bluuebunny/crossref_metadata_2025_split huggingface dataset:
Expression profiles, biological functions and clinical significance of circRNAs in bladder cancer
Authors: Yang Xiaoqi , Ye Tao , Liu Haoran , Lv Peng , Duan Chen , Wu Xiaoliang , Jiang Kehua , Lu Hongyan , Xia Ding , Peng Ejun , Chen Zhiqiang , Tang Kun , Ye Zhangqun 
Published: January 2021

AbstractCircular RNAs (circRNAs), which are single-stranded closed-loop RNA molecules lacking terminal 5′ caps and 3′ poly(A) tails, are attracting increasing scientific attention for their crucial regulatory roles in the occurrence and development of various diseases. With the rapid development of high-throughput sequencing technologies, increasing numbers of differentially expressed circRNAs have been identified in bladder cancer (BCa) via exploration of the expression profiles of BCa and normal tissues and cell lines. CircRNAs are critically involved in BCa biological behaviours, including cell proliferation, tumour growth suppression, cell cycle arrest, apoptosis, invasion, migration, metastasis, angiogenesis, and cisplatin chemoresistance. Most of the studied circRNAs in BCa regulate cancer biological behaviours via miRNA sponging regulatory mechanisms. CircRNAs have been reported to be significantly associated with many clinicopathologic characteristics of BCa, including tumour size, grade, differentiation, and stage; lymph node metastasis; tumour numbers; distant metastasis; invasion; and recurrence. Moreover, circRNA expression levels can be used to predict BCa patients’ survival parameters, such as overall survival (OS), disease-free survival (DFS), and progression-free survival (PFS). The abundance, conservation, stability, specificity and detectability of circRNAs render them potential diagnostic and prognostic biomarkers for BCa. Additionally, circRNAs play crucial regulatory roles upstream of various signalling pathways related to BCa carcinogenesis and progression, reflecting their potential as therapeutic targets for BCa. Herein, we briefly summarize the expression profiles, biological functions and mechanisms of circRNAs and the potential clinical applications of these molecules for BCa diagnosis, prognosis, and targeted therapy.
Primary metastatic prostate cancer between prognosis or adequate/proper medical therapy
Authors: Mustafa Mahmoud , Rass Honood Abu , Yahya Mothafr , Hamdan Khaleel , Eiss Yazan 
Published: January 2021

Abstract
Purpose
To define the efficacy of standard androgen deprivation therapy (ADT) in the treatment of metastatic prostate cancer (PCa).

Materials and methods
Fifty patients with mean age of 70.48 ± 9.95 years old (range 52–87) who had metastatic PCa and received ADT between 2014 and 2019 were retrospectively evaluated. Median values of pre-therapeutic PSA and Gleason scores were 50 ng/ml (range 8–1201) and 8 (range 6–9), respectively. All patients received luteinizing hormone-releasing hormone (LHRH) analogue and anti-androgen. The patients were evaluated in terms of age, pre-therapeutic PSA serum levels, Gleason scores, presence of metastasis, number and percentage of cores involved, nadir PSA, time to nadir PSA, duration of ADT, and PSA at last follow-up. Multivariate analysis was used to define the factors which have impact on ADT response. The mean follow-up period was 13.87 ± 7.78 months, (range 2–32).

Results
All patients showed reduction in serum PSA level after initiation of ADT, and the median value of nadir PSA was 1.12 ng/ml (range 0.02–50). The mean value of time to nadir PSA was 3.85 ± 1.57 months (range 2–7). The median value of PSA at last follow-up was 2 ng/ml (range 0.02–50.21). Multi-variant analysis showed that nadir PSA have a significant correlation with pre-therapeutic PSA, PSA at last follow-up, age, and Gleason scores (p < .05).

Conclusion
Standard ADT is a feasible option in the treatment of metastatic PCa. Gleason scores, age, pre-therapeutic PSA, and PSA at last follow-up have significant impact on outcomes of ADT. Further studies of high number of patients with long-term follow-up including other chemo-hormonal therapy and androgen receptor blockers should be carried out to confirm and improve efficacy of ADT.
A systematic review and meta-analysis of school-based interventions with health education to reduce body mass index in adolescents aged 10 to 19 years
Authors: Jacob Chandni Maria , Hardy-Johnson Polly Louise , Inskip Hazel M. , Morris Taylor , Parsons Camille M. , Barrett Millie , Hanson Mark , Woods-Townsend Kathryn , Baird Janis 
Published: January 2021

AbstractBackgroundAdolescents are increasingly susceptible to obesity, and thus at risk of later non-communicable diseases, due to changes in food choices, physical activity levels and exposure to an obesogenic environment. This review aimed to synthesize the literature investigating the effectiveness of health education interventions delivered in school settings to prevent overweight and obesity and/ or reduce BMI in adolescents, and to explore the key features of effectiveness.MethodsA systematic search of electronic databases including MEDLINE, CINAHL, PsychINFO and ERIC for papers published from Jan 2006 was carried out in 2020, following PRISMA guidelines. Studies that evaluated health education interventions in 10–19-year-olds delivered in schools in high-income countries, with a control group and reported BMI/BMI z-score were selected. Three researchers screened titles and abstracts, conducted data extraction and assessed quality of the full text publications. A third of the papers from each set were cross-checked by another reviewer. A meta-analysis of a sub-set of studies was conducted for BMI z-score.ResultsThirty-three interventions based on 39 publications were included in the review. Most studies evaluated multi-component interventions using health education to improve behaviours related to diet, physical activity and body composition measures. Fourteen interventions were associated with reduced BMI/BMI z-score. Most interventions (n = 22) were delivered by teachers in classroom settings, 19 of which trained teachers before the intervention. The multi-component interventions (n = 26) included strategies such as environment modifications (n = 10), digital interventions (n = 15) and parent involvement (n = 16). Fourteen studies had a low risk of bias, followed by 10 with medium and nine with a high risk of bias. Fourteen studies were included in a random-effects meta-analysis for BMI z-score. The pooled estimate of this meta-analysis showed a small difference between intervention and control in change in BMI z-score (− 0.06 [95% CI -0.10, − 0.03]). A funnel plot indicated that some degree of publication bias was operating, and hence the effect size might be inflated.ConclusionsFindings from our review suggest that school-based health education interventions have the public health potential to lower BMI towards a healthier range in adolescents. Multi-component interventions involving key stakeholders such as teachers and parents and digital components are a promising strategy.
Progranulin induces immune escape in breast cancer via up-regulating PD-L1 expression on tumor-associated macrophages (TAMs) and promoting CD8+ T cell exclusion
Authors: Fang Wenli , Zhou Ting , Shi He , Yao Mengli , Zhang Dian , Qian Husun , Zeng Qian , Wang Yange , Jin Fangfang , Chai Chengsen , Chen Tingmei 
Published: January 2021

Abstract
Background
Progranulin (PGRN), as a multifunctional growth factor, is overexpressed in multiple tumors, but the role of PGRN on tumor immunity is still unclear. Here, we studied the effect of PGRN on breast cancer tumor immunity and its possible molecular mechanism.

Methods
The changes of macrophage phenotypes after PGRN treatment were detected by western blot, quantitative polymerase chain reaction (PCR) and flow cytometry. Western blot was used to study the signal molecular mechanism of PGRN regulating this process. The number and localization of immune cells in Wild-type (WT) and PGRN−/− breast cancer tissues were analyzed by immunohistochemical staining and immunofluorescence techniques. The activation and proliferation of CD8+ T cells were measured by flow cytometry.

Results
After being treated with PGRN, the expressions of M2 markers and programmed death ligand 1 (PD-L1) on macrophages increased significantly. Signal transducer and activator of transcription 3 (STAT3) signaling pathway inhibitor Stattic significantly inhibited the expression of PD-L1 and M2 related markers induced by PGRN. In WT group, CD8 were co-localized with macrophages and PD-L1, but not tumor cells. The number of immune cells in PGRN−/− breast cancer tissue increased, and their infiltration into tumor parenchyma was also enhanced. Moreover, in the co-culture system, WT peritoneal macrophages not only reduced the ratio of activated CD8+ T cells but also reduced the proportion of proliferating CD8+ T cells. The addition of programmed death receptor 1 (PD-1) and PD-L1 neutralizing antibodies effectively reversed this effect and restored the immune function of CD8+ T cells.

Conclusion
These results demonstrate that PGRN promotes M2 polarization and PD-L1 expression by activating the STAT3 signaling pathway. Furthermore, through PD-1/PD-L1 interaction, PGRN can promote the breast tumor immune escape. Our research may provide new ideas and targets for clinical breast cancer immunotherapy.
Choline kinase alpha impairment overcomes TRAIL resistance in ovarian cancer cells
Authors: Rizzo Andrea , Satta Alessandro , Garrone Giulia , Cavalleri Adalberto , Napoli Alessandra , Raspagliesi Francesco , Figini Mariangela , De Cecco Loris , Iorio Egidio , Tomassetti Antonella , Mezzanzanica Delia , Bagnoli Marina 
Published: January 2021

Abstract
Background
Choline kinase-α (ChoKα/CHKA) overexpression and hyper-activation sustain altered choline metabolism conferring the cholinic phenotype to epithelial ovarian cancer (OC), the most lethal gynecological tumor. We previously proved that CHKA down-modulation reduced OC cell aggressiveness and increased sensitivity to in vitro chemotherapeutics’ treatment also affecting intracellular content of one-carbon metabolites. In tumor types other than ovary, methionine decrease was shown to increase sensitivity to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-receptor 2 triggering. These effects were suggestive of a potential role for ChoKα in regulating susceptibility to TRAIL cytokine.

Methods
The relationship between ChoKα/CHKA and TRAIL-receptor 2 (TRAIL-R2) expression was investigated in silico in OC patients’ GEO datasets and in vitro in a panel of OC cell lines upon transient CHKA silencing (siCHKA). The effect of siCHKA on metabolites content was assessed by LC-MS. The triggered apoptotic signalling was studied following soluble-TRAIL or anti-TRAIL-R2 agonist antibody treatment. Lipid rafts were isolated by Triton X-100 fractionation. Preclinical ex vivo studies were performed in OC cells derived from patients’ ascites using autologous PBLs as effectors and a bispecific anti-TRAIL-R2/anti-CD3 antibody as triggering agent.

Results
Here we demonstrate that siCHKA specifically overcomes resistance to TRAIL-mediated apoptosis in OC cells. Upon siCHKA we detected: a significant sensitization to caspase-dependent apoptosis triggered by both soluble TRAIL and anti-TRAIL-R2 agonist antibody, a specific increase of TRAIL-R2 expression and TRAIL-R2 relocation into lipid rafts. In siCHKA-OC cells the acquired TRAIL sensitivity was completely reverted upon recovery of ChoKα expression but, at variance of other tumor cell types, TRAIL sensitivity was not efficiently phenocopied by methionine deprivation. Of note, we were also able to show that siCHKA sensitized tumor cells derived ex vivo from OC patients’ ascites to the cytotoxic activity of autologous lymphocytes redirected by a bispecific anti-TRAIL-R2/anti-CD3 antibody.

Conclusions
Our findings suggest that ChoKα/CHKA impairment, by restoring drug-induced or receptor-mediated cell death, could be a suitable therapeutic strategy to be used in combination with chemotherapeutics or immunomodulators to improve OC patients’ outcome.
Age-related decline in the expression of GDF9 and BMP15 genes in follicle fluid and granulosa cells derived from poor ovarian responders
Authors: Gong Yan , Li-Ling Jesse , Xiong Dongsheng , Wei Jiajing , Zhong Taiqing , Tan Hao 
Published: January 2021

Abstract
Background
Growth differentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15) genes play important roles in folliculogenesis. Altered expression of the two have been found among patients with poor ovarian response (POR). In this prospective cohort study, we have determined the expression of the GDF9 and BMP15 genes in follicle fluid (FF) and granulosa cells (GCs) derived from poor ovarian responders grouped by age, and explored its correlation with the outcome of in vitro fertilization and embryo transfer (IVF-ET) treatment.

Methods
A total of 196 patients with POR were enrolled from a tertiary teaching hospital. The patients were diagnosed by the Bologna criteria and sub-divided into group A (< 35 year old), group B (35–40 year old), and group C (> 40 year old). A GnRH antagonist protocol was conducted for all patients, and FF and GCs were collected after oocyte retrieval. Expression of the GDF9 and BMP15 genes in the FF and GCs was determined with enzyme-linked immunosorbent assay (ELISA), quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting.

Results
Compared with group C, groups A and B had significantly more two pronuclei (2PN) oocytes and transplantable embryos, in addition with higher rates of implantation and clinical pregnancy (P <  0.05). The expression level of GDF9 and BMP15 genes in the FF and GCs differed significantly among the three groups (P <  0.05), showing a trend of decline along with age. The ratio of GDF9/BMP15 mRNA levels were similar among the three groups (P > 0.05). The relative levels of GDF9 and BMP15 proteins in GCs have correlated with the relative mRNA levels in GCs and protein concentrations in FF (P <  0.05).

Conclusions
For poor ovarian responders, in particular those over 40, the expression of GDF9 and BMP15 is declined along with increased age and in accompany with poorer oocyte quality and IVF outcome, whilst the ratio of GDF9/BMP15 mRNA levels remained relatively constant.

Trial registration
Chinese Clinical Trial Registry Center (ChiCTR1800016107). Registered on 11 May 2018.
Comparison of anticoagulation strategies for veno-venous ECMO support in acute respiratory failure
Authors: Seeliger Benjamin , Döbler Michael , Friedrich Robert , Stahl Klaus , Kühn Christian , Bauersachs Johann , Steinhagen Folkert , Ehrentraut Stefan F. , Schewe Jens-Christian , Putensen Christian , Welte Tobias , Hoeper Marius M. , Tiede Andreas , David Sascha , Bode Christian 
Published: January 2021

Abstract
Background
Extracorporeal membrane oxygenation (ECMO) support in acute respiratory failure may be lifesaving, but bleeding and thromboembolic complications are common. The optimal anticoagulation strategy balancing these factors remains to be determined. This retrospective study compared two institutional anticoagulation management strategies focussing on oxygenator changes and both bleeding and thromboembolic events.

Methods
We conducted a retrospective observational cohort study between 04/2015 and 02/2020 in two ECMO referral centres in Germany in patients receiving veno-venous (VV)-ECMO support for acute respiratory failure for > 24 h. One centre routinely applied low-dose heparinization aiming for a partial thromboplastin time (PTT) of 35–40 s and the other routinely used a high-dose therapeutic heparinization strategy aiming for an activated clotting time (ACT) of 140–180 s. We assessed number of and time to ECMO oxygenator changes, 15-day freedom from oxygenator change, major bleeding events, thromboembolic events, 30-day ICU mortality, activated clotting time and partial thromboplastin time and administration of blood products. Primary outcome was the occurrence of oxygenator changes depending on heparinization strategy; main secondary outcomes were the occurrence of severe bleeding events and occurrence of thromboembolic events. The transfusion strategy was more liberal in the low-dose centre.

Results
Of 375 screened patients receiving VV-ECMO support, 218 were included in the analysis (117 high-dose group; 101 low-dose group). Disease severity measured by SAPS II score was 46 (IQR 36–57) versus 47 (IQR 37–55) and ECMO runtime was 8 (IQR 5–12) versus 11 (IQR 7–17) days (P = 0.003). There were 14 oxygenator changes in the high-dose group versus 48 in the low-dose group. Freedom from oxygenator change at 15 days was 73% versus 55% (adjusted HR 3.34 [95% confidence interval 1.2–9.4]; P = 0.023). Severe bleeding events occurred in 23 (19.7%) versus 14 (13.9%) patients (P = 0.256) and thromboembolic events occurred in 8 (6.8%) versus 19 (19%) patients (P = 0.007). Mortality at 30 days was 33.3% versus 30.7% (P = 0.11).

Conclusions
In this retrospective study, ECMO management with high-dose heparinization was associated with lower rates of oxygenator changes and thromboembolic events when compared to a low-dose heparinization strategy. Prospective, randomized trials are needed to determine the optimal anticoagulation strategy in patients receiving ECMO support.
Protective reactive thymus hyperplasia in COVID-19 acute respiratory distress syndrome
Authors: Cuvelier Pelagia , Roux Hélène , Couëdel-Courteille Anne , Dutrieux Jacques , Naudin Cécile , Charmeteau de Muylder Bénédicte , Cheynier Rémi , Squara Pierre , Marullo Stefano 
Published: January 2021

Abstract
Background
Patients with COVID-19 (COVID) may develop acute respiratory distress syndrome with or without sepsis, coagulopathy and visceral damage. While chest CT scans are routinely performed in the initial assessment of patients with severe pulmonary forms, thymus involvement and reactivation have not been investigated so far.

Methods
In this observational study, we systematically scored the enlargement of the thymus and the lung involvement, using CT scans, in all adult patients admitted to the ICU for COVID or any other cause (control group) at one centre between March and April 2020. Initial biological investigations included nasal detection of SARS-CoV-2 ribonucleic acid by polymerase chain reaction (PCR). In a subgroup of 24 patients with different degrees of pulmonary involvement and thymus hypertrophy, plasma cytokine concentrations were measured and the export of mature T cells from the thymus was estimated simultaneously by PCR quantification of T cell receptor excision circles (TRECs).

Results
Eighty-seven patients were studied: 50 COVID patients and 37 controls. Non-atrophic or enlarged thymus was more commonly observed in COVID patients than in controls (66% vs. 24%, p < 0.0001). Thymus enlargement in COVID patients was associated with more extensive lung injury score on CT scans (4 [3–5] vs. 2 [1.5–4], p = 0.01), but a lower mortality rate (8.6% vs. 41.2%, p < 0.001). Other factors associated with mortality were age, lymphopaenia, high CRP and co-morbidities. COVID patients had higher concentrations of IL-7 (6.00 [3.72–9.25] vs. 2.17 [1.76–4.4] pg/mL; p = 0.04) and higher thymic production of new lymphocytes (sj/βTREC ratio = 2.88 [1.98–4.51] vs. 0.23 [0.15–0.60]; p = 0.004). Thymic production was also correlated with the CT scan thymic score (r = 0.38, p = 0.03) and inversely correlated with the number of lymphocytes (r = 0.56, p = 0.007).

Conclusion
In COVID patients, thymus enlargement was frequent and associated with increased T lymphocyte production, which appears to be a beneficial adaptation to virus-induced lymphopaenia. The lack of thymic activity/reactivation in older SARS-CoV-2 infected patients could contribute to a worse prognosis.
Genome-wide association study implicates novel loci and reveals candidate effector genes for longitudinal pediatric bone accrual
Authors: Cousminer Diana L. , Wagley Yadav , Pippin James A. , Elhakeem Ahmed , Way Gregory P. , Pahl Matthew C. , McCormack Shana E. , Chesi Alessandra , Mitchell Jonathan A. , Kindler Joseph M. , Baird Denis , Hartley April , Howe Laura , Kalkwarf Heidi J. , Lappe Joan M. , Lu Sumei , Leonard Michelle E. , Johnson Matthew E. , Hakonarson Hakon , Gilsanz Vicente , Shepherd John A. , Oberfield Sharon E. , Greene Casey S. , Kelly Andrea , Lawlor Deborah A. , Voight Benjamin F. , Wells Andrew D. , Zemel Babette S. , Hankenson Kurt D. , Grant Struan F. A. 
Published: January 2021

AbstractBackgroundBone accrual impacts lifelong skeletal health, but genetic discovery has been primarily limited to cross-sectional study designs and hampered by uncertainty about target effector genes. Here, we capture this dynamic phenotype by modeling longitudinal bone accrual across 11,000 bone scans in a cohort of healthy children and adolescents, followed by genome-wide association studies (GWAS) and variant-to-gene mapping with functional follow-up.ResultsWe identify 40 loci, 35 not previously reported, with various degrees of supportive evidence, half residing in topological associated domains harboring known bone genes. Of several loci potentially associated with later-life fracture risk, a candidate SNP lookup provides the most compelling evidence for rs11195210 (SMC3). Variant-to-gene mapping combining ATAC-seq to assay open chromatin with high-resolution promoter-focused Capture C identifies contacts between GWAS loci and nearby gene promoters. siRNA knockdown of gene expression supports the putative effector gene at three specific loci in two osteoblast cell models. Finally, using CRISPR-Cas9 genome editing, we confirm that the immediate genomic region harboring the putative causal SNP influences PRPF38A expression, a location which is predicted to coincide with a set of binding sites for relevant transcription factors.ConclusionsUsing a new longitudinal approach, we expand the number of genetic loci putatively associated with pediatric bone gain. Functional follow-up in appropriate cell models finds novel candidate genes impacting bone accrual. Our data also raise the possibility that the cell fate decision between osteogenic and adipogenic lineages is important in normal bone accrual.
Histone modifications during the life cycle of the brown alga Ectocarpus
Authors: Bourdareau Simon , Tirichine Leila , Lombard Bérangère , Loew Damarys , Scornet Delphine , Wu Yue , Coelho Susana M. , Cock J. Mark 
Published: January 2021

AbstractBackgroundBrown algae evolved complex multicellularity independently of the animal and land plant lineages and are the third most developmentally complex phylogenetic group on the planet. An understanding of developmental processes in this group is expected to provide important insights into the evolutionary events necessary for the emergence of complex multicellularity. Here, we focus on mechanisms of epigenetic regulation involving post-translational modifications of histone proteins.ResultsA total of 47 histone post-translational modifications are identified, including a novel mark H2AZR38me1, butEctocarpuslacks both H3K27me3 and the major polycomb complexes. ChIP-seq identifies modifications associated with transcription start sites and gene bodies of active genes and with transposons. H3K79me2 exhibits an unusual pattern, often marking large genomic regions spanning several genes. Transcription start sites of closely spaced, divergently transcribed gene pairs share a common nucleosome-depleted region and exhibit shared histone modification peaks. Overall, patterns of histone modifications are stable through the life cycle. Analysis of histone modifications at generation-biased genes identifies a correlation between the presence of specific chromatin marks and the level of gene expression.ConclusionsThe overview of histone post-translational modifications in the brown alga presented here will provide a foundation for future studies aimed at understanding the role of chromatin modifications in the regulation of brown algal genomes.