bluuebunny/crossref_metadata_2025_split huggingface dataset:
Design of placebo-controlled randomized trials of anticancer agents: Ethical considerations based on a review of published trials
Authors: Doussau Adélaïde , Agarwal Isha , Fojo Tito , Tannock Ian F , Grady Christine 
Published: October 2021

Background Limited information exists about the design of placebo-controlled cancer trials. Through a systematic review of trials published in 2013, we describe placebo use in randomized trials testing anticancer agents and analyze strategies that increase exposure to the experimental regimen. Methods Trials were classified as add-on (placebo in combination with standard treatment) or placebo-only. Strategies to allow more than half of the participants to receive the experimental regimen were reviewed. The risk–benefit ratio of receiving the experimental agent was considered favorable if the difference in primary outcome was significant (p ≤ 0.05), neutral if there was no significant difference in the primary outcome and the experimental agent did not add substantial toxicity, and unfavorable otherwise. Results Eighty trials were included (32,694 participants). Most trials were add-on (69%). The risk–benefit outcome was favorable, neutral, and unfavorable to the experimental agent in 52%, 32%, and 16% of placebo-only trials and 25%, 53%, and 22%, respectively, of add-on trials. Four strategies increased exposure to the experimental regimen: one-way crossover (23%), uneven randomization (21%), three-arms (13%), and randomized discontinuation design (4%); these strategies were used more often in placebo-only trials. Conclusion A minority of participants received placebo alone and strategies to increase experimental exposure were used commonly. Fewer than half of the studies had favorable outcomes, thus defending the use of placebo controls, when there is no established treatment. Strategies that increase patient exposure to experimental agents rather than placebo may expose them to non-beneficial, sometimes toxic, experimental agents.
CGRP monoclonal antibodies in migraine: an efficacy and tolerability comparison with standard prophylactic drugs
Authors: Vandervorst Fenne , Van Deun Laura , Van Dycke Annelies , Paemeleire Koen , Reuter Uwe , Schoenen Jean , Versijpt Jan 
Published: October 2021

Abstract
Background
Several drugs are available for the preventive treatment of both episodic and chronic migraine. The choice of which therapy to initiate first, second, or third is not straightforward and is based on multiple factors, including general efficacy, tolerability, potential for serious adverse events, comorbid conditions, and costs. Recently, a new class of migraine preventive drugs was introduced, i.e. monoclonal antibodies against calcitonin gene-related peptide (CGRP) or its receptor.

Methods
The present article summarizes the evidence gathered with this new migraine preventive drug class from randomized placebo-controlled clinical trials. It further puts this into perspective next to the evidence gained by the most widely used agents for the prevention of episodic and chronic migraine with an emphasis on efficacy and the robustness with which this efficacy signal was obtained.

Results
Although being a relatively new class of migraine preventive drugs, monoclonal antibodies blocking the CGRP pathway have an efficacy which is at least comparable if not higher than those of the currently used preventive drugs. Moreover, the robustness of this efficacy signal is substantiated by several randomized clinical trials each including large numbers of patients. In addition, because of their excellent tolerability and with long-term safety data emerging, they seem to have an unprecedented efficacy over adverse effect profile, clearly resulting in an added value for migraine prevention.

Conclusions
Balancing the data presented in the current manuscript with additional data concerning long term safety on the one hand and cost issues on the other hand, can be of particular use to health policy makers to implement this new drug class in the prevention of migraine.
Improve hot region prediction by analyzing different machine learning algorithms
Authors: Hu Jing , Zhou Longwei , Li Bo , Zhang Xiaolong , Chen Nansheng 
Published: October 2021

Abstract
Background
In the process of designing drugs and proteins, it is crucial to recognize hot regions in protein–protein interactions. Each hot region of protein–protein interaction is composed of at least three hot spots, which play an important role in binding. However, it takes time and labor force to identify hot spots through biological experiments. If predictive models based on machine learning methods can be trained, the drug design process can be effectively accelerated.

Results
The results show that different machine learning algorithms perform similarly, as evaluating using the F-measure. The main differences between these methods are recall and precision. Since the key attribute of hot regions is that they are packed tightly, we used the cluster algorithm to predict hot regions. By combining Gaussian Naïve Bayes and DBSCAN, the F-measure of hot region prediction can reach 0.809.

Conclusions
In this paper, different machine learning models such as Gaussian Naïve Bayes, SVM, Xgboost, Random Forest, and Artificial Neural Network are used to predict hot spots. The experiment results show that the combination of hot spot classification algorithm with higher recall rate and clustering algorithm with higher precision can effectively improve the accuracy of hot region prediction.
Comparative phenotypic and transcriptomic analyses unravel conserved and distinct mechanisms underlying shade avoidance syndrome in Brassicaceae vegetables
Authors: Nguyen Nguyen Hoai , Sng Benny Jian Rong , Yeo Hock Chuan , Jang In-Cheol 
Published: October 2021

Abstract
Background
Plants grown under shade are exposed to low red/far-red ratio, thereby triggering an array of altered phenotypes called shade avoidance syndrome (SAS). Shade negatively influences plant growth, leading to a reduction in agricultural productivity. Understanding of SAS is crucial for sustainable agricultural practices, especially for high-density indoor farming. Brassicaceae vegetables are widely consumed around the world and are commonly cultivated in indoor farms. However, our understanding of SAS in Brassicaceae vegetables and their genome-wide transcriptional regulatory networks are still largely unexplored.

Results
Shade induced common signs of SAS, including hypocotyl elongation and reduced carotenoids/anthocyanins biosynthesis, in two different Brassicaceae species: Brassica rapa (Choy Sum and Pak Choy) and Brassica oleracea (Kai Lan). Phenotype-assisted transcriptome analysis identified a set of genes induced by shade in these species, many of which were related to auxin biosynthesis and signaling [e.g. YUCCA8 (YUC8), YUC9, and INDOLE-3-ACETIC ACID INDUCIBLE (IAAs)] and other phytohormones signaling pathways including brassinosteroids and ethylene. The genes functioning in plant defense (e.g. MYB29 and JASMONATE-ZIM-DOMAIN PROTEIN 9) as well as in biosynthesis of anthocyanins and glucosinolates were repressed upon shade. Besides, each species also exhibited distinct SAS phenotypes. Shade strongly reduced primary roots and elongated petioles of B. oleracea, Kai Lan. However, these SAS phenotypes were not clearly recognized in B. rapa, Choy Sum and Pak Choy. Some auxin signaling genes (e.g. AUXIN RESPONSE FACTOR 19, IAA10, and IAA20) were specifically induced in B. oleracea, while homologs in B. rapa were not up-regulated under shade. Contrastingly, shade-exposed B. rapa vegetables triggered the ethylene signaling pathway earlier than B. oleracea, Kai Lan. Interestingly, shade induced the transcript levels of LONG HYPOCOTYL IN FAR-RED 1 (HFR1) homolog in only Pak Choy as B. rapa. As HFR1 is a key negative regulator of SAS in Arabidopsis, our finding suggests that Pak Choy HFR1 homolog may also function in conferring higher shade tolerance in this variety.

Conclusions
Our study shows that two Brassicaceae species not only share a conserved SAS mechanism but also exhibit distinct responses to shade, which will provide comprehensive information to develop new shade-tolerant cultivars that are suitable for high-density indoor farms.
Alternative splicing regulation appears to play a crucial role in grape berry development and is also potentially involved in adaptation responses to the environment
Authors: Maillot Pascale , Velt Amandine , Rustenholz Camille , Butterlin Gisèle , Merdinoglu Didier , Duchêne Eric 
Published: October 2021

AbstractBackgroundAlternative splicing (AS) produces transcript variants playing potential roles in proteome diversification and gene expression regulation. AS modulation is thus essential to respond to developmental and environmental stimuli. In grapevine, a better understanding of berry development is crucial for implementing breeding and viticultural strategies allowing adaptation to climate changes. Although profound changes in gene transcription have been shown to occur in the course of berry ripening, no detailed study on splicing modifications during this period has been published so far. We report here on the regulation of gene AS in developing berries of two grapevine (Vitis vinifera L.) varieties, Gewurztraminer (Gw) and Riesling (Ri), showing distinctive phenotypic characteristics. Using the software rMATS, the transcriptomes of berries at four developmental steps, from the green stage to mid-ripening, were analysed in pairwise comparisons between stages and varieties.ResultsA total of 305 differential AS (DAS) events, affecting 258 genes, were identified. Interestingly, 22% of these AS events had not been reported before. Among the 80 genes that underwent the most significant variations during ripening, 22 showed a similar splicing profile in Gw and Ri, which suggests their involvement in berry development. Conversely, 23 genes were subjected to splicing regulation in only one variety. In addition, the ratios of alternative isoforms were different in Gw and Ri for 35 other genes, without any change during ripening. This last result indicates substantial AS differences between the two varieties. Remarkably, 8 AS events were specific to one variety, due to the lack of a splice site in the other variety. Furthermore, the transcription rates of the genes affected by stage-dependent splicing regulation were mostly unchanged, identifying AS modulation as an independent way of shaping the transcriptome.ConclusionsThe analysis of AS profiles in grapevine varieties with contrasting phenotypes revealed some similarity in the regulation of several genes with developmental functions, suggesting their involvement in berry ripening. Additionally, many splicing differences were discovered between the two varieties, that could be linked to phenotypic specificities and distinct adaptive capacities. Together, these findings open perspectives for a better understanding of berry development and for the selection of grapevine genotypes adapted to climate change.
Prevalence of cognitive impairment in Chinese older inpatients and its relationship with 1-year adverse health outcomes: a multi-center cohort study
Authors: Yuan Li , Zhang Xiaoming , Guo Na , Li Zhen , Lv Dongmei , Wang Hui , Jin Jingfen , Wen Xianxiu , Zhao Shengxiu , Xu Tao , Jiao Jing , Wu Xinjuan 
Published: October 2021

Abstract
Background
Previous studies on the relationship between cognitive impairment and adverse outcomes among geriatric inpatients are not representative of older inpatients in China because of insufficient sample sizes or single-center study designs. The purpose of our study was to examine the prevalence of cognitive impairment and the relationship between cognitive impairment and 1-year adverse health outcomes in older inpatients.

Methods
This study was a large-scale multi-center cohort study conducted from October 2018 to February 2020. Six tertiary hospitals across China were selected using a two-stage cluster sampling method, and eligible older inpatients were selected for the baseline survey and follow-up. The Mini Cognitive Scale and the FRAIL scale were used to screen for cognitive impairment and frailty, respectively. The EuroQol-5 Dimension-5 Level questionnaire was used to assess health-related quality of life (HRQoL). We used a generalized estimating model to evaluate the relationship between cognitive impairment and adverse outcomes.

Results
The study included 5008 men (58.02%) and 3623 women (41.98%), and 70.64% were aged 65–75 years, and 26.27% were aged 75–85 years. Cognitive impairment was observed in 1756 patients (20.35%). There were significant differences between participants with cognitive impairment and those with normal cognitive function for age, gender, surgery status, frailty, depression, handgrip strength and so on. After adjusting for multiple covariates, compared with patients with normal cognitive function, the odds ratio for 1-year mortality was 1.216 (95% confidence interval [CI]: 1.076–1.375) and for 1-year incidence of frailty was 1.195 (95% CI: 1.037–1.376) in patients with cognitive impairment. Similarly, the regression coefficient of 1-year HRQoL was − 0.013 (95% CI: − 0.024−− 0.002). In the stratified analysis, risk of adverse outcome within 1 year was higher in older patients with cognitive impairment aged over 75 years than those aged 65–74 years.

Conclusions
We revealed that cognitive impairment was highly correlated with occurrence of 1-year adverse health outcomes (death, frailty, and decreased HRQoL) in older inpatients, which provides a basis for formulating effective intervention measures.

Trial registration
Chinese Clinical Trial Registry, ChiCTR1800017682, registered 09 August 2018.
Tear miRNA expression analysis reveals miR-203 as a potential regulator of corneal epithelial cells
Authors: Nakagawa Ayumi , Nakajima Takeshi , Azuma Mitsuyoshi 
Published: October 2021

Abstract
Background
microRNAs (miRNAs) are small noncoding RNAs that negatively regulate gene expression. They are found within cells and in body fluids. Extracellular miRNAs have been shown to associate with the surrounding tissues. Therefore, we predicted that miRNAs in tears may contribute to regulate corneal epithelial cell function. However, information on the miRNA expression profile of tears is limited and the specific functions of tear miRNAs for corneal epithelial cells are still unknown. To study the role of tear miRNAs, we determined which miRNAs are highly expressed in tears and examined the involvement of miRNAs in corneal epithelial cell viability.

Methods
miRNAs extracted from monkey tears and sera were subjected to microarray analysis. miRNAs of which expression levels were higher in tears than in sera were selected, and their expression levels were quantified by quantitative polymerase chain reaction (qPCR). To examine miRNA function, mimics and inhibitors of miRNAs were transfected into human corneal epithelial (HCE-T) cells and incubated for 24 or 48 h. After transfection of miRNA mimics and inhibitors, the viability of HCE-T cells was measured using the water soluble tetrazolium salt (WST) assay, and microarray analysis and qPCR were performed using total RNA extracted from HCE-T cells. siRNAs of the candidate targets for miR-203 were transfected into HCE-T cells and the WST assay was performed. To determine a direct target gene for miR-203, a dual luciferase reporter assay was performed in HCE-T cells using a luciferase reporter plasmid containing 3′-UTR of human IGFBP5.

Results
Microarray and qPCR analyses showed that miR-184 and miR-203 were expressed significantly more highly in tears than in sera (165,542.8- and 567.8-fold, respectively, p < 0.05). Of these two miRNAs, transfection of a miR-203 mimic significantly reduced the viability of HCE-T cells (p < 0.05), while a miR-203 inhibitor significantly increased this viability (p < 0.05). miR-203 mimic downregulated insulin-like growth factor-binding protein 5 (IGFBP5) and nuclear casein kinase and cyclin-dependent kinase substrate 1 (NUCKS1), while miR-203 inhibitor upregulated these two genes. Transfection of IGFBP5-siRNA decreased the viability of HCE-T cells. miR-203 mimic significantly diminished the luciferase reporter activity.

Conclusions
In this study, we identified miRNAs that are highly expressed in tears, and the inhibition of miR-203 increases the viability of corneal epithelial cells. Our results suggest that miR-203 contributes to regulating the homeostasis of corneal epithelial cells.
Expression of FRS2 in atypical lipomatous tumor/well-differentiated liposarcoma and dedifferentiated liposarcoma: an immunohistochemical analysis of 182 cases with genetic data
Authors: Jing Wenyi , Lan Ting , Qiu Yan , Peng Ran , Lu Yang , Chen Huijiao , Chen Min , He Xin , Chen Chen , Zhang Hongying 
Published: October 2021

Abstract
Background
The fibroblast growth factor receptor substrate 2 (FRS2) gene is located close to MDM2 and CDK4 within the 12q13-15 chromosomal region. FRS2 gene was recently found to be consistently amplified in atypical lipomatous tumor (ALT)/well-differentiated liposarcoma (WDL) and dedifferentiated liposarcoma (DDL), suggesting the detection of FRS2 amplification could be a diagnostic tool for ALT/WDL/DDLs. However, the expression of FRS2 protein and diagnostic value of FRS2 immunohistochemistry (IHC) has not been evaluated in a large cohort of ALT/WDL/DDLs.

Methods
A SNOMED search of hospital surgical pathology files from January 2007 to July 2020 identified 182 ALT/WDL/DDLs with available materials. FRS2 fluorescence in situ hybridization (FISH) and IHC were performed on 182 ALT/WDL/DDLs and 64 control samples. The expression of FRS2 was also compared with that of classic immunomarkers (MDM2 and CDK4) of this tumor entity.

Results
This study included 91 ALT/WDLs and 91 DDLs. The FISH results showed 172 of 182 (94.5%) cases were FRS2-amplified, and 10 cases were FRS2-nonamplified. Immunostaining results showed 171 (94.0%) ALT/WDL/DDLs were positive for FRS2 and 11 cases (6.0%) were FRS2-immunonegative. In 172 FRS2-amplified cases, 166 (96.5%) were FRS2-immunopositive, and 6 (3.5%) were negative. Among 10 FRS2-nonamplified ALT/WDL/DDL cases, 5 cases were FRS2-immunonegative, and 5 tumors displayed 1+ staining for this marker. In 64 control cases, none of them exhibited FRS2 amplification. Forty-seven (73.5%) control cases were negative for FRS2 immunostaining, while 17 cases (26.5%) were FRS2-immunopositive. Fifteen of these false positive samples (15/17, 88.2%) showed 1+ positivity and only 2 cases (2/17, 11.8%) displayed 2+ positivity. In ALT/WDL/DDLs, the sensitivity of FRS2 immunostaining was slightly lower than MDM2 (FRS2 vs. MDM2: 94.0% vs 100.0%) and CDK4 (FRS2 vs. CDK4: 94.0% vs 97.0%). However, the specificity of FRS2 (73.5%) was slightly higher than that of MDM2 (67.8%) and CDK4 (64.4%).

Conclusion
This study indicated that FRS2 IHC had relatively good consistency with FRS2 FISH, suggesting that FRS2 immunostaining could be utilized as an additional screening tool for the diagnosis of ALT/WDL/DDL. It must be emphasized that MDM2/CDK4/FRS2 especially MDM2 FISH remains the gold standard and the most recommended method to diagnose this entity.
The geometry of colors in van Gogh’s Sunflowers
Authors: Liao Shuting , Koehl Patrice , Schultens Jennifer , Hsieh Fushing 
Published: October 2021

Abstract
“Paintings fade like flowers”: van Gogh’s prediction on the impact of age on paintings came true for most of his paintings. We have studied the consequences of this aging on the Sunflowers in a vase with a yellow background series, namely its original, F454, currently in London, and two replicates, F457, in Tokyo, and F458, in Amsterdam, which van Gogh painted using the original as a model. The background and flower renditions in those paintings have faded and turned brown, making them less vibrant that van Gogh had most likely intended. We have attempted to restore van Gogh’s intent using a computational approach based on data science. After identifications of regions of interest (ROI) within the three paintings F454, F457, and F458 that capture the flowers, stems of the flowers, and background, respectively, we studied the geometry of the color space (in RGB representation) occupied by those ROIs. By comparing those color spaces with those occupied by similar ROIs in photographs of real sunflowers, we identified shifts in all three color coordinates, R, G, and B, with the positive shift in the blue coordinate being the more salient. We have proposed two algorithms, PCR-1 and PCR-2, for correcting that shift in blue and generate representations of the paintings that aim to restore their original conditions. The reduction of the blue component in the yellow hues has lead to more vibrant and less brownish digital rendition of the three Sunflowers in a vase with a yellow background.
“The City of Combat”
Authors: Nesci Catherine 
Published: October 2021

AbstractThis essay builds on Priscilla Parkhurst Ferguson’s pioneering inquiry on reading and writing Paris as the site of a democratizing and modernizing process and, more specifically, on her approach to Jules Vallès’s “performance of politics” in Le Tableau de Paris and L’Insurgé. I examine the ways in which Vallès’s reading of the Paris of the early 1880s and excavation of the multilayered city’s past and cultural representations help foster the return of repressed voices and collective memories. Using the trope of the city as palimpsest, I argue that the critical power of nostalgia for revolutionary Paris aims to generate a new street aesthetics and an egalitarian public sphere.
Long-Term Passive Leg Stretch Improves Systemic Vascular Responsiveness as Much as Single-Leg Exercise Training
Authors: CÈ EMILIANO , VENTURELLI MASSIMO , BISCONTI ANGELA VALENTINA , LONGO STEFANO , PEDRINOLLA ANNA , CORATELLA GIUSEPPE , SCHENA FEDERICO , ESPOSITO FABIO 
Published: October 2021

ABSTRACT

Purpose
The current study compared the local and systemic vascular responsiveness after small muscle mass endurance training or passive stretching training (PST).

Methods
Thirty-six sex-matched healthy participants underwent 8-wk single-leg knee extension (SLKE) (n = 12) training or PST (n = 12), or no intervention (control, n = 12). Before and after the intervention, local and systemic vascular responsiveness was assessed by Doppler ultrasound at the femoral (local effect) and brachial artery (systemic effect) during single passive leg movement and brachial flow-mediated dilation (FMD) test, respectively.

Results
After training, delta femoral blood flow (representing the local vascular responsiveness) increased after SLKE and PST by +54 (7)% (effect size, 2.72; P < 0.001) and +20 (2)% (effect size, 2.43; P < 0.001), respectively, albeit with a greater extent in SLKE (post-SLKE vs post-PST: +56 [8]% [effect size, 2.92; P < 0.001]). Interestingly, the %FMD (standing for the systemic effect) increased after SLKE and PST by +12 (2)% (effect size, 0.68; P < 0.001) and +11 (1)% (effect size, 0.83; P < 0.001), respectively, without any between-groups difference (P > 0.05). No changes occurred in control.

Conclusions
The present findings revealed that both active and passive training modalities induced similar improvements in the brachial artery dilatation capacity, whereas the former was more effective in improving femoral artery blood flow. Passive stretching could be used in people with limited mobility to improve vascular responsiveness both at the local and systemic level and in this latter case has similar effects as small muscle mass endurance training.