bluuebunny/crossref_metadata_2025_split huggingface dataset:
Peptide targeting of lysophosphatidylinositol-sensing GPR55 for osteoclastogenesis tuning
Authors: Mosca Maria Giovanna , Mangini Maria , Cioffi Stefania , Barba Pasquale , Mariggiò Stefania 
Published: April 2021

AbstractBackgroundThe G-protein-coupled receptor GPR55 has been implicated in multiple biological activities, which has fuelled interest in its functional targeting. Its controversial pharmacology and often species-dependent regulation have impacted upon the potential translation of preclinical data involving GPR55.ResultsWith the aim to identify novel GPR55 regulators, we have investigated lysophosphatidylinositol (LPI)-induced GPR55-mediated signal transduction. The expression system for wild-type and mutated GPR55 was HeLa cells silenced for their endogenous receptor by stable expression of a short-hairpin RNA specific forGPR555′-UTR, which allowed definition of the requirement of GPR55 Lys80for LPI-induced MAPK activation and receptor internalisation. In RAW264.7 macrophages, GPR55 pathways were investigated byGpr55silencing using small-interfering RNAs, which demonstrated that LPI increased intracellular Ca2+levels and induced actin filopodium formation through GPR55 activation. Furthermore, the LPI/GPR55 axis was shown to have an active role in osteoclastogenesis of precursor RAW264.7 cells induced by ‘receptor-activator of nuclear factor kappa-β ligand’ (RANKL). Indeed, this differentiation into mature osteoclasts was associated with a 14-fold increase inGpr55mRNA levels. Moreover, GPR55 silencing and antagonism impaired RANKL-induced transcription of the osteoclastogenesis markers: ‘nuclear factor of activated T-cells, cytoplasmic 1′, matrix metalloproteinase-9, cathepsin-K, tartrate-resistant acid phosphatase, and the calcitonin receptor, as evaluated by real-time PCR. Phage display was previously used to identify peptides that bind to GPR55. Here, the GPR55-specific peptide-P1 strongly inhibited osteoclast maturation of RAW264.7 macrophages, confirming its activity as a blocker of GPR55-mediated functions. Although osteoclast syncytium formation was not affected by pharmacological regulation of GPR55, osteoclast activity was dependent on GPR55 signalling, as shown with resorption assays on bone slices, where LPI stimulated and GPR55 antagonists inhibited bone erosion.ConclusionsOur data indicate that GPR55 represents a target for development of novel therapeutic approaches for treatment of pathological conditions caused by osteoclast-exacerbated bone degradation, such as in osteoporosis or during establishment of bone metastases.
COVID-19 related mortality in post-operative cardiac surgical patients
Authors: Hussain Azhar , Khalil Amina , Kolvekar Priyanka , Gupta Prity , Kolvekar Shyamsunder 
Published: April 2021

Abstract
Background
COVID-19 has caused a global pandemic of unprecedented proportions. Elective cardiac surgery has been universally postponed with only urgent and emergency cardiac operations being performed. The National Health Service in the United Kingdom introduced national measures to conserve intensive care beds and significantly limit elective activity shortly after lockdown.

Case presentation
We report two cases of early post-operative mortality secondary to COVID-19 infection immediately prior to the implementation of these widespread measures.

Conclusion
The role of cardiac surgery in the presence of COVID-19 is still very unpredictable and further studies on both short term and long term outcomes are warranted.
A multi-stakeholder multicriteria decision analysis for the reimbursement of orphan drugs (FinMHU-MCDA study)
Authors:   the FinMHU-MCDA Group, de Andrés-Nogales Fernando , Cruz Encarnación , Calleja Miguel Ángel , Delgado Olga , Gorgas Maria Queralt , Espín Jaime , Mestre-Ferrándiz Jorge , Palau Francesc , Ancochea Alba , Arce Rosabel , Domínguez-Hernández Raquel , Casado Miguel Ángel 
Published: April 2021

Abstract
Background
Patient access to orphan medicinal products (OMPs) is limited and varies between countries, reimbursement decisions on OMPs are complex, and there is a need for more transparent processes to know which criteria should be considered to inform these decisions. This study aimed to determine the most relevant criteria for the reimbursement of OMPs in Spain, from a multi-stakeholder perspective, and using multicriteria decision analysis (MCDA).

Methods
An MCDA was developed in 3 phases and included 28 stakeholders closely related to the field of rare diseases (6 physicians, 5 hospital pharmacists, 7 health economists, 4 patient representatives and 6 members from national and regional health authorities). Initially [phase A], a bibliographic review was conducted to identify the potential reimbursement criteria. Then, a reduced advisory board (8 members) proposed, selected, and defined the final list of criteria that could be relevant for reimbursement. A discrete choice experiment (DCE) [phase B] was developed to determine the relevance and relative importance weight of such criteria according to the stakeholders’ preferences by choosing between pairs of hypothetical financing scenarios. A multinomial logit model was fitted to analyze the DCE responses. Finally [phase C], the advisory board review the results using a deliberative process.

Results
Thirteen criteria were selected, related to 4 dimensions: patient population, disease, treatment, and economic evaluation. Nine criteria were deemed relevant for decision-making and associated with a higher relative importance: Health-related quality of life (HRQL) (23.53%), treatment efficacy (14.64%), availability of treatment alternatives (13.51%), disease severity (12.62%), avoided costs (11.21%), age of target population (7.75%), safety (seriousness of adverse events) (4.72%), quality of evidence (3.82%) and size of target population (3.12%). The remaining criteria had a < 3% relative importance: economic burden of disease (2.50%), cost of treatment (1.73%), cost-effectiveness (0.83%) and safety (frequency of adverse events) (0.03%).

Conclusion
The reimbursement of OMPs in Spain should be determined by its effect on patient’s HRQL, the extent of its therapeutic benefit from efficacy and the availability of other therapeutic options. Furthermore, the severity of the rare disease should also influence the decision along with the potential of the treatment to avoid associated costs.
Inhibition of retinoic acid receptor α phosphorylation represses the progression of triple-negative breast cancer via transactivating miR-3074-5p to target DHRS3
Authors: Lou Siyue , Gao Hang , Hong Huanwu , Zhu Zhihui , Zhao Huajun 
Published: April 2021

Abstract
Background
Retinoids are promising agents in the treatment of different types of neoplasia including estrogen receptor-positive breast cancers, whereas refractoriness/low sensitivity is observed in triple-negative breast cancer (TNBC) subtype. However, the reason for these diverse retinoid-sensitivity remains elusive.

Methods
Determinants of retinoid sensitivity were investigated using immunohistochemistry of primary patient samples, and identified retinoic acid receptor α (RARα) as a putative factor. The anti-tumor activity of hypo-phosphorylated RARα was investigated in TNBC cell models and a xenograft mouse model. Next, miRNA sequencing analysis was performed to identify the target miRNA of RARα, and luciferase reporter was used to confirm the direct target gene of miR-3074-5p.

Results
We discovered that serine-77 residue of RARα was constantly phosphorylated, which correlated with TNBC’s resistance to retinoids. Overexpression of a phosphorylation-defective mutant RARαS77A mimicked activated RARα and repressed TNBC cell progression both in vitro and in vivo, via activating cell cycle arrest, apoptosis, and cytotoxic autophagy, independent of RARα agonists. We further revealed that the anti-tumor action of RARαS77A was, at least in part, mediated by the up-regulation of miR-3074-5p, which directly targeted DHRS3, a reductase negatively associated with TNBC patient survival. Our results suggest that the inhibition of RARαS77 phosphorylation by either expressing RARαS77A or inhibiting RARα’s phosphokinase CDK7, can bypass RA stimuli to transactivate tumor-suppressive miR-3074-5p and reduce oncogenic DHRS3, thus overcoming the RA-resistance of TNBC.

Conclusion
The novel regulatory network, involving RARαS77 phosphorylation, miR-3074-5p, and DHRS3, emerges as a new target for TNBC treatment.
Systematic review of the use of translated patient-reported outcome measures in cancer trials
Authors: Slade A. L. , Retzer A. , Ahmed K. , Kyte D. , Keeley T. , Armes J. , Brown J. M. , Calman L. , Gavin A. , Glaser A. W. , Greenfield D. M. , Lanceley A. , Taylor R. M. , Velikova G. , Turner G. , Calvert M. J. 
Published: April 2021

AbstractBackgroundPatient-reported outcomes (PROs) are used in clinical trials to assess the effectiveness and tolerability of interventions. Inclusion of participants from different ethnic backgrounds is essential for generalisability of cancer trial results. PRO data collection should include appropriately translated patient-reported outcome measures (PROMs) to minimise missing data and sample attrition.MethodsProtocols and/or publications from cancer clinical trials using a PRO endpoint and registered on the National Institute for Health Research Portfolio were systematically reviewed for information on recruitment, inclusion of ethnicity data, and use of appropriately translated PROMs. Semi-structured interviews were conducted with key stakeholders to explore barriers and facilitators for optimal PRO trial design, diverse recruitment and reporting, and use of appropriately translated PROMs.ResultsEighty-four trials met the inclusion criteria, only 14 (17%) (n = 4754) reported ethnic group data, and ethnic group recruitment was low, 611 (13%). Although 8 (57%) studies were multi-centred and multi-national, none reported using translated PROMs, although available for 7 (88%) of the studies.Interviews with 44 international stakeholders identified a number of perceived barriers to ethnically diverse recruitment including diverse participant engagement, relevance of ethnicity to research question, prominence of PROs, and need to minimise investigator burden. Stakeholders had differing opinions on the use of translated PROMs, the impact of trial designs, and recruitment strategies on diverse recruitment. Facilitators of inclusive research were described and examples of good practice identified.ConclusionsGreater transparency is required when PROs are used as primary or secondary outcomes in clinical trials. Protocols and publications should demonstrate that recruitment was accessible to diverse populations and facilitated by trial design, recruitment strategies, and appropriate PROM usage. The use of translated PROMs should be made explicit when used in cancer clinical trials.
Current advances of epigenetics in periodontology from ENCODE project: a review and future perspectives
Authors: Cho Young-Dan , Kim Woo-Jin , Ryoo Hyun-Mo , Kim Hong-Gee , Kim Kyoung-Hwa , Ku Young , Seol Yang-Jo 
Published: April 2021

Abstract
Background
The Encyclopedia of DNA Elements (ENCODE) project has advanced our knowledge of the functional elements in the genome and epigenome. The aim of this article was to provide the comprehension about current research trends from ENCODE project and establish the link between epigenetics and periodontal diseases based on epigenome studies and seek the future direction.

Main body
Global epigenome research projects have emphasized the importance of epigenetic research for understanding human health and disease, and current international consortia show an improved interest in the importance of oral health with systemic health. The epigenetic studies in dental field have been mainly conducted in periodontology and have focused on DNA methylation analysis. Advances in sequencing technology have broadened the target for epigenetic studies from specific genes to genome-wide analyses.

Conclusions
In line with global research trends, further extended and advanced epigenetic studies would provide crucial information for the realization of comprehensive dental medicine and expand the scope of ongoing large-scale research projects.
Repeat individualized assessment using isomorphic questions: a novel approach to increase peer discussion and learning
Authors: Millar Russell , Manoharan Sathiamoorthy 
Published: April 2021

AbstractIt is demonstrated that the fully automatic generation of isomorphic questions allows for both repeat assessment, and for this assessment to be individualized. While this does require a substantial up-front effort, once prepared assessments can be reproduced with relative ease and with a near-zero probability of students receiving the same question a second time. We show the effectiveness of this approach using survey and performance data obtained from large year 2 and year 3 computer science classes. A greater than 10-fold increase in online peer discussion was observed, compared to the previous year. Contents analysis of the surveys showed that repeat testing was generally regarded favourably. Quantitative analyses found that prior homework did little to improve initial test performance, but was of vital importance in studying for the follow-up isomorphic test. Moreover, the performance gain on the isomorphic questions was the same for all students regardless of their overall ability, and was retained in the final exam.
Harmonizing evidence-based practice, implementation context, and implementation strategies with user-centered design: a case example in young adult cancer care
Authors: Haines Emily R. , Dopp Alex , Lyon Aaron R. , Witteman Holly O. , Bender Miriam , Vaisson Gratianne , Hitch Danielle , Birken Sarah 
Published: April 2021

AbstractBackgroundAttempting to implement evidence-based practices in contexts for which they are not well suited may compromise their fidelity and effectiveness or burden users (e.g., patients, providers, healthcare organizations) with elaborate strategies intended to force implementation. To improve the fit between evidence-based practices and contexts, implementation science experts have called for methods for adapting evidence-based practices and contexts and tailoring implementation strategies; yet, methods for considering the dynamic interplay among evidence-based practices, contexts, and implementation strategies remain lacking. We argue that harmonizing the three can be facilitated by user-centered design, an iterative and highly stakeholder-engaged set of principles and methods.MethodsThis paper presents a case example in which we used a three-phase user-centered design process to design and plan to implement a care coordination intervention for young adults with cancer. Specifically, we usedusability testingto redesign and augment an existing patient-reported outcome measure that served as the basis for our intervention to optimize its usability and usefulness,ethnographic contextual inquiryto prepare the context (i.e., a comprehensive cancer center) to promote receptivity to implementation, and iterativeprototyping workshops with a multidisciplinary design teamto design the care coordination intervention and anticipate implementation strategies needed to enhance contextual fit.ResultsOur user-centered design process resulted in the Young Adult Needs Assessment and Service Bridge (NA-SB), including a patient-reported outcome measure and a collection of referral pathways that are triggered by the needs young adults report, as well as implementation guidance. By ensuring NA-SB directly responded to features of users and context, we designed NA-SBfor implementation, potentially minimizing the strategies needed to address misalignment that may have otherwise existed. Furthermore, we designed NA-SBfor scale-up; by engaging users from other cancer programs across the country to identify points of contextual variation which would require flexibility in delivery, we created a tool intended to accommodate diverse contexts.ConclusionsUser-centered design can help maximize usability and usefulness when designing evidence-based practices, preparing contexts, and informing implementation strategies—in effect, harmonizing evidence-based practices, contexts, and implementation strategies to promote implementation and effectiveness.
Intercellular Relations in the Development of Amphibian Pigmentation
Authors: Twitty Victor C. 
Published: April 2021

ABSTRACT
The role of intercellular influences in the control of differentiation finds many illustrations in the development of amphibian pigmentation. From the time the chromatophores leave the neural crest as colourless, amoeboid cells, until they come to rest as differentiated elements of the distinctive pigment pattern, their developmental behaviour is conditioned throughout by effects exerted mutually by the chromatophores themselves or imposed upon them by the cells of neighbouring tissues. For the purposes of the present discussion, I shall limit myself to examples of intercellular relations affecting (1) the migration of chromatoblasts and (2) their synthesis of pigment.
Influence of Certain Substances on the Fluidity of the Cytoplasm and the Fertilizability of the Egg of the Sea-urchin, Psammechinus miliaris
Authors: Wicklund Elsa , Kriszat Georg , Runnström John 
Published: April 2021

ABSTRACT
After nuclear maturation the eggs of Psammechinus (Ps.) miliaris are still ‘underripe’ with respect to their cytoplasm. This phenomenon is particularly conspicuous in Ps. miliaris from the Swedish west coast (see, for a summary, Runnström, 1949). In the small individuals of Ps. miliaris dredged from a depth of 30–40 metres this state of underripeness may last for months, so that full cytoplasmic maturity may be reached only in the latter half of August (Lindahl & Runnström, 1929). The littoral form of Ps. miliaris, on the other hand, has already attained cytoplasmic maturity in the latter half of June. Temperature conditions evidently play a decisive role in the phenomenon.
Inter-specific Transfers of Eggs Between Rat and Mouse
Authors: Tarkowski Andrzej K. 
Published: April 2021

ABSTRACT
Mouse 2- and 8-cell and rat 2-, 4-, and 8-cell eggs develop into blastocysts when reciprocally transferred to the oviduct of the other species. Some rat eggs, after attaining the blastocyst stage in the mouse oviduct, do not shed the zona pellucida at the normal time and continue to increase in volume beyond the normal. This is accompanied by spreading of cells of the inner mass beneath the trophoblast, leaving the blastocyst without any compact embryonic structure. Other eggs develop into normal blastocysts with an inner cell mass present. Mouse eggs in the rat give rise to normally built blastocysts. Both kinds of rat blastocysts—hollow and normal—and mouse blastocysts evoke a typical decidual reaction in the uterus of the foreign species. Normal crypts are formed with the blastocysts attached to the epithelium. These processes begin well before any changes in the uterine epithelium become visible. The blastocysts of neither species are able to secure a normal contact with the mucosa. Degeneration of the epithelium under the influence of the trophoblast is delayed, irregular, and only small areas are involved. In the mouse, the eventual denudation of the mucosa around the blastocyst is thought to be largely an effect of spontaneous degeneration of the epithelium due to oedomatous changes in the underlying mucosa. The survival of mouse and rat blastocysts after implantation is very limited, the upper time limit being, in the mouse, the 7th day and, in the rat, the 8th day. Those rat blastocysts which have succeeded in establishing a contact with the mucosa undergo some differentiation, i.e. form small egg cylinders. This is accompanied by growth which in some cases is, however, very slight. Mouse blastocysts in the most successful cases exhibit immense increase in size but neither differentiation nor growth have been observed in their inner cell masses. The kidney surface of both species provides a favourable environment for the development of rat and mouse blastocysts reciprocally transferred. The trophoblast gives rise to numerous giant cells. The cells presumably of ‘inner mass’ origin are also visible, but organized embryonic development has not been observed. A number of rat eggs which developed into blastocysts in the mouse were re-transferred to rat recipients. The subsequent mortality rate was very high. Three purely trophoblastic vesicles were encountered and it is believed that they have developed from hollow blastocysts. These findings are discussed in the light of embryology and reproductive physiology.
Spinal neurite reabsorption and regrowth in vitro depend on the polarity of an applied electric field
Authors: McCaig Colin D. 
Published: April 2021

Abstract
Retraction and regrowth of frog neural tube neurites have been studied in vitro in control cultures and in the presence of a small, continuously applied electrical field. In control cultures, some degree of retraction was seen in 39 % of neurites while 7 % were reabsorbed completely. Reabsorption of anodalfacing neurites was at least twice as common, with 67 % showing some retraction and 17 % almost totally reabsorbed. Cathodal-facing neurites were spared from retraction. Following extreme reabsorption of anodal-facing neurites, reversal of the electric field promoted regeneration in 47 % (9/19) of cases studied.
Growth cone morphology also was determined by the polarity of the applied field. Anodal-facing growth cones had fewer filopodia than cathodal-facing growth cones sharing the same cell body. Field reversal induced a polarity-specific change in filopodia number on individual growth cones: a shift from anodal to cathodal increased filopodia numbers and vice versa. Some possible mechanisms involved and the significance of these results are discussed.
An analysis of cell shape and the neuroepithelial basal lamina during optic vesicle formation in the mouse embryo
Authors: Svoboda Kathy K. H. , O’Shea K. Sue 
Published: April 2021

ABSTRACT
The optic vesicle develops as an evagination of the cephalic neural folds. We have examined the early development of the optic vesicle in Swiss Webster mice using correlated transmission electron microscopy (TEM), scanning electron microscopy (SEM), light microscopic (LM) measurements of cell shape changes, immunohistochemical localization of basal lamina (BL) components (type IV collagen, laminin and heparan sulphate proteoglycan (HSPG)) and ultrastructural analysis of the BL.
Like the neuroepithelium in other regions, the low columnar cells of the neural plate in the future optic vesicle region become high columnar, then wedge shaped following constriction of the cell apices to form the C-shaped vesicle. In this region, the cells elongate 2 times their initial height before the neural tube closes, then shorten 20 % as the vesicle is completed. Cell apices decrease in width by about one half during vesicle formation. Deposition of BL components was initially even, with type IV collagen and laminin reduced in deposition in regions of outpouching. At later stages the linear, even distribution of all four components was re-established. Ultrastructural analysis confirmed the BL discontinuity and re-establishment and correlated the observed cell shaping alterations with apparent increases in the number of microtubules (during elongation) and microfilaments (during apical constriction). The number of apical intercellular junctions also appeared to increase in number during optic vesicle formation, possibly providing stability and coordination to the évagination process.