bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cost-effectiveness analysis of brolucizumab versus aflibercept for the treatment of neovascular age-related macular degeneration (nAMD) in Italy
Authors: Ferrante Nicola , Ritrovato Daniela , Bitonti Rossella , Furneri Gianluca 
Published: April 2022

Abstract
Background
Age-related macular degeneration (AMD) is a common and chronic eye condition characterized by the presence of progressive degenerative abnormalities in the central retina (macula). Notably, neovascular, or wet, AMD (nAMD) occurs when new, abnormal blood vessels grow under the macula causing scarring of the macula itself and resulting in a loss of central vision, visual distortion, and an impaired capacity of perceiving colour contrast and intensity. Brolucizumab, a new generation anti-vascular endothelial growth factor (anti-VEGF) monoclonal antibody, was approved by the European Medicines Agency for the treatment of nAMD. The aim of this analysis is to evaluate the cost-effectiveness profile of brolucizumab, compared to the main therapeutic alternative available (aflibercept), for the treatment of nAMD.

Methods
The simulation of costs and outcomes was carried out using a Markov model over a time horizon of 15 years. In base-case, treatment effectiveness inputs for brolucizumab and aflibercept were extracted from the HAWK and HARRIER studies and from a network meta-analysis. The Italian National Healthcare Service (NHS) perspective was considered, therefore only healthcare direct costs (treatment acquisition, administration, adverse events, disease monitoring) were analysed. In the alternative scenarios, the societal perspective and a prolonged time horizon were considered. Model robustness was tested through sensitivity analyses.

Results
In the base-case analysis, brolucizumab was dominant over aflibercept (+ 0.11 years QALY gained and -€15,679 costs). Both one-way deterministic and probabilistic sensitivity analyses confirmed the robustness and reliability of base-case results. The results of the probabilistic sensitivity analysis showed that when the willingness to pay is equal to €50,000 per QALY gained, brolucizumab would be dominant in 84% of simulations and in the remaining simulations brolucizumab would be cost-effective compared to aflibercept. Results of the alternative scenarios and sensitivity analyses confirmed the results of base-case.

Conclusion
The cost-utility analysis shows that brolucizumab is dominant over aflibercept. Treatment with brolucizumab reduces the economic impact of nAMD and determined a slight increase of quality-adjusted survival. This analysis gives a high level of confidence that the treatment with brolucizumab would reduce the burden of intravitreal injections, compared to aflibercept, a relevant therapeutic alternative in Italy.
Transcriptional inhibition of miR-486-3p by BCL6 upregulates Snail and induces epithelial–mesenchymal transition during radiation-induced pulmonary fibrosis
Authors: Yan Ziyan , Ao Xingkun , Liang Xinxin , Chen Zhongmin , Liu Yuhao , Wang Ping , Wang Duo , Liu Zheng , Liu Xiaochang , Zhu Jiaojiao , Zhou Shenghui , Zhou Pingkun , Gu Yongqing 
Published: April 2022

Abstract
Background
Ionizing radiation (IR) can induce pulmonary fibrosis by causing epithelial mesenchymal transition (EMT), but the exact mechanism has not been elucidated. To investigate the molecular mechanism of how radiation induces pulmonary fibrosis by altering miR-486-3p content and thus inducing EMT.

Methods
The changes of miR-486-3p in cells after irradiation were detected by RT-qPCR. Western blot was used to detect the changes of cellular epithelial marker protein E-cadherin, mesenchymal marker N-cadherin, Vimentin and other proteins. The target gene of miR-486-3p was predicted by bioinformatics method and the binding site was verified by dual luciferase reporter system. In vivo experiments, adeno-associated virus (AAV) was used to carry miR-486-3p mimic to lung. Radiation-induced pulmonary fibrosis (RIPF) model was constructed by 25Gy60Co γ-rays. The structural changes of mouse lung were observed by HE and Masson staining. The expression of relevant proteins in mice was detected by immunohistochemistry.

Results
IR could decrease the miR-486-3p levels in vitro and in vivo, and that effect was closely correlated to the occurrence of RIPF. The expression of Snail, which induces EMT, was shown to be restrained by miR-486-3p. Therefore, knockdown of Snail blocked the EMT process induced by radiation or knockdown of miR-486-3p. In addition, the molecular mechanism underlying the IR-induced miRNA level reduction was explored. The increased in BCL6 could inhibit the formation of pri-miR-486-3p, thereby reducing the levels of miR-486-3p in the alveolar epithelial cells, which would otherwise promote EMT and contribute to RIPF by targeting Snail.

Conclusion
IR can exacerbate RIPF in mice by activating the transcription factor BCL6, which inhibits the transcription of miR-486-3p and decreases its content, which in turn increases the content of the target gene slug and triggers EMT.
Functional interaction between endothelin-1 and ZEB1/YAP signaling regulates cellular plasticity and metastasis in high-grade serous ovarian cancer
Authors: Sestito Rosanna , Tocci Piera , Roman Celia , Di Castro Valeriana , Bagnato Anna 
Published: April 2022

Abstract
Background
Epithelial-to-mesenchymal transition (EMT) encompasses a highly dynamic and complex key process which leads to metastatic progression. In high-grade serous ovarian carcinoma (HG-SOC), endothelin-1 (ET-1)/endothelin A receptor (ETAR) signaling promotes EMT driving tumor progression. However, the complex nature of intertwined regulatory circuits activated by ET-1 to trigger the metastatic process is not fully elucidated.

Methods
The capacity of ET-1 pathway to guide a critical transcriptional network that is instrumental for metastatic growth was identified in patient-derived HG-SOC cells and cell lines through immunoblotting, q-RT-PCR, co-immunoprecipitation, in situ proximity ligation, luciferase reporter, chromatin immunoprecipitation assays and publicly available databases. Functional assays in HG-SOC cells and HG-SOC xenografts served to test the inhibitory effects of ET-1 receptors (ET-1R) antagonist in vitro and in vivo.

Results
We demonstrated that ET-1/ETAR axis promoted the direct physical ZEB1/YAP interaction by inducing their nuclear accumulation in HG-SOC cells. Moreover, ET-1 directed their engagement in a functional transcriptional complex with the potent oncogenic AP-1 factor JUN. This led to the aberrant activation of common target genes, including EDN1 (ET-1) gene, thereby creating a feed-forward loop that sustained a persistent ET-1/ZEB1 signaling activity. Notably, ET-1-induced Integrin-linked kinase (ILK) signaling mediated the activation of YAP/ZEB1 circuit driving cellular plasticity, invasion and EMT. Of therapeutic interest, treatment of HG-SOC cells with the FDA approved ET-1R antagonist macitentan, targeting YAP and ZEB1-driven signaling, suppressed metastasis in vivo in mice. High gene expression of ETAR/ILK/YAP/AP-1/ZEB1 was a strong predictor of poor clinical outcome in serous ovarian cancer patients, indicating the translational relevance of this signature expression.

Conclusions
This study provides novel mechanistic insights of the ET-1R-driven mediators that support the ability of HG-SOC to acquire metastatic traits which include the cooperation of YAP and ZEB1 regulatory circuit paving the way for innovative treatment of metastatic ovarian cancer.
Systematic evaluation of colorectal cancer organoid system by single-cell RNA-Seq analysis
Authors: Wang Rui , Mao Yunuo , Wang Wendong , Zhou Xin , Wang Wei , Gao Shuai , Li Jingyun , Wen Lu , Fu Wei , Tang Fuchou 
Published: April 2022

AbstractBackgroundPatient-derived organoid culture is a powerful system for studying the molecular mechanisms of cancers, especially colorectal cancer (CRC), one of the most prevalent cancers worldwide. There are two main types of 3D culture methods for colonic cells, but the similarities and differences between gene expression patterns in different culture media remain largely unexplored.ResultsHere, we establish patient-derived organoids from colorectal cancer patients and perform single-cell RNA-Seq for pairwise samples from seven patients for both organoids and their corresponding tumor and normal tissues in vivo. We find that organoids derived from tumor tissues faithfully recapitulate the main gene expression signatures of cancer cells in vivo. On the other hand, organoids derived from normal tissues exhibited some tumor-like features at the whole transcriptome level but retained normal genomic features, such as CNVs, point mutations, and normal global DNA methylation levels, for both cultural media. More importantly, we show that conditioned medium outperforms chemical-defined medium in long-term culture of tumor epithelial cells. Finally, we mutually exchange the culture medium for the organoids and find that after interchanging the medium, the organoid cells basically maintain the transcriptome characteristics of the original medium.ConclusionsOur work gives a thorough evaluation of both the cultural conditions and the biological features of organoids of CRC patients.
Relationship between scapular control during isometric shoulder flexion and scapular motion during baseball pitching: a cross-sectional study
Authors: Nomura Yuki , Toda Hajime , Katayose Masaki , Watanabe Shun , Yoshida Masahiro , Yoshida Makoto , Yamamoto Keizo 
Published: April 2022

Abstract
Background
A baseball pitcher with decreased scapular control may not be able to achieve suitable scapular motion at maximum shoulder external rotation (MER) of baseball pitching during the pitching action. It is common clinically to compare scapular control of the throwing and non-throwing arms to detect side-to-side differences. However, it remains unclear whether scapular control is different between the throwing and non-throwing arms. Moreover, no data exist on the relationship between scapular control and scapular motion at MER of pitching. Primarily, this study aimed to compare scapular control during isometric shoulder flexion between the throwing and non-throwing arms. Secondly, this study aimed to investigate the relationship between scapular control during isometric shoulder flexion and scapular motion at MER of pitching.

Methods
Fifteen healthy collegiate baseball pitchers (age, 20.2 ± 1.9 years; height, 1.76 ± 0.05 m; body mass, 73.3 ± 6.7 kg) were recruited. An optical motion tracking system was used to assess scapular motion. Scapular control was defined as the amount of change in the scapular internal rotation angle, downward rotation angle, and anterior tilt angle during isometric shoulder flexion. We assessed scapular position at MER of pitching.

Results
No significant differences were detected for any of the scapular angles during isometric shoulder flexion between the throwing and non-throwing arms. The amount of change in the scapular internal rotation angle, scapular downward rotation angle, and scapular anterior tilt angle during isometric shoulder flexion had a significant relationship with the scapular downward rotation angle at MER.

Conclusions
No side-to-side difference was noted in scapular control during isometric shoulder flexion in healthy collegiate baseball pitchers at the group level. Further studies are required to understand the side-to-side differences at the individual level. Additionally, there was a relationship between scapular control during isometric shoulder flexion and scapular position at MER. These findings suggest that clinicians may consider using isometric shoulder flexion to assess scapular control in baseball pitchers.
Feasibility and usability of GPS data in exploring associations between training load and running-related knee injuries in recreational runners
Authors: Cloosterman Kyra L. A. , Fokkema Tryntsje , de Vos Robert-Jan , van Oeveren Ben , Bierma-Zeinstra Sita M. A. , van Middelkoop Marienke 
Published: April 2022

Abstract
Background
The purpose of the present study was to explore the feasibility of collecting GPS data and the usability of GPS data to evaluate associations between the training load and onset of running-related knee injuries (RRKIs).

Methods
Participants of the INSPIRE-trial, a randomized-controlled trial on running injury prevention, were asked to participate in this study. At baseline, demographic variables were collected. Follow-up questionnaires assessed information on RRKIs. Participants with a new reported RRKI and uninjured participants were sent a GPS export request. Weekly GPS-based training distances were used to calculate Acute:Chronic Workload Ratios (ACWRs).

Results
A total of 240 participants (62.7%) tracked their running training sessions with the use of a GPS-enabled device or platform and were willing to share their GPS data. From the participants (N = 144) who received a GPS export request, 50.0% successfully shared their data. The majority (69.4%) of the shared GPS data were usable for analyses (N = 50). GPS data were used to present weekly ACWRs of participants with and without an RRKI eight weeks prior to RRKI onset or running event.

Conclusions
It seems feasible to collect GPS data from GPS-enabled devices and platforms used by recreational runners. The results indicate that GPS data is usable to calculate weekly ACWRs to evaluate associations between training load and onset of RRKIs in recreational runners. Therefore, GPS-based ACWR measures can be used for future studies to evaluate associations between training load and onset of RRIs.
A cartilage-forming tumor of the mandibular angle: a case report
Authors: Ismail Ayman , Boujguenna Imane , Hattab Koussay , Mansouri Nadia , El Ganouni Najat Cherif Idrissi , Idrissi Mariem Ouali , Hazmiri Fatima Ezzahra , Rais Hanane 
Published: April 2022

AbstractBackgroundMandible can be the site of benign or malignant lesions of different origins, including odontogenic and non-odontogenic lesions. Cartilage-forming tumors have been rarely reported at this site. Chondrosarcoma is a rare malignant cartilage-producing neoplasm that is extremely rare in the mandible. The rarity of cartilage-forming tumor occurrence in the mandible can make diagnosis difficult for pathologists, as they do not expect this type of tumor at this anatomical site. Here we report a case of chondrosarcoma of mandibular angle.Case presentationA 70-year-old Moroccan male patient consulted a dentist for wisdom tooth pain. Wisdom tooth extraction was conducted. After 6 months, the patient reported the recurrence of pain associated with swelling in the mandibular area and paresthesia along the path of the mandibular nerve. A panoramic radiograph demonstrated a mixed radiolucent–opaque lesion involving the mandibular angle. Computed tomography showed a large osteolytic spontaneously hypointense and multilobulated lesion. A biopsy was done. Histopathological examination revealed sheets and irregular lobules of atypical cells presenting cartilaginous differentiation. Tumor cells showed severe nuclear atypia and were located within a hyaline cartilage matrix. Some foci of necrosis were noted. Osteoid deposits were not found. The patient was diagnosed with grade III chondrosarcoma and underwent a right segmental mandibulectomy with submandibular lymph node dissection. Macroscopically, the tumor was localized in the mandibular angle with extension in the mandibular body. Histopathology confirmed the previous diagnosis of grade III chondrosarcoma and did not show any lymph node metastasis.ConclusionsOwing to many histological similarities, grade III chondrosarcoma must be distinguished from chondroblastic osteosarcoma and metastatic lesions. In addition, chondroblastic osteosarcoma of the jawbones has a worse prognosis than chondrosarcoma, making the distinction between these two malignant tumors the most important concern of the pathologist when dealing with a cartilage-forming tumor at this site. Surgery with wide excision margins remains the best therapeutic approach, while the role of radiotherapy is controversial. The management of mandibular chondrosarcoma requires a multidisciplinary approach involving maxillofacial surgeons, radiologists, pathologists, and oncologists.
CircCRIM1 promotes nasopharyngeal carcinoma progression via the miR-34c-5p/FOSL1 axis
Authors: He Weifeng , Zhou Xiangqi , Mao Yini , Wu YangJie , Tang Xiyang , Yan Sijia , Tang Sanyuan 
Published: April 2022

AbstractBackgroundNasopharyngeal carcinoma (NPC) is a rare malignancy with multiple risk factors (Epstein–Barr virus, etc.) that seriously threatens the health of people. CircRNAs are known to regulate the tumorigenesis of malignant tumours, including NPC. Moreover, circCRIM1 expression is reported to be upregulated in NPC. Nevertheless, the impact of circCRIM1 on NPC progression is not clear.MethodsAn MTT assay was performed to assess cell viability. In addition, cell invasion and migration were assessed by the transwell assay. Dual luciferase assays were performed to assess the association among circCRIM1, miR-34c-5p and FOSL1. Moreover, RT-qPCR was applied to assess mRNA levels, and protein levels were determined by Western blot.ResultsCircCRIM1 and FOSL1 were upregulated in NPC cells, while miR-34c-5p was downregulated. Knockdown of circCRIM1 significantly decreased the invasion, viability and migration of NPC cells. The miR-34c-5p inhibitor notably promoted the malignant behaviour of NPC cells, while miR-34c-5p mimics exerted the opposite effect. Moreover, circCRIM1 could bind with miR-34c-5p, and FOSL1 was identified to be downstream of miR-34c-5p. Furthermore, circCRIM1 downregulation notably inhibited the proliferation and invasion of NPC cells, while this phenomenon was significantly reversed by FOSL1 overexpression.ConclusionSilencing circCRIM1 inhibited the tumorigenesis of NPC. Thus, circCRIM1 might be a novel target for NPC.
Exploring the form of big data products and the supporting systems
Authors: Ye Yazhen , Zhang Yao , Zhu Yangyong 
Published: April 2022

AbstractThere have been studies and practices about forms and supporting systems of single-type data products. However, little literature is dedicated to these factors of big data products, which are huge in volume and contain a variety of different types of data. For example, we do not know the form of data composed of a relation table and a digital video file at the same time. The lack of certain forms of big data products makes it impossible to design its base unit for measuring. It also causes difficulties in pricing and valuation of big data products, and further causes issues of circulation and supporting services. In this paper, we analyze the challenges of productizing big data. By referring to information media such as books, a product form and supporting systems of big data products based on Data Box are proposed. Different from previous studies, we focus on the system-level design and systematically study the pipeline including containerization, circulation, pricing, protection and etc. The proposed Data Box-based big data products and supporting systems can have a positive influence on the research, exploitation, exchange, and circulation of big data products.
Adaptive multiple imputations of missing values using the class center
Authors: Phiwhorm Kritbodin , Saikaew Charnnarong , Leung Carson K. , Polpinit Pattarawit , Saikaew Kanda Runapongsa 
Published: April 2022

AbstractBig data has become a core technology to provide innovative solutions in many fields. However, the collected dataset for data analysis in various domains will contain missing values. Missing value imputation is the primary method for resolving problems involving incomplete datasets. Missing attribute values are replaced with values from a selected set of observed data using statistical or machine learning methods. Although machine learning techniques can generate reasonably accurate imputation results, they typically require longer imputation durations than statistical techniques. This study proposes the adaptive multiple imputations of missing values using the class center (AMICC) approach to produce effective imputation results efficiently. AMICC is based on the class center and defines a threshold from the weighted distances between the center and other observed data for the imputation step. Additionally, the distance can be an adaptive nearest neighborhood or the center to estimate the missing values. The experimental results are based on numerical, categorical, and mixed datasets from the University of California Irvine (UCI) Machine Learning Repository with introduced missing values rate from 10 to 50% in 27 datasets. The proposed AMICC approach outperforms the other missing value imputation methods with higher average accuracy at 81.48% which is higher than those of other methods about 9 – 14%. Furthermore, execution time is different from the Mean/Mode method, about seven seconds; moreover, it requires significantly less time for imputation than some machine learning approaches about 10 – 14 s.
Detecting Denial of Service attacks using machine learning algorithms
Authors: Kumari Kimmi , Mrunalini M. 
Published: April 2022

AbstractCurrently, Distributed Denial of Service Attacks are the most dangerous cyber danger. By inhibiting the server's ability to provide resources to genuine customers, the affected server's resources, such as bandwidth and buffer size, are slowed down. A mathematical model for distributed denial-of-service attacks is proposed in this study. Machine learning algorithms such as Logistic Regression and Naive Bayes, are used to detect attacks and normal scenarios. The CAIDA 2007 Dataset is used for experimental study. The machine learning algorithms are trained and tested using this dataset and the trained algorithms are validated. Weka data mining platform are used in this study for implementation and results of the same are analysed and compared. Other machine learning algorithms used with respect to denial of service attacks are compared with the existing work.
Bioproduction of quercetin using recombinant thermostable glycosidases from Dictyoglomus thermophilum
Authors: Yu Shiqin , Shan Xiaoyu , Lyv Yunbin , Zhou Jingwen 
Published: April 2022

AbstractQuercetin is an essential ingredient in functional foods and nutritional supplements, as well as a promising therapeutic reagent. Also, the green technique to produce quercetin via rutin biotransformation is attractive. Genes encoding two thermostable glycosidases from Dictyoglomus thermophilum were cloned and expressed in Escherichia coli, which were applied in rutin biotransformation to produce highly pure quercetin at a high temperature. The production of biocatalysts were scaled up in a 5-L bioreactor, yielding a several-fold increase in total enzyme activity and a quercetin production of 14.22 ± 0.26 g/L from 30 g/L of rutin. Feeding strategies were optimized to boost biomass and enzyme production, achieving an activity of 104,801.80 ± 161.99 U/L for rhamnosidase and 12,637.23 ± 17.94 U/L for glucosidase, and a quercetin yield of 20.24 ± 0.27 g/L from the complete conversion of rutin. This study proposes a promising approach for producing high-quality quercetin in an industrial setting.
Graphical Abstract