bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transcriptional epigenetic regulation of Fkbp1/Pax9 genes is associated with impaired sensitivity to platinum treatment in ovarian cancer
Authors: Soto Javier Andrés , Rodríguez-Antolín Carlos , Vera Olga , Pernía Olga , Esteban-Rodríguez Isabel , Dolores Diestro Maria , Benitez Javier , Sánchez-Cabo Fátima , Alvarez Rafael , De Castro Javier , Ibanez de Cáceres Inmaculada 
Published: August 2021

Abstract
Background
In an effort to contribute to overcoming the platinum resistance exhibited by most solid tumors, we performed an array of epigenetic approaches, integrating next-generation methodologies and public clinical data to identify new potential epi-biomarkers in ovarian cancer, which is considered the most devastating of gynecological malignancies.

Methods
We cross-analyzed data from methylome assessments and restoration of gene expression through microarray expression in a panel of four paired cisplatin-sensitive/cisplatin-resistant ovarian cancer cell lines, along with publicly available clinical data from selected individuals representing the state of chemoresistance. We validated the methylation state and expression levels of candidate genes in each cellular phenotype through Sanger sequencing and reverse transcription polymerase chain reaction, respectively. We tested the biological role of selected targets using an ectopic expression plasmid assay in the sensitive/resistant tumor cell lines, assessing the cell viability in the transfected groups. Epigenetic features were also assessed in 189 primary samples obtained from ovarian tumors and controls.

Results
We identified PAX9 and FKBP1B as potential candidate genes, which exhibited epigenetic patterns of expression regulation in the experimental approach. Re-establishment of FKBP1B expression in the resistant OVCAR3 phenotype in which this gene is hypermethylated and inhibited allowed it to achieve a degree of platinum sensitivity similar to the sensitive phenotype. The evaluation of these genes at a translational level revealed that PAX9 hypermethylation leads to a poorer prognosis in terms of overall survival. We also set a precedent for establishing a common epigenetic signature in which the validation of a single candidate, MEST, proved the accuracy of our computational pipelines.

Conclusions
Epigenetic regulation of PAX9 and FKBP1B genes shows that methylation in non-promoter areas has the potential to control gene expression and thus biological consequences, such as the loss of platinum sensitivity. At the translational level, PAX9 behaves as a predictor of chemotherapy response to platinum in patients with ovarian cancer. This study revealed the importance of the transcript-specific study of each gene under potential epigenetic regulation, which would favor the identification of new markers capable of predicting each patient’s progression and therapeutic response.
Longitudinal analysis of individual cfDNA methylome patterns in metastatic prostate cancer
Authors: Silva Romina , Moran Bruce , Baird Anne-Marie , O’Rourke Colm J. , Finn Stephen P. , McDermott Ray , Watson William , Gallagher William M. , Brennan Donal J. , Perry Antoinette S. 
Published: August 2021

Abstract
Background
Disease progression and therapeutic resistance are hallmarks of advanced stage prostate cancer (PCa), which remains a major cause of cancer-related mortality around the world. Longitudinal studies, coupled with the use of liquid biopsies, offer a potentially new and minimally invasive platform to study the dynamics of tumour progression. Our aim was to investigate the dynamics of personal DNA methylomic profiles of metastatic PCa (mPCa) patients, during disease progression and therapy administration.

Results
Forty-eight plasma samples from 9 mPCa patients were collected, longitudinally, over 13–21 months. After circulating cell-free DNA (cfDNA) isolation, DNA methylation was profiled using the Infinium MethylationEPIC BeadChip. The top 5% most variable probes across time, within each individual, were utilised to study dynamic methylation patterns during disease progression and therapeutic response. Statistical testing was carried out to identify differentially methylated genes (DMGs) in cfDNA, which were subsequently validated in two independent mPCa (cfDNA and FFPE tissue) cohorts. Individual cfDNA global methylation patterns were temporally stable throughout the disease course. However, a proportion of CpG sites presented a dynamic temporal pattern that was consistent with clinical events, including different therapies, and were prominently associated with genes linked to immune response pathways. Additionally, study of the tumour fraction of cfDNA identified > 2000 DMGs with dynamic methylation patterns.

Conclusions
Longitudinal assessment of cfDNA methylation in mPCa patients unveiled dynamic patterns associated with disease progression and therapy administration, thus highlighting the potential of using liquid biopsies to study PCa evolution at a methylomic level.
HDAC6 inactivates Runx2 promoter to block osteogenesis of bone marrow stromal cells in age-related bone loss of mice
Authors: Ma Chao , Gao Juan , Liang Jun , Dai Weixiang , Wang Zhenfei , Xia Mengjiao , Chen Tao , Huang Sen , Na Jian , Xu Long , Feng Shiming , Dai Kerong , Liu Guangwang 
Published: August 2021

Abstract
Background
Senile osteoporosis can cause bone fragility and increased risk for fractures and has been one of the most prevalent and severe diseases affecting the elderly population worldwidely. The underlying mechanisms are currently intensive areas of investigation. In age-related bone loss, decreased bone formation overweighs increased bone resorption. The molecular mechanisms underlying defective bone formation in age-related bone loss are not completely understood. In particular, the specific role of histone acetylation in age-related bone loss has not been examined thoroughly.

Methods
We employed 6- and 18-month-old mice to investigate the mechanisms of defective bone formation in age-related bone loss. Bone marrow stromal cells (BMSCs) were induced to undergo in vitro osteogenic differentiation. Chromatin immunoprecipitation (ChIP) was used to investigate the binding of histone deacetylases (HDACs) on Runx2 promoter in BMSCs. Luciferase reporter and transient transfection assay were employed to study Runx2 gene expression modulation by HDAC and androgen receptor (AR). siRNA and HDAC6 inhibitor, Tubastatin A, were used to inhibit HDAC6 in vitro. And systemic administration of Tubastatin A was used to block HDAC6 in vivo.

Results
Age-related trabecular bone loss was observed in 18-month-old mice compared with 6-month-old mice. In vitro osteogenic differentiation potential of BMSCs from 18-month-old mice was weaker than 6-month-old mice, in which there was Runx2 expression inactivation in BMSCs of 18-month-old mice compared with 6-month-old mice, which was attributable to HDAC6-mediated histone hypoacetylation in Runx2 promoter. There was competitive binding of HDAC6 and AR on Runx2 promoter to modulate Runx2 expression in BMSCs. More importantly, through siRNA- or specific inhibitor-mediated HDAC6 inhibition, we could activate Runx2 expression, rescue in vitro osteogenesis potential of BMSCs, and alleviate in vivo age-related bone loss of mice.

Conclusion
HDAC6 accumulation and histone hypoacetylation on Runx2 promoter contributed to the attenuation of in vitro osteogenic differentiation potential of BMSCs from aged mice. Through HDAC6 inhibition, we could activate Runx2 expression and osteogenic differentiation potential of BMSCs from aged mice and alleviate the age-related bone loss of aged mice. Our study will benefit not only for understanding the age-related bone loss, but also for finding new therapies to treat senile osteoporosis.
Pimecrolimus interferes the therapeutic efficacy of human mesenchymal stem cells in atopic dermatitis by regulating NFAT-COX2 signaling
Authors: Shin Nari , Jung Namhee , Lee Seung-Eun , Kong Dasom , Kim Nam Gyo , Kook Myung Geun , Park Hwanhee , Choi Soon Won , Lee Seunghee , Kang Kyung-Sun 
Published: August 2021

AbstractBackgroundHuman mesenchymal stem cells (hMSCs) therapy has recently been considered a promising treatment for atopic dermatitis (AD) due to their immunomodulation and tissue regeneration ability. In our previous studies, we demonstrated that hMSCs alleviate allergic inflammation in murine AD model by inhibiting the activation of mast cells and B cells. Also our phase I/IIa clinical trial showed clinical efficacy and safety of hMSCs in moderate-to-severe adult AD patients. However, hMSCs therapy against atopic dermatitis have had poor results in clinical field. Therefore, we investigated the reason behind this result. We hypothesized that drug–cell interaction could interfere with the therapeutic efficacy of stem cells, and investigated whether coadministration with pimecrolimus, one of the topical calcineurin inhibitors, could influence the therapeutic potential of human umbilical cord blood mesenchymal stem cells (hUCB-MSCs) in AD.MethodshUCB-MSCs were subcutaneously injected to AD-induced mice with or without pimecrolimus topical application. To examine whether pimecrolimus influenced the immunomodulatory activity of hUCB-MSCs, hUCB-MSCs were treated with pimecrolimus.ResultsPimecrolimus disturbed the therapeutic effect of hUCB-MSCs when they were co-administered in murine AD model. Moreover, the inhibitory functions of hUCB-MSCs against type 2 helper T (Th2) cell differentiation and mast cell activation were also deteriorated by pimecrolimus treatment. Interestingly, we found that pimecrolimus decreased the production of PGE2, one of the most critical immunomodulatory factors in hUCB-MSCs. And we demonstrated that pimecrolimus downregulated COX2-PGE2axis by inhibiting nuclear translocation of NFAT3.ConclusionsCoadministration of pimecrolimus with hMSCs could interfere with the therapeutic efficacy of hMSCs in atopic dermatitis, and this is the first study that figured out the interaction of hMSCs with other drugs in cell therapy of atopic dermatitis. Therefore, this study might give rise to improvement of the clinical application of hMSCs therapy and facilitate the widespread application of hMSCs in clinical field.
A novel conjunctive microenvironment derived from human subcutaneous adipose tissue contributes to physiology of its superficial layer
Authors: Baptista Leandra Santos , Côrtes Isis , Montenegro Bianca , Claudio-da-Silva Cesar , Bouschbacher Marielle , Jobeili Lara , Auxenfans Celine , Sigaudo-Roussel Dominique 
Published: August 2021

AbstractBackgroundIn human subcutaneous adipose tissue, the superficial fascia distinguishes superficial and deep microenvironments showing extensions called retinacula cutis. The superficial subcutaneous adipose tissue has been described as hyperplastic and the deep subcutaneous adipose tissue as inflammatory. However, few studies have described stromal-vascular fraction (SVF) content and adipose-derived stromal/stem cells (ASCs) behavior derived from superficial and deep subcutaneous adipose tissue. In this study, we analyzed a third conjunctive microenvironment: the retinacula cutis superficialis derived from superficial subcutaneous adipose tissue.MethodsThe samples of abdominal human subcutaneous adipose tissue were obtained during plastic aesthetic surgery in France (Declaration DC-2008-162) and Brazil (Protocol 145/09).ResultsThe SVF content was characterized in situ by immunofluorescence and ex vivo by flow cytometry revealing a high content of pre-adipocytes rather in superficial subcutaneous adipose tissue microenvironment. Adipogenic assays revealed higher percentage of lipid accumulation area in ASCs from superficial subcutaneous adipose tissue compared with retinacula cutis superficialis (p < 0.0001) and deep subcutaneous adipose tissue (p < 0.0001). The high adipogenic potential of superficial subcutaneous adipose tissue was corroborated by an up-regulation of adipocyte fatty acid-binding protein (FABP4) compared with retinacula cutis superficialis (p < 0.0001) and deep subcutaneous adipose tissue (p < 0.0001) and of C/EBPα (CCAAT/enhancer-binding protein alpha) compared with retinacula cutis superficialis (p < 0.0001) and deep subcutaneous adipose tissue (p < 0.0001) microenvironments. Curiously, ASCs from retinacula cutis superficialis showed a higher level of adiponectin receptor gene compared with superficial subcutaneous adipose tissue (p = 0.0409), widely known as an anti-inflammatory hormone. Non-induced ASCs from retinacula cutis superficialis showed higher secretion of human vascular endothelial growth factor (VEGF), compared with superficial (p = 0.0485) and deep (p = 0.0112) subcutaneous adipose tissue and with adipogenic-induced ASCs from superficial (p = 0.0175) and deep (p = 0.0328) subcutaneous adipose tissue. Furthermore, ASCs from retinacula cutis superficialis showed higher secretion of Chemokine (C–C motif) ligand 5 (CCL5) compared with non-induced (p = 0.0029) and induced (p = 0.0089) superficial subcutaneous adipose tissue.ConclusionsThis study highlights the contribution to ASCs from retinacula cutis superficialis in their angiogenic property previously described for the whole superficial subcutaneous adipose tissue besides supporting its adipogenic potential for superficial subcutaneous adipose tissue.
Targeted gene correction and functional recovery in achondroplasia patient-derived iPSCs
Authors: Zou Huan , Guan Mingfeng , Li Yundong , Luo Fang , Wang Wenyuan , Qin Yiren 
Published: August 2021

Abstract
Background
Achondroplasia (ACH) is the most common genetic form of dwarfism and belongs to dominant monogenic disorder caused by a gain-of-function point mutation in the transmembrane region of FGFR3. There are no effective treatments for ACH. Stem cells and gene-editing technology provide us with effective methods and ideas for ACH research and treatment.

Methods
We generated non-integrated iPSCs from an ACH girl’s skin and an ACH boy’s urine by Sendai virus. The mutation of ACH iPSCs was precisely corrected by CRISPR-Cas9.

Results
Chondrogenic differentiation ability of ACH iPSCs was confined compared with that of healthy iPSCs. Chondrogenic differentiation ability of corrected ACH iPSCs could be restored. These corrected iPSCs displayed pluripotency, maintained normal karyotype, and demonstrated none of off-target indels.

Conclusions
This study may provide an important theoretical and experimental basis for the ACH research and treatment.
Bioreactance reliably detects preload responsiveness by the end-expiratory occlusion test when averaging and refresh times are shortened
Authors: Gavelli Francesco , Beurton Alexandra , Teboul Jean-Louis , De Vita Nello , Azzolina Danila , Shi Rui , Pavot Arthur , Monnet Xavier 
Published: August 2021

Abstract
Background
The end-expiratory occlusion (EEXPO) test detects preload responsiveness, but it is 15 s long and induces small changes in cardiac index (CI). It is doubtful whether the Starling bioreactance device, which averages CI over 24 s and refreshes the displayed value every 4 s (Starling-24.4), can detect the EEXPO-induced changes in CI (ΔCI). Our primary goal was to test whether this Starling device version detects preload responsiveness through EEXPO. We also tested whether shortening the averaging and refresh times to 8 s and one second, respectively, (Starling-8.1) improves the accuracy of the device in detecting preload responsiveness using EEXPO.

Methods
In 42 mechanically ventilated patients, during a 15-s EEXPO, we measured ∆CI through calibrated pulse contour analysis (CIpulse, PiCCO2 device) and using the Starling device. For the latter, we considered both CIStarling-24.4 from the commercial version and CIStarling-8.1 derived from the raw data. For relative ∆CIStarling-24.4 and ∆CIStarling-8.1 during EEXPO, we calculated the area under the receiver operating characteristic curve (AUROC) to detect preload responsiveness, defined as an increase in CIpulse ≥ 10% during passive leg raising (PLR). For both methods, the correlation coefficient vs. ∆CIpulse was calculated.

Results
Twenty-six patients were preload responders and sixteen non preload-responders. The AUROC for ∆CIStarling-24.4 was significantly lower compared to ∆CIStarling-8.1 (0.680 ± 0.086 vs. 0.899 ± 0.049, respectively; p = 0.027). A significant correlation was observed between ∆CIStarling-8.1 and ∆CIpulse (r = 0.42; p = 0.009), but not between ∆CIStarling-24.4 and ∆CIpulse. During PLR, both ∆CIStarling-24.4 and ∆CIStarling-8.1 reliably detected preload responsiveness.

Conclusions
Shortening the averaging and refresh times of the bioreactance signal to 8 s and one second, respectively, increases the reliability of the Starling device in detection of EEXPO-induced ∆CI.
Trial registration: No. IDRCB:2018-A02825-50. Registered 13 December 2018.
Continuous energy consumption measure approach using a DMA double-buffering technique
Authors: Vaquerizo-Hdez Daniel , Muñoz Pablo , Barrero David F. , R-Moreno Maria D. 
Published: August 2021

AbstractMeasuring the consumption of electronic devices is a difficult and sensitive task. Data acquisition (DAQ) systems are often used to determine such consumption. In theory, measuring energy consumption is straight forward, just by acquiring current and voltage signals we can determine the consumption. However, a number of issues arise when a fine analysis is required. The main problem is that sampling frequencies have to be high enough to detect variations in the assessed signals over time. In that regard, some popular DAQ systems are based on RISC ARM processors for microcontrollers combined with analog-to-digital converters to meet high-frequency acquisition requirements. The efficient use of direct memory access (DMA) modules combined with pipelined processing in a microcontroller allows to improve the sample rate overcoming the processing time and the internal communication protocol limitations. This paper presents a novel approach for high-frequency energy measurement composed of a DMA rate improvement (data acquisition logic), a data processing logic and a low-cost hardware. The contribution of the paper is the combination of a double-buffered signal acquisition mechanism and an algorithm that computes the device’s energy consumption using parallel data processing. The combination of these elements enables a high-frequency (continuous) energy consumption measurement of an electronic device, improving the accuracy and reducing the cost of existing systems. We have validated our approach by measuring the energy consumed by elemental circuits and wireless sensors networks (WSNs) motes. The results indicate that the energy measurement error is less than 5% and that the proposed method is suitable to measure WSN motes even during sleep cycles, enabling a better characterization of their consumption profile.
Patient-reported outcome measures in pediatric palliative care—a protocol for a scoping review
Authors: Holmen Heidi , Winger Anette , Steindal Simen A. , Castor Charlotte , Kvarme Lisbeth Gravdal , Riiser Kirsti , Mariussen Kari L. , Lee Anja 
Published: August 2021

Abstract
Background
In pediatric palliative care (PPC), there is a need to involve the child’s voice in situations regarding their symptoms and care needs. Patient-reported outcome measures (PROMs) can be tools to systematically gather data reported from the child or a proxy if the child is not capable to self-report in order to provide the services they need. There has been a rapid development in PROM research the last decade, and there is a need for an overview of current knowledge and experiences in the field. Thus, we aim to explore and summarize what is known from the published research about PROMs in PPC.

Methods
We propose a scoping review following the framework by Arksey and O’Malley and the PRISMA Extension for Scoping Reviews checklist. A systematic search will be performed in the following databases: Medical Literature Analysis and Retrieval System Online (Medline), Excerpta Medica database (EMBASE), Cumulative Index to Nursing and Allied Health Literature (CINAHL), American Psychological Association (APA) PsycInfo, Health and Psychosocial Instruments (HaPI), and Allied and Complementary Medicine Database (AMED). The search will be followed by snowballing to identify key papers and significant researchers for additional citations. Covidence will facilitate the independent review of eligible citations, and data will be extracted and presented descriptively, and thematically analyzed using NVivo.

Discussion
The scoping review suggested in this protocol will identify PROMs which have been proposed in PPC and clarify the experiences with their use. The findings of this review will be relevant for researchers and healthcare personnel caring for children and adolescents in PPC. In addition, by highlighting knowledge gaps about the use of PROMs in PPC, this review will point out future needs within this field of research, which is crucial for improving quality of care in PPC.

Systematic review registration
https://osf.io/yfch2/.
Security-Aware computation offloading for Mobile edge computing-Enabled smart city
Authors: Peng Kai , Liu Peichen , Tao Peng , Huang Qingjia 
Published: August 2021

AbstractSmart city has obtained increasing attention from both academic and industry which has the potential to improve human living standards. A smart city consists of a great number of smart devices which are generating large amounts of data and emerging applications all the time. However, the computing capacity of smart devices are limited. Fortunately, the emergence of MEC can solve the above problem. However, the resources of edge servers in MEC are limited and the capabilities of edge servers are heterogeneous. It is important to improve the average resource utilization of all edge servers and keep load balancing of edge server cluster simultaneously. On the other hand, quite a few numbers of applications are delay-sensitive, it is necessary to ensure the security of these applications. In this paper, we consider joint optimization of mobile device and edge server in MEC-enabled smart city, improving the overall performance of the system. Technically, a new multi-objective computation offloading method is implemented to reduce time consumption, energy consumption, and keep load balancing of edge servers, as well as increase average resource utilization of edge servers while meeting the deadline constraint of delay-sensitive applications. Sufficient experiments have been conducted to prove the effectiveness and superiority of our proposed method in different scenarios.