostasis.
Ultra Short Echo Time MRI of Iron-Labelled Mesenchymal Stem Cells in an Ovine Osteochondral Defect Model
Authors: Kaggie Joshua D. , Markides Hareklea , Graves Martin J. , MacKay James , Houston Gavin , El Haj Alicia , Gilbert Fiona , Henson Frances 
Published: May 2020

AbstractMultipotent Mesenchymal Stem/Stromal Cells (MSCs) are widely used in cellular therapy for joint repair. However, the use of MSC therapies is complicated by a lack of understanding of the behaviour of cells and repair within the joint. Current methods of MSC tracking include labelling the cells with Super Paramagnetic Iron Oxide nanoparticles (SPIOs). However, standard acquisition sequences (T2 and T2*) give poor anatomical definition in the presence of SPIOs. To avoid anatomical compromise in the presence of SPIOs, we have investigated the use of Ultra-short Echo Time (UTE) MRI, using a 3D cones acquisition trajectory. This method was used to track SPIO labelled MSC injected into joints containing osteochondral defects in experimental sheep. This study demonstrates that multiple echo times from UTE with 3 T MRI can provide excellent anatomical detail of osteochondral defects and demonstrate similar features to histology. This work also monitors the location of SPIO-labelled cells for regenerative medicine of the knee with MRI, histology, and Prussian blue staining. With these methods, we show that the SPIOs do not hone to the site of defect but instead aggregate in the location of injection, which suggests that any repair mechanism with this disease model must trigger a secondary process.
Selection of Endogenous Control Reference Genes for Studies on Type 1 or Type 2 Endometrial Cancer
Authors: Ayakannu Thangesweran , Taylor Anthony H. , Konje Justin C. 
Published: May 2020

AbstractA panel of 32 candidate reference genes was used to identify the most stable genes for gene normalisation in quantitative RT-PCR studies using endometrial biopsies obtained from women with endometrial cancer (type 1 or type 2) and without cancer (controls). RNA from the biopsies was isolated, examined for purity and quality, and then reverse transcribed into cDNA before being subjected to real-time qRT-PCR analysis in triplicate within the TaqMan gene Expression Assay kit. The most ‘stable’ endogenous control genes were then identified using the geNorm qbase + 2 and NormFinder software packages. PSMC4, PUM1 and IPO8 were identified as the best reference genes combination for type 1 endometrial cancer (grades 1, 2 and 3), whereas for type 2 endometrial cancer (serous and carcinosarcoma), UBC, MRPL19, PGK1 and PPIA were the best reference genes combination. We conclude that the use of these normaliser combinations should provide accurate interpretation of gene expression at the transcript level in endometrial cancer studies especially for types 1 and 2 cancers.
Collapse dynamics of spherical cavities in a solid under shock loading
Authors: Escauriza E. M. , Duarte J. P. , Chapman D. J. , Rutherford M. E. , Farbaniec L. , Jonsson J. C. , Smith L. C. , Olbinado M. P. , Skidmore J. , Foster P. , Ringrose T. , Rack A. , Eakins D. E. 
Published: May 2020

AbstractExtraordinary states of highly localised pressure and temperature can be generated upon the collapse of impulsively driven cavities. Direct observation of this phenomenon in solids has proved challenging, but recent advances in high-speed synchrotron radiography now permit the study of highly transient, subsurface events in real time. We present a study on the shock-induced collapse of spherical cavities in a solid polymethyl methacrylate medium, driven to shock states between 0.49 and 16.60 GPa. Utilising multi-MHz phase contrast radiography, extended sequences of the collapse process have been captured, revealing new details of interface motion, material failure and jet instability formation. Results reveal a rich array of collapse characteristics dominated by strength effects at low shock pressures and leading to a hydrodynamic response at the highest loading conditions.
Spiny lobster sounds can be detectable over kilometres underwater
Authors: Jézéquel Youenn , Chauvaud Laurent , Bonnel Julien 
Published: May 2020

AbstractThe detection ranges of broadband sounds produced by marine invertebrates are not known. To address this deficiency, a linear array of hydrophones was built in a shallow water area to experimentally investigate the propagation features of the sounds from various sizes of European spiny lobsters (Palinurus elephas), recorded between 0.5 and 100 m from the animals. The peak-to-peak source levels (SL, measured at one meter from the animals) varied significantly with body size, the largest spiny lobsters producing SL up to 167 dB re 1 µPa2. The sound propagation and its attenuation with the distance were quantified using the array. This permitted estimation of the detection ranges of spiny lobster sounds. Under the high ambient noise conditions recorded in this study, the sounds propagated between 5 and 410 m for the smallest and largest spiny lobsters, respectively. Considering lower ambient noise levels and different realistic propagation conditions, spiny lobster sounds can be detectable up to several kilometres away from the animals, with sounds from the largest individuals propagating over 3 km. Our results demonstrate that sounds produced byP. elephascan be utilized in passive acoustic programs to monitor and survey this vulnerable species at kilometre scale in coastal waters.
Towards developing a test of global motion for use with Paralympic athletes
Authors: Roberts James W. , Thompson Benjamin , Leat Susan J. , Dalton Kristine 
Published: May 2020

AbstractThe Paralympic classification system for visual impairment only assesses static visual acuity and static visual field despite many Paralympic sports being dynamic in nature. As a first step towards determining whether motion perception tests should be used in Paralympic classification, we assessed whether motion coherence thresholds could be measured when visual acuity or visual fields were impaired at levels consistent with the current Paralympic classification criteria. Visual acuity and visual field impairments corresponding to Paralympic classification criteria were simulated in normally sighted individuals and motion coherence thresholds were measured. Mild-to-moderate visual acuity impairments had no effect on motion coherence thresholds. The most severe Paralympic class of acuity impairment (≥2.6 logMAR) significantly elevated thresholds. A trend towards superior motion coherence thresholds in the peripheral visual field compared to the central visual field was also present. Global motion perception appears to be measurable under simulated visual impairments that are consistent with the Paralympic classification. Poorer global motion perception was found for visual acuities >2.6 logMAR and visual fields <10° in diameter. Further research is needed to investigate the relationship between global motion perception and sports performance in athletes with real visual impairment.
Transmission of highly pathogenic avian influenza in the nomadic free-grazing duck production system in Viet Nam
Authors: Willgert Katriina , Meyer Anne , Tung Dinh Xuan , Thu Nhu Van , Long Pham Thanh , Newman Scott , Thuy Nguyen Thi Thanh , Padungtod Pawin , Fournié Guillaume , Pfeiffer Dirk Udo , Vergne Timothée 
Published: May 2020

AbstractThe presence of free-grazing ducks (FGD) has consistently been shown to be associated with highly pathogenic avian influenza virus (HPAIV) H5N1 outbreaks in South-East Asia. However, the lack of knowledge about the transmission pathways limits the effectiveness of control efforts. To address this gap, we developed a probabilistic transmission model of HPAIV H5N1 in the nomadic FGD production system in Viet Nam, assuming different scenarios to address parameter uncertainty. Results suggested that HPAIV H5N1 could spread within the nomadic FGD production system, with an estimated flock-level effective reproduction number (re) ranging from 2.16 (95% confidence interval (CI): 1.39-3.49) to 6.10 (95%CI: 3.93-9.85) depending on the scenario. Indirect transmission via boats and trucks was shown to be the main transmission route in all scenarios. Results suggest that re could be reduced below one with 95% confidence if 86% of FGD flocks were vaccinated in the best-case scenario or 95% in the worst-case scenario. If vaccination was combined with cleaning and disinfection of transport vehicles twice a week, vaccination coverage could be lowered to 60% in the best-case scenario. These findings are of particular relevance for prioritising interventions for effective control of HPAIV in nomadic free-grazing duck production systems.
The impact of Hurricane Michael on longleaf pine habitats in Florida
Authors: Zampieri Nicole E. , Pau Stephanie , Okamoto Daniel K. 
Published: May 2020

AbstractGlobal biodiversity hotspots (GBHs) are increasingly vulnerable to human stressors such as anthropogenic climate change, which will alter the ecology of these habitats, even where protected. The longleaf pine (Pinus palustris) ecosystem (LPE) of the North American Coastal Plain is a GBH where disturbances are integral for ecosystem maintenance. However, stronger storms due to climate change may be outside their historical norm. In this study, we estimate the extent of Florida LPE that was directly affected by Hurricane Michael in 2018, an unprecedented Category 5 storm. We then leveraged a unique data set in a Before-After study of four sites within this region. We used variable-area transects and generalized linear mixed-effects models to estimate tree densities and logistic regression to estimate mortality by size class. We found at least 28% of the global total remaining extent of LPE was affected in Florida alone. Mortality was highest in medium sized trees (30–45 cm dbh) and ranged from 4.6–15.4% at sites further from the storm center, but increased to 87.8% near the storm center. As the frequency and intensity of extreme events increases, management plans to mitigate climate change need to account for large-scale stochastic mortality events to preserve critical habitats.
Language can shape the perception of oriented objects
Authors: Navarrete Eduardo , Miozzo Michele , Peressotti Francesca 
Published: May 2020

AbstractSeeing an object is a natural source for learning about the object’s configuration. We show that language can also shape our knowledge about visual objects. We investigated sign language that enables deaf individuals to communicate through hand movements with as much expressive power as any other natural language. A few signs represent objects in a specific orientation. Sign-language users (signers) recognized visual objects faster when oriented as in the sign, and this match in orientation elicited specific brain responses in signers, as measured by event-related potentials (ERPs). Further analyses suggested that signers’ responsiveness to object orientation derived from changes in the visual object representations induced by the signs. Our results also show that language facilitates discrimination between objects of the same kind (e.g., different cars), an effect never reported before with spoken languages. By focusing on sign language we could better characterize the impact of language (a uniquely human ability) on object visual processing.