bluuebunny/crossref_metadata_2025_split huggingface dataset:
CDK13 upregulation-induced formation of the positive feedback loop among circCDK13, miR-212-5p/miR-449a and E2F5 contributes to prostate carcinogenesis
Authors: Qi Jin-Chun , Yang Zhan , Lin Tao , Ma Long , Wang Ya-Xuan , Zhang Yong , Gao Chun-Cheng , Liu Kai-Long , Li Wei , Zhao An-Ning , Shi Bei , Zhang Hong , Wang Dan-Dan , Wang Xiao-Lu , Wen Jin-Kun , Qu Chang-Bao 
Published: January 2021

Abstract
Background
Both E2F transcription factor and cyclin-dependent kinases (CDKs), which increase or decrease E2F activity by phosphorylating E2F or its partner, are involved in the control of cell proliferation, and some circRNAs and miRNAs regulate the expression of E2F and CDKs. However, little is known about whether dysregulation among E2Fs, CDKs, circRNAs and miRNAs occurs in human PCa.

Methods
The expression levels of CDK13 in PCa tissues and different cell lines were determined by quantitative real-time PCR and Western blot analysis. In vitro and in vivo assays were preformed to explore the biological effects of CDK13 in PCa cells. Co-immunoprecipitation anlysis coupled with mass spectrometry was used to identify E2F5 interaction with CDK13. A CRISPR-Cas9 complex was used to activate endogenous CDK13 and circCDK13 expression. Furthermore, the mechanism of circCDK13 was investigated by using loss-of-function and gain-of-function assays in vitro and in vivo.

Results
Here we show that CDK13 is significantly upregulated in human PCa tissues. CDK13 depletion and overexpression in PCa cells decrease and increase, respectively, cell proliferation, and the pro-proliferation effect of CDK13 is strengthened by its interaction with E2F5. Mechanistically, transcriptional activation of endogenous CDK13, but not the forced expression of CDK13 by its expression vector, remarkably promotes E2F5 protein expression by facilitating circCDK13 formation. Further, the upregulation of E2F5 enhances CDK13 transcription and promotes circCDK13 biogenesis, which in turn sponges miR-212-5p/449a and thus relieves their repression of the E2F5 expression, subsequently leading to the upregulation of E2F5 expression and PCa cell proliferation.

Conclusions
These findings suggest that CDK13 upregulation-induced formation of the positive feedback loop among circCDK13, miR-212-5p/miR-449a and E2F5 is responsible for PCa development. Targeting this newly identified regulatory axis may provide therapeutic benefit against PCa progression and drug resistance.
Early clearance of serum HE4 and CA125 in predicting platinum sensitivity and prognosis in epithelial ovarian cancer
Authors: Rong Yan , Li Li 
Published: January 2021

Abstract
Objectives
To assess the clinical value of early clearance of HE4 and CA125 for platinum sensitivity and prognosis in patients with ovarian cancer.

Method
HE4 and CA125 value including clinical data of 89 patients with ovarian cancer were collected. The clearance of HE4 and CA125 were assessed base on the platinum sensitivity, two-year PFS, PFS and OS.

Results
Sixteen patients were classified as platinum resistant and 73 as platinum sensitive according to the response to platinum-base chemotherapy. When HE4 clearance after 3rd cycle chemotherapy or CA125 clearance after 1st cycle chemotherapy, it gave the highest AUC of 0.788, with 100% of sensitivity and 57.5% of specificity respectively between platinum resistant and platinum sensitive group. In addition, 59 patients were classified as two-year PFS group and 30 as not achieved two-year PFS group according to obtaining two-year PFS or not. It gave the highest AUC of 0.730, with 83.3% of sensitivity and 62.7% of specificity respectively when HE4 clearance after 3rd cycle chemotherapy or CA125 clearance after 1st cycle. The prolonged PFS and OS were significantly associated by the clearance of HE4 after 3rd cycle chemotherapy (p< 0.0001, p< 0.0001) as well as CA125 after 1st cycle chemotherapy (p< 0.0001, p< 0.0001).

Conclusions
Our data suggested that the early clearance of HE4 and CA125 could predict platinum response and prognosis in patients with ovarian cancer. Monitoring the HE4 and CA125 during first-line chemotherapy might be helpful in predicting platinum sensitivity and risk to progress and relapse.
Younger age and female gender are determinants of underestimated cardiovascular risk in rheumatoid arthritis patients: a prospective cohort study
Authors: Rohrich Daphne C. , van de Wetering Eline H. M. , Rennings Alexander J. , Arts Elke E. , Meek Inger L. , den Broeder Alfons A. , Fransen Jaap , Popa Calin D. 
Published: January 2021

Abstract
Background
Rheumatoid arthritis (RA) patients have an increased cardiovascular (CV) risk. Here, we aimed to investigate whether gender and age are contributing to the misclassification of CV risk in RA patients.

Methods
Prospectively collected data on cardiovascular risk factors and incident events from the Nijmegen inception cohort were analyzed, with up to 10 years follow-up. Original as well as the EULAR-modified (M)_SCORE algorithms were used to calculate CV risk. Patients were stratified in deciles according to predicted risk; the Hosmer-Lemeshow test was used to check concordance between observed and predicted risk, in subgroups of gender and age.

Results
There were 863 RA patients included with 128 incident CV events. When using SCORE in the whole group, there was evidence of a discrepancy between the predicted and observed CV risk (H-L test p < 0.003), mainly present in the female subgroup (H-L test p < 0.001). Interestingly, 36% of females who developed an event belonged to the low CV risk group, whereas this was just 10% in RA males. When analyzing the subgroups based on age, a discrepancy was present only in the youngest patients (H-L test p < 0.001 in patients < 55 years) consisting of an underestimation of CV risk (5.3% predicted vs. 8.0% observed). Similar results were obtained when the M_SCORE was applied.

Conclusion
CV risk is especially underestimated in female and younger RA patients. This suggests that modifying the weight for the female gender and/or younger age in currently used CV risk algorithms might improve their predictive value in RA, contributing to better CV risk management.
Region-specific amyloid-β accumulation in the olfactory system influences olfactory sensory neuronal dysfunction in 5xFAD mice
Authors: Son Gowoon , Yoo Seung-Jun , Kang Shinwoo , Rasheed Ameer , Jung Da Hae , Park Hyunjun , Cho Bongki , Steinbusch Harry W. M. , Chang Keun-A , Suh Yoo-Hun , Moon Cheil 
Published: January 2021

Abstract
Background
Hyposmia in Alzheimer’s disease (AD) is a typical early symptom according to numerous previous clinical studies. Although amyloid-β (Aβ), which is one of the toxic factors upregulated early in AD, has been identified in many studies, even in the peripheral areas of the olfactory system, the pathology involving olfactory sensory neurons (OSNs) remains poorly understood.

Methods
Here, we focused on peripheral olfactory sensory neurons (OSNs) and delved deeper into the direct relationship between pathophysiological and behavioral results using odorants. We also confirmed histologically the pathological changes in 3-month-old 5xFAD mouse models, which recapitulates AD pathology. We introduced a numeric scale histologically to compare physiological phenomenon and local tissue lesions regardless of the anatomical plane.

Results
We observed the odorant group that the 5xFAD mice showed reduced responses to odorants. These also did not physiologically activate OSNs that propagate their axons to the ventral olfactory bulb. Interestingly, the amount of accumulated amyloid-β (Aβ) was high in the OSNs located in the olfactory epithelial ectoturbinate and the ventral olfactory bulb glomeruli. We also observed irreversible damage to the ectoturbinate of the olfactory epithelium by measuring the impaired neuronal turnover ratio from the basal cells to the matured OSNs.

Conclusions
Our results showed that partial and asymmetrical accumulation of Aβ coincided with physiologically and structurally damaged areas in the peripheral olfactory system, which evoked hyporeactivity to some odorants. Taken together, partial olfactory dysfunction closely associated with peripheral OSN’s loss could be a leading cause of AD-related hyposmia, a characteristic of early AD.
Differences between memory encoding and retrieval failure in mild cognitive impairment: results from quantitative electroencephalography and magnetic resonance volumetry
Authors: Han Su-Hyun , Pyun Jung-Min , Yeo Soeun , Kang Dong Won , Jeong Ho Tae , Kang Seung Wan , Kim SangYun , Youn Young Chul 
Published: January 2021

Abstract
Background
The memory impairments in mild cognitive impairment (MCI) can be classified into encoding (EF) and retrieval (RF) failure, which can be affected by underlying pathomechanism. We explored the differences structurally and functionally.

Methods
We compared quantitative electroencephalography (qEEG) power spectra and connectivity between 87 MCI patients with EF and 78 MCI with RF using iSyncBrain® (iMediSync Inc., Republic of Korea) (https://isyncbrain.com/). Voxel-based morphometric analysis of the gray matter (GM) in the MCI groups and 71 cognitive normal controls was also done using the Computational Anatomy Toolbox 12 (http://www.neuro.uni-jena.de/cat/).

Results
qEEG showed higher frontal theta and lower beta2 band power, and higher theta connectivity in the EF. There was no statistically significant difference in GM volume between the EF and RF. However, when compared to normal control, GM volume reductions due to EF in the left thalamus and bilateral hippocampi and reductions due to RF in the left thalamus, right superior frontal lobe, right superior temporal lobe, and right middle cingulum were observed (p < 0.05, family-wise error correction).

Conclusions
MCI differs functionally and structurally according to their specific memory impairments. The EF findings are structurally and functionally more consistent with the prodromal Alzheimer’s disease stage than the RF findings. Since this study is a cross-sectional study, prospective follow-up studies are needed to investigate whether different types of memory impairments can predict the underlying pathology of amnestic MCI. Additionally, insufficient sample size may lead to ambiguous statistical findings in direct comparisons, and a larger patient cohort could more robustly identify differences in GM volume reductions between the EF and the RF group.
The association of APOE ε4 with cognitive function over the adult life course and incidence of dementia: 20 years follow-up of the Whitehall II study
Authors: Gharbi-Meliani Amin , Dugravot Aline , Sabia Séverine , Regy Melina , Fayosse Aurore , Schnitzler Alexis , Kivimäki Mika , Singh-Manoux Archana , Dumurgier Julien 
Published: January 2021

AbstractBackgroundApproximately 25% of the general population carries at least one ε4 allele of the Apolipoprotein E (APOEε4), the strongest genetic risk factor for late onset Alzheimer’s disease. Beyond its association with late-onset dementia, the association betweenAPOEε4 and change in cognition over the adult life course remains uncertain. This study aims to examine whether the association between Apolipoprotein E (APOE) ε4 zygosity and cognition function is modified between midlife and old age.MethodsA cohort study of 5561 participants (mean age 55.5 (SD = 5.9) years, 27.1% women) withAPOEgenotyping and repeated cognitive tests for reasoning, memory, and semantic and phonemic fluency, during a mean (SD) follow-up of 20.2 (2.8) years (the Whitehall II study). We used joint models to examine the association ofAPOEgenotype with cognitive function trajectories between 45 and 85 years taking drop-out, dementia, and death into account and Fine and Gray models to examine associations with dementia.ResultsCompared to non-carriers, heterozygote (prevalence 25%) and homozygote (prevalence 2%)APOEε4 carriers had increased risk of dementia, sub-distribution hazard ratios 2.19 (95% CI 1.73, 2.77) and 5.97 (95% CI 3.85, 9.28) respectively. Using data spanning 45–85 years with non-ε4 carriers as the reference, ε4 homozygotes had poorer global cognitive score starting from 65 years; ε4 heterozygotes had better scores between 45 and 55 years, then no difference until poorer cognitive scores from 75 years onwards. In analysis of individual cognitive tests, better cognitive performance in the younger ε4 heterozygotes was primarily attributable to executive function.ConclusionsBoth heterozygous and homozygous ε4 carriers had poorer cognition and greater risk of dementia at older ages. Our findings show some support for a complex antagonist pleiotropic effect ofAPOEε4 heterozygosity over the adult life course, characterized by cognitive advantage in midlife.
The molecular tweezer CLR01 improves behavioral deficits and reduces tau pathology in P301S-tau transgenic mice
Authors: Di Jing , Siddique Ibrar , Li Zizheng , Malki Ghattas , Hornung Simon , Dutta Suman , Hurst Ian , Ishaaya Ella , Wang Austin , Tu Sally , Boghos Ani , Ericsson Ida , Klärner Frank-Gerrit , Schrader Thomas , Bitan Gal 
Published: January 2021

Abstract
Background
Molecular tweezers (MTs) are broad-spectrum inhibitors of abnormal protein aggregation. A lead MT, called CLR01, has been demonstrated to inhibit the aggregation and toxicity of multiple amyloidogenic proteins in vitro and in vivo. Previously, we evaluated the effect of CLR01 in the 3 × Tg mouse model of Alzheimer’s disease, which overexpresses mutant human presenilin 1, amyloid β-protein precursor, and tau and found that subcutaneous administration of the compound for 1 month led to a robust reduction of amyloid plaques, neurofibrillary tangles, and microgliosis. CLR01 also has been demonstrated to inhibit tau aggregation in vitro and tau seeding in cell culture, yet because in Alzheimer’s disease (AD) and in the 3 × Tg model, tau hyperphosphorylation and aggregation are thought to be downstream of Aβ insults, the study in this model left open the question whether CLR01 affected tau in vivo directly or indirectly.

Methods
To determine if CLR01 could ameliorate tau pathology directly in vivo, we tested the compound similarly using the P301S-tau (line PS19) mouse model. Mice were administered 0.3 or 1.0 mg/kg per day CLR01 and tested for muscle strength and behavioral deficits, including anxiety- and disinhibition-like behavior. Their brains then were analyzed by immunohistochemical and biochemical assays for pathological forms of tau, neurodegeneration, and glial pathology.

Results
CLR01 treatment ameliorated muscle-strength deterioration, anxiety-, and disinhibition-like behavior. Improved phenotype was associated with decreased levels of pathologic tau forms, suggesting that CLR01 exerts a direct effect on tau in vivo. Limitations of the study included a relatively short treatment period of the mice at an age in which full pathology is not yet developed. In addition, high variability in this model lowered the statistical significance of the findings of some outcome measures.

Conclusions
The findings suggest that CLR01 is a particularly attractive candidate for the treatment of AD because it targets simultaneously the two major pathogenic proteins instigating and propagating the disease, amyloid β-protein (Aβ), and tau, respectively. In addition, our study suggests that CLR01 can be used for the treatment of other tauopathies in the absence of amyloid pathology.
Trichostatin A ameliorates Alzheimer’s disease-related pathology and cognitive deficits by increasing albumin expression and Aβ clearance in APP/PS1 mice
Authors: Su Qiang , Li Tian , He Pei-Feng , Lu Xue-Chun , Yu Qi , Gao Qi-Chao , Wang Zhao-Jun , Wu Mei-Na , Yang Dan , Qi Jin-Shun 
Published: January 2021

Abstract
Background
Alzheimer’s disease (AD) is an intractable neurodegenerative disorder in the elderly population, currently lacking a cure. Trichostatin A (TSA), a histone deacetylase inhibitor, showed some neuroprotective roles, but its pathology-improvement effects in AD are still uncertain, and the underlying mechanisms remain to be elucidated. The present study aims to examine the anti-AD effects of TSA, particularly investigating its underlying cellular and molecular mechanisms.

Methods
Novel object recognition and Morris water maze tests were used to evaluate the memory-ameliorating effects of TSA in APP/PS1 transgenic mice. Immunofluorescence, Western blotting, Simoa assay, and transmission electron microscopy were utilized to examine the pathology-improvement effects of TSA. Microglial activity was assessed by Western blotting and transwell migration assay. Protein-protein interactions were analyzed by co-immunoprecipitation and LC-MS/MS.

Results
TSA treatment not only reduced amyloid β (Aβ) plaques and soluble Aβ oligomers in the brain, but also effectively improved learning and memory behaviors of APP/PS1 mice. In vitro study suggested that the improvement of Aβ pathology by TSA was attributed to the enhancement of Aβ clearance, mainly by the phagocytosis of microglia, and the endocytosis and transport of microvascular endothelial cells. Notably, a meaningful discovery in the study was that TSA dramatically upregulated the expression level of albumin in cell culture, by which TSA inhibited Aβ aggregation and promoted the phagocytosis of Aβ oligomers.

Conclusions
These findings provide a new insight into the pathogenesis of AD and suggest TSA as a novel promising candidate for the AD treatment.
Gender differences in the efficacy of pioglitazone treatment in nonalcoholic fatty liver disease patients with abnormal glucose metabolism
Authors: Yan Hongmei , Wu Weiyun , Chang Xinxia , Xia Mingfeng , Ma Sicheng , Wang Liu , Gao Jian 
Published: January 2021

Abstract
Background
Pioglitazone is a promising therapeutic method for nonalcoholic fatty liver disease (NAFLD) patients with or without type 2 diabetes. However, there is remarkable variability in treatment response. We analyzed our previous randomized controlled trial to examine the effects of gender and other factors on the efficacy of pioglitazone in treating Chinese nonalcoholic fatty liver disease (NAFLD) patients with abnormal glucose metabolism.

Methods
This is a post hoc analysis of a previous randomized, parallel controlled, open-label clinical trial (RCT) with an original purpose of evaluating the efficacy of berberine and pioglitazone on NAFLD. The total population (n = 185) was randomly divided into three groups: lifestyle intervention (LSI), LSI + pioglitazone (PGZ) 15 mg qd, and LSI + berberine (BBR) 0.5 g tid, respectively, for 16 weeks. The study used proton magnetic resonance spectroscopy (1H-MRS) to assess liver fat content.

Results
As compared with LSI, PGZ + LSI treatment further decreased liver fat content in women (− 15.24% ± 14.54% vs. − 8.76% ± 13.49%, p = 0.025), but less decreased liver fat content in men (− 9.95% ± 15.18% vs. − 12.64% ± 17.78%, p = 0.046). There was a significant interaction between gender and efficacy of pioglitazone before and after adjustment for age, smoking, drinking, baseline BMI, BMI change, treatment adherence, baseline liver fat content, and glucose metabolism.

Conclusion
The study recommends pioglitazone plus lifestyle intervention for Chinese NAFLD female patients with abnormal glucose metabolism.

Trial registration
Role of Pioglitazone and Berberine in Treatment of Non-Alcoholic Fatty Liver Disease, NCT00633282. Registered on 3 March 2008, https://register.clinicaltrials.gov.
The associations of hostility and defensiveness with telomere length are influenced by sex and health status
Authors: Starnino Louisia , Dupuis Gilles , Busque Lambert , Bourgoin Vincent , Dubé Marie-Pierre , Busseuil David , D’Antono Bianca 
Published: January 2021

Abstract
Background
Shorter telomere length (TL) may indicate premature cellular aging and increased risk for disease. While there is substantial evidence for shorter TL in individuals suffering from psychiatric disorders, data is scarce on maladaptive personality traits related to coronary artery disease (CAD). The purpose of this study was to evaluate the association of TL with hostility and defensiveness in individuals with CAD or other non-cardiovascular illnesses and whether associations were moderated by CAD status and sex.

Methods
One thousand thirty-six individuals (Mage = 65.40 ± 6.73 years) with and without CAD completed the Marlowe-Crowne Social Desirability Scale and the Cook–Medley Hostility Scale. Relative TL was measured via quantitative polymerase chain reaction of total genomic DNA samples. Analyses involved hierarchical regressions on TL, performed separately for hostility and defensiveness, controlling for pertinent sociodemographic, behavioural, and medical risk factors. Separate analyses were performed on 25 healthy participants.

Results
A hostility by sex interaction emerged (β = − .08, p = .006) in the patient groups, where greater hostility was associated with shorter TL in women only (p < .01). A Defensiveness by CAD status interaction (β = − .06, p = .049) revealed longer TL in more defensive CAD patients only (p = .06). In healthy men, shorter TL was observed in those with greater defensiveness (β = .52, p = .006) but lower hostility (β = − .43, p = .049).

Conclusion
Hostility and defensiveness are differentially associated with TL as a function of sex and health status. The implication of these results for health remains to be determined, but propose an additional pathway through which the effect of maladaptive personality traits may contribute to CV and other disease.
Do consumers’ values and attitudes affect food retailer choice? Evidence from a national survey on farmers’ market in Germany
Authors: Cicia Gianni , Furno Marilena , Del Giudice Teresa 
Published: January 2021

AbstractNew trends in food consumption are shaping consumers’ preferences and buying behavior. Non-traditional food retailing and short supply chains (SSCs) are offering bundles of attributes that fit the needs of larger consumers’ segments. Several studies have analyzed factors affecting the choice of traditional and non-traditional food retailing. Very few, however, are those studies that analyze the predictive role of human values and attitudes on the choice of traditional and non-traditional food retailing and supply chains. Usually, due to the low percentage of consumers involved in SSC, analyses of consumer behavior have been conducted using convenience samples. This study, based on online questionnaires submitted to a representative sample composed by 1009 German consumers, tests the hypothesis that the frequency of purchases at farmers’ markets is related to human values: attitude toward the industrialized food market and attitude toward the environment. The econometric approach here implemented computes the model on average and in the tails of the dependent variable, frequency of purchases at farmers’ market, thus investigating the model in a representative sample even where the percentage of non-traditional food retailing consumers is low, as occurs in the tails for low/high frequency of purchases. The questionnaire included the Schwartz value survey, attitudes toward environment and attitude toward industrialized food market, and self-reported estimates of the frequency of buying at farmers’ market. Results suggest that the frequency of buying at farmers’ market is hierarchically related to attitudes and values. The frequency of purchases at farmers’ market is negatively related to industrialized food attitude and positively related to pro-environment attitude. Attitudes are in turn affected by values: self-transcendence has a positive impact on pro-environment attitude and the reverse is true for conservation. Furthermore, these relationships are not constant in the sample: they change according to the selected frequency of purchases.