bluuebunny/crossref_metadata_2025 huggingface dataset:
Assistance by Routine CT Features Combined With 3D Texture Analysis in the Diagnosis of BRCA Gene Mutation Status in Advanced Epithelial Ovarian Cancer
Authors: Li Meng-ru , Liu Ming-zhu , Ge Ya-qiong , Zhou Ying , Wei Wei
Published: July 2021

Purpose

To evaluate the predictive value of routine CT features combined with 3D texture analysis for prediction of BRCA gene mutation status in advanced epithelial ovarian cancer.

Method

Retrospective analysis was performed on patients with masses occupying the pelvic space confirmed by pathology and complete preoperative images in our hospital, including 37 and 58 cases with mutant type and wild type BRCA, respectively (total: 95 cases). The enrolled patients’ routine CT features were analyzed by two radiologists. Then, ROIs were jointly determined through negotiation, and the ITK-SNAP software package was used for 3D outlining of the third-stage images of the primary tumor lesions and obtaining texture features. For routine CT features and texture features, Mann-Whitney U tests, single-factor logistic regression analysis, minimum redundancy, and maximum correlation were used for feature screening, and the performance of individual features was evaluated by ROC curves. Multivariate logistic regression analysis was used to further screen features, find independent predictors, and establish the prediction model. The established model’s diagnostic efficiency was evaluated by ROC curve analysis, and the histogram was obtained to conduct visual analysis of the prediction model.

Results

Among the routine CT features, the type of peritoneal metastasis, mesenteric involvement, and supradiaphragmatic lymph node enlargement were correlated with BRCA gene mutation (P < 0.05), whereas the location of the peritoneal metastasis (in the gastrohepatic ligament) was not significantly correlated with BRCA gene mutation (P > 0.05). Multivariate logistic regression analysis retained six features, including one routine CT feature and five texture features. Among them, the type of peritoneal metastasis was used as an independent predictor (P < 0.05), which had the highest diagnostic efficiency. Its AUC, accuracy, specificity, and sensitivity were 0.74, 0.79, 0.90, and 0.62, respectively. The prediction model based on the combination of routine CT features and texture features had an AUC of 0.86 (95% CI: 0.79–0.94) and accuracy, specificity, and sensitivity of 0.80, 0.76, and 0.81, respectively, indicating a better performance than that of any single feature.

Conclusions

Both routine CT features and texture features had value for predicting the mutation state of the BRCA gene, but their predictive efficiency was low. When the two types of features were combined to establish a predictive model, the model’s predictive efficiency was significantly higher than that of independent features.
Pyroptosis, a New Breakthrough in Cancer Treatment
Authors: Wu Dengqiang , Wei Changhong , Li Yujie , Yang Xuejia , Zhou Sufang
Published: July 2021

The way of cell death can be roughly divided into two categories: cell necrosis and PCD(programmed cell death). Pyroptosis is a kind of PCD, its occurrence depends on the gasdermin protein family and it will produce inflammatory response. With constant research in recent years, more and more evidences show that pyroptosis is closely related to the occurrence and development of tumors. The treatment of tumors is a big problem worldwide. We focus on whether we can discover new potential tumor markers and new therapeutic targets from the mechanism. If we can understand the mechanism of pyroptosis and clear the relationship between pyroptosis and the development of tumors, this may provide a new reference for clinical cancer treatment.
Predicting Malignancy and Invasiveness of Pulmonary Subsolid Nodules on CT Images Using Deep Learning
Authors: Shen Tianle , Hou Runping , Ye Xiaodan , Li Xiaoyang , Xiong Junfeng , Zhang Qin , Zhang Chenchen , Cai Xuwei , Yu Wen , Zhao Jun , Fu Xiaolong
Published: July 2021

Background

To develop and validate a deep learning–based model on CT images for the malignancy and invasiveness prediction of pulmonary subsolid nodules (SSNs).

Materials and Methods

This study retrospectively collected patients with pulmonary SSNs treated by surgery in our hospital from 2012 to 2018. Postoperative pathology was used as the diagnostic reference standard. Three-dimensional convolutional neural network (3D CNN) models were constructed using preoperative CT images to predict the malignancy and invasiveness of SSNs. Then, an observer reader study conducted by two thoracic radiologists was used to compare with the CNN model. The diagnostic power of the models was evaluated with receiver operating characteristic curve (ROC) analysis.

Results

A total of 2,614 patients were finally included and randomly divided for training (60.9%), validation (19.1%), and testing (20%). For the benign and malignant classification, the best 3D CNN model achieved a satisfactory AUC of 0.913 (95% CI: 0.885–0.940), sensitivity of 86.1%, and specificity of 83.8% at the optimal decision point, which outperformed all observer readers’ performance (AUC: 0.846±0.031). For pre-invasive and invasive classification of malignant SSNs, the 3D CNN also achieved satisfactory AUC of 0.908 (95% CI: 0.877–0.939), sensitivity of 87.4%, and specificity of 80.8%.

Conclusion

The deep-learning model showed its potential to accurately identify the malignancy and invasiveness of SSNs and thus can help surgeons make treatment decisions.
Personalized Neoantigen-Pulsed DC Vaccines: Advances in Clinical Applications
Authors: Tang Lin , Zhang Rui , Zhang Xiaoyu , Yang Li
Published: July 2021

In the past few decades, great progress has been made in the clinical application of dendritic cell (DC) vaccines loaded with personalized neoantigens. Personalized neoantigens are antigens arising from somatic mutations in cancers, with specificity to each patient. DC vaccines work based on the fundamental characteristics of DCs, which are professional antigen-presenting cells (APCs), responsible for the uptake, processing, and presentation of antigens to T cells to activate immune responses. Neoantigens can exert their antitumor effects only after they are taken up by APCs and presented to T cells. In recent years, neoantigen-based personalized tumor therapeutic vaccines have proven to be safe, immunogenic and feasible treatment strategies in patients with melanoma and glioblastoma that provide new hope in the treatment of cancer patients and a new approach to cure cancer. In addition, according to ClinicalTrials.gov, hundreds of registered DC vaccine trials are either completed or ongoing worldwide, of which 9 are in early phase I, 191 in phase I, 166 in phase II and 8 in phase III. Hundreds of clinical studies on therapeutic tumor vaccines globally have proven that DC vaccines are stable, reliable and very safe. However, in this process, many other factors still limit the effectiveness of the vaccine. This review will focus on the current research progress on personalized neoantigen-pulsed DC vaccines, their limitations and future research directions of DC vaccines loaded with neoantigens. This review aims to provide a better understanding of DCs biology and manipulation of activated DCs for DCs researchers to produce the next generation of highly efficient cancer vaccines for patients.
TPL Inhibits the Invasion and Migration of Drug-Resistant Ovarian Cancer by Targeting the PI3K/AKT/NF-κB-Signaling Pathway to Inhibit the Polarization of M2 TAMs
Authors: Le Fuyin , Yang Lilan , Han Yiwen , Zhong Yanying , Zhan Fuliang , Feng Ying , Hu Hui , Chen Tingtao , Tan Buzhen
Published: July 2021

Chemoresistance is the primary reason for the poor prognosis of patients with ovarian cancer, and the search for a novel drug treatment or adjuvant chemotherapy drug is an urgent need. The tumor microenvironment plays key role in the incidence and development of tumors. As one of the most important components of the tumor microenvironment, M2 tumor-associated macrophages are closely related to tumor migration, invasion, immunosuppressive phenotype and drug resistance. Many studies have confirmed that triptolide (TPL), one of the principal components of Tripterygium wilfordii, possesses broad-spectrum anti-tumor activity. The aims of this study were to determine whether TPL could inhibit the migration and invasion of A2780/DDP cells in vitro and in vivo by inhibiting the polarization of M2 tumor-associated macrophages (TAMs); to explore the mechanism(s) underlying TPL effects; and to investigate the influence of TPL on murine intestinal symbiotic microbiota. In vitro results showed that M2 macrophage supernatant slightly promoted the proliferation, invasion, and migration of A2780/DDP cells, which was reversed by TPL in a dose-dependent manner. Animal experiments showed that TPL, particularly TPL + cisplatin (DDP), significantly reduced the tumor burden, prolonged the life span of mice by inhibiting M2 macrophage polarization, and downregulated the levels of CD31 and CD206 (CD31 is the vascular marker and CD206 is the macrophage marker), the mechanism of which may be related to the inhibition of the PI3K/Akt/NF-κB signaling pathway. High-throughput sequencing results of the intestinal microbiota in nude mice illustrated that Akkermansia and Clostridium were upregulated by DDP and TPL respective. We also found that Lactobacillus and Akkermansia were downregulated by DDP combined with TPL. Our results highlight the importance of M2 TAMs in Epithelial Ovarian Cancer (EOC) migration ability, invasiveness, and resistance to DDP. We also preliminarily explored the mechanism governing the reversal of the polarization of M2 macrophages by TPL.
Intra-Tumoral Activation of Endosomal TLR Pathways Reveals a Distinct Role for TLR3 Agonist Dependent Type-1 Interferons in Shaping the Tumor Immune Microenvironment
Authors: Thomas Graham , Micci Luca , Yang Wenjing , Katakowski Joseph , Oderup Cecilia , Sundar Purnima , Wang Xiao , Geles Kenneth G. , Potluri Shobha , Salek-Ardakani Shahram
Published: July 2021

Toll-like receptor (TLR) agonists have received considerable attention as therapeutic targets for cancer immunotherapy owing to their ability to convert immunosuppressive tumor microenvironments towards a more T-cell inflamed phenotype. However, TLRs differ in their cell expression profiles and intracellular signaling pathways, raising the possibility that distinct TLRs differentially influence the tumor immune microenvironment. Using single-cell RNA-sequencing, we address this by comparing the tumor immune composition of B16F10 melanoma following treatment with agonists of TLR3, TLR7, and TLR9. Marked differences are observed between treatments, including decreased tumor-associated macrophages upon TLR7 agonist treatment. A biased type-1 interferon signature is elicited upon TLR3 agonist treatment as opposed to a type-2 interferon signature with TLR9 agonists. TLR3 stimulation was associated with increased macrophage antigen presentation gene expression and decreased expression of PD-L1 and the inhibitory receptors Pirb and Pilra on infiltrating monocytes. Furthermore, in contrast to TLR7 and TLR9 agonists, TLR3 stimulation ablated FoxP3 positive CD4 T cells and elicited a distinct CD8 T cell activation phenotype highlighting the potential for distinct synergies between TLR agonists and combination therapy agents.
Advances of Targeted Therapy for Hepatocellular Carcinoma
Authors: Niu Mengke , Yi Ming , Li Ning , Wu Kongju , Wu Kongming
Published: July 2021

Hepatocellular carcinoma (HCC) is one of the common and fatal malignancies, which is a significant global health problem. The clinical applicability of traditional surgery and other locoregional therapies is limited, and these therapeutic strategies are far from satisfactory in improving the outcomes of advanced HCC. In the past decade, targeted therapy had made a ground-breaking progress in advanced HCC. Those targeted therapies exert antitumor effects through specific signals, including anti-angiogenesis or cell cycle progression. As a standard systemic therapy option, it tremendously improves the survival of this devastating disease. Moreover, the combination of targeted therapy with immune checkpoint inhibitor (ICI) has demonstrated more potent anticancer effects and becomes the hot topic in clinical studies. The combining medications bring about a paradigm shift in the treatment of advanced HCC. In this review, we presented all approved targeted agents for advanced HCC with an emphasis on their clinical efficacy, summarized the advances of multi-target drugs in research for HCC and potential therapeutic targets for drug development. We also discussed the exciting results of the combination between targeted therapy and ICI.
Hsa-miR-4277 Decelerates the Metabolism or Clearance of Sorafenib in HCC Cells and Enhances the Sensitivity of HCC Cells to Sorafenib by Targeting cyp3a4
Authors: He Xi , Sun Huiwei , Jiang Qiyu , Chai Yantao , Li Xiaojuan , Wang Zhijie , Zhu Bing , You Shaoli , Li Boan , Hao Junfeng , Xin Shaojie
Published: July 2021

Increasing evidence has shown that the metabolism and clearance of molecular targeted agents, such as sorafenib, plays an important role in mediating the resistance of HCC cells to these agents. Metabolism of sorafenib is performed by oxidative metabolism, which is initially mediated by CYP3A4. Thus, targeting CYP3A4 is a promising approach to enhance the sensitivity of HCC cells to chemotherapeutic agents. In the present work, we examined the association between CYP3A4 and the prognosis of HCC patients receiving sorafenib. Using the online tool miRDB, we predicted that has-microRNA-4277 (miR-4277), an online miRNA targets the 3’UTR of the transcript of cyp3a4. Furthermore, overexpression of miR-4277 in HCC cells repressed the expression of CYP3A4 and reduced the elimination of sorafenib in HCC cells. Moreover, miR-4277 enhanced the sensitivity of HCC cells to sorafenib in vitro and in vivo. Therefore, our results not only expand our understanding of CYP3A4 regulation in HCC, but also provide evidence for the use of miR-4277 as a potential therapeutic in advanced HCC.
Network Pharmacology–Based Analysis and Experimental Exploration of Antidiabetic Mechanisms of Gegen Qinlian Decoction
Authors: Xu Yu , Huang Jihan , Wang Ning , Tan Hor-Yue , Zhang Cheng , Li Sha , Tang Guoyi , Feng Yibin
Published: July 2021

Type-2 diabetes mellitus (T2DM) and therapy options have been studied increasingly due to their rising incidence and prevalence. The trend of applying traditional Chinese medicine (TCM) to treat T2DM is increasing as a crucial medical care for metabolic dysfunctions. Gegen Qinlian decoction (GQL), a well-known classical TCM formula used in China, has been clinically applied to treat various types of chronic metabolic diseases. However, antidiabetic effects of GQL administration during T2DM have never been studied systematically. We assessed physiological and molecular targets associated with therapeutic effects of GQL by evaluating network topological characteristics. The GQL-related biological pathways are closely associated with antidiabetic effects, including the TNF and PI3K–AKT signaling pathways. Associated primary biological processes such as RNA polymerase II promoter transcription participate in the inflammatory response, oxidative stress reduction, and glucose metabolic process, thereby exerting multiple biological effects on the antidiabetic mechanism. Furthermore, our results showed that GQL can affect blood glycemic levels and ameliorate inflammatory symptoms, and liver and pancreas tissue injury in high-fat diet plus streptozotocin-induced diabetic mice. In vivo and in vitro experiments confirmed that antidiabetic effects of GQL were associated with a modulation of the TNF and PI3K–AKT–MTOR pathways.
The New PI3K/mTOR Inhibitor GNE-477 Inhibits the Malignant Behavior of Human Glioblastoma Cells
Authors: Wang Yixuan , Shen Heng , Sun Qian , Zhao Linyao , Liu Hao , Ye Liguo , Xu Yang , Cai Jiayang , Li Yuntao , Gao Lun , Tan Yinqiu , Liu Baohui , Chen Qianxue
Published: July 2021

The most common primary central nervous system tumor in adults is glioblastoma multiforme (GBM). The high invasiveness of GBM cells is an important factor leading to inevitable tumor recurrence and a poor prognosis of patients. GNE-477, a novel PI3K/mTOR inhibitor, has been reported to exert antiproliferative effects on other cancer cells. However, researchers have not clearly determined whether GNE-477 produces antitumor effects on GBM. In the present study, GNE-477 significantly inhibited the proliferation, migration and invasion of U87 and U251 cells. In addition, GNE-477 also induced apoptosis of GBM cells, arresting the cell cycle in G0/G1 phase. More importantly, GNE-477 also reduced the levels of AKT and mTOR phosphorylation in the AKT/mTOR signaling pathway in a concentration-dependent manner. An increase in AKT activity induced by SC79 rescued the GNE-477-mediated inhibition of GBM cell proliferation and apoptosis. The antitumor effects of GNE-477 and the regulatory effects on related molecules were further confirmed in vivo using a nude mouse intracranial xenograft model. In conclusion, our study indicated that GNE-477 exerted significant antitumor effects on GBM cells in vitro and in vivo by downregulating the AKT/mTOR pathway.
Anti-Obesity Effect of Fermented Panax notoginseng Is Mediated Via Modulation of Appetite and Gut Microbial Population
Authors: Shin Na Rae , Bose Shambhunath , Choi Yura , Kim Young-Mi , Chin Young-Won , Song Eun-Ji , Nam Young-Do , Kim Hojun
Published: July 2021

Panax notoginseng (PN) is a traditional herbal medicine containing several active compounds such as saponins and ginsenosides with many therapeutic applications including anti-obesity activity. Fermentation by lactic acid bacteria has the potential to metabolize ginsenosides to more active forms. This study examined whether fermentation has any benefits on the protective effects of a PN extract against obesity using a high-fat diet (HFD)-fed mouse model. PN was fermented with Lactobacillus plantarum which exhibited high β-glucosidase activity. Upon fermentation, the PN extract exhibited an altered ginsenoside profile, a dramatic increase in the lactate level. Treatment of the HFD group with fermented PN (FPN), but not PN, decreased both the food and calorie intake significantly, which was consistent with the more potent suppressing effects of FPN than PN on the signaling pathways involved in appetite and energy intake. The PN treatment also modulated the gut microbial composition. The PN and FPN treatment groups showed clear differences in the population of gut microbiota. The relative abundance of Bacteroidetes, Erysipelotrichaceae, Coprococus, and Dehalobacterium were significantly higher in the FPN group then the normal, HFD, and XEN groups. Furthermore, the relative abundances of Akkermansia, Dehalobacterium, Erysipeliotrichaceae and parpabacteroides were significantly higher in the FPN group than the PN group, but the relative abundances of Allobaculum, Erysipelotrichi and Erysipelotrichale were significantly lower. The relative abundance of Bacteroides and Lactococcus was significantly higher and lower, respectively in the PN and FPN groups than the HFD group. In conclusion, the altered ginsenoside and organic acid’s profile, and altered gut microbial composition are believed to be the major factors contributing to the anti-obesity properties of FPN.
Oral Aminoacids Supplementation Improves Corneal Reinnervation After Photorefractive Keratectomy: A Confocal-Based Investigation
Authors: Roszkowska Anna M , Rusciano Dario , Inferrera Leandro , Severo Alice Antonella , Aragona Pasquale
Published: July 2021

Aim of this retrospective study was to estimate the effect of oral supplementation with amino acids (AA) on corneal nerves regrowth after excimer laser refractive surgery with photorefractive keratectomy (PRK). Based on the pre and post-surgical treatment received, 40 patients with 12 months of follow-up were distributed in two groups: 20 patients had received oral AA supplementation 7 days before and 30 days after PRK, and 20 patients without AA supplementation, as untreated reference control. All patients followed the same standard post-operative topical therapy consisting of an association of antibiotic and steroid plus sodium hyaluronate during the first week, then steroid alone progressively decreasing during 30 days and sodium hyaluronate for the following 3 months. In vivo corneal confocal microscopy was used to evaluate the presence of sub-basal corneal nerve fibers during 12 months after PRK. Results have shown that sub-basal nerves regenerated significantly faster (p <0.05), and nerve fibers density was significantly higher (p <0.05) with a more regular pattern in the eyes of AA treated patients with respect to the untreated control group. Therefore, our data indicate that oral supplementation with AA improved significantly corneal nerve restoration after PRK and could thus be considered as an additional treatment during corneal surgical procedures.
Caffeine for the Pharmacological Treatment of Apnea of Prematurity in the NICU: Dose Selection Conundrum, Therapeutic Drug Monitoring and Genetic Factors
Authors: Long Jia-Yi , Guo Hong-Li , He Xin , Hu Ya-Hui , Xia Ying , Cheng Rui , Ding Xuan-Sheng , Chen Feng , Xu Jing
Published: July 2021

Caffeine citrate is the drug of choice for the pharmacological treatment of apnea of prematurity. Factors such as maturity and genetic variation contribute to the interindividual variability in the clinical response to caffeine therapy in preterm infants, making the optimal dose administered controversial. Moreover, the necessity for therapeutic drug monitoring (TDM) of caffeine is still worth discussing due to the need to achieve the desired target concentrations as well as concerns about the safety of higher doses. Therefore, we reviewed the pharmacokinetic profile of caffeine in preterm infants, evidence of the safety and efficacy of different doses of caffeine, therapeutic concentration ranges of caffeine and impact of genetic variability on caffeine therapy. Whereas the safety and efficacy of standard-dose caffeine have been demonstrated, evidence for the safety of higher administered doses is insufficient. Thus, preterm infants who lack clinical response to standard-dose caffeine therapy are of interest for TDM when dose optimization is performed. Polymorphisms in pharmacodynamics-related genes, but not in pharmacokinetics-related genes, have a significant impact on the interindividual variability in clinical response to caffeine therapy. For preterm infants lacking clinical response, how to develop individualized medication regimens for caffeine remains to be explored.
Analysis of Drug-Induced Gastrointestinal Obstruction and Perforation Using the Japanese Adverse Drug Event Report Database
Authors: Satake Riko , Matsumoto Kiyoka , Tanaka Mizuki , Mukai Ririka , Shimada Kazuyo , Yoshida Yu , Inoue Misaki , Hasegawa Shiori , Iguchi Kazuhiro , Ikesue Hiroaki , Shimizu Shinya , Nishida Shohei , Suzuki Akio , Hashida Tohru , Nakamura Mitsuhiro
Published: July 2021

Drug-induced gastrointestinal obstruction (DIGO) and gastrointestinal perforation (DIGP) may be the result of gastrointestinal hypomotility and severe constipation, which may lead to potentially fatal complications of bowel ischemia, sepsis and perforation. We evaluated the onset profile of DIGs (DIGO and DIGP) associated with prescription drugs by analyzing data in the Japanese Adverse Drug Event Report (JADER) database. We selected 161 DIG-related drugs and categorized them into 19 classes based on the Anatomical Therapeutic Chemical (ATC) Classification System. Finally, we focused on 58 drugs and conducted subsequent analyses for the time-to-onset and outcomes. We extracted 79 preferred terms (PTs) with the strings “ileus,” “stenosis,” “obstruction,” “obstructive,” “impaction,” “perforation,” “perforated,” “hypomotility,” and “intussusception” from the Standardized Medical Dictionary for Regulatory Activities (MedDRA) Queries (SMQs) of SMQ20000104: gastrointestinal perforation, ulcer, hemorrhage, obstruction non-specific findings/procedures; SMQ20000105: gastrointestinal obstruction; and SMQ20000107: gastrointestinal perforation. Among the 667, 729 reports in the JADER database submitted between April 2004 and November 2020, we identified 11,351 occurrences of DIGs. The reporting odds ratios (RORs) (95% confidence interval) of “barium sulfate containing X-ray media,” “drugs for treatment of hyperkalemia and hyperphosphatemia,” and “oral bowel cleanser” were 142.0 (127.1–158.6), 25.8 (23.1–28.8), and 29.7 (24.8–35.6), respectively. The median number of days (interquartile range) until the onset of an adverse event caused by each drug category was as follows: barium sulfate containing X-ray contrast media [2.0 (1.0–3.0)], diazepines, oxazepines, thiazepines, and oxepines [8.0 (8.0–18.5)], drugs for treatment of hyperkalemia and hyperphosphatemia [29.0 (8.0–55.0)], non-selective monoamine reuptake inhibitors [19.0 (7.0–47.5)], and oral bowel cleanser [0.0 (0.0–0.0)]. Depending on the drug, the time to onset of side effects ranged from days to several months. Our results highlighted the need to perform detailed monitoring of each drug for possible association with DIGs, which might otherwise have fatal consequences.
Kidney Organoid and Microphysiological Kidney Chip Models to Accelerate Drug Development and Reduce Animal Testing
Authors: Chen Wei-Yang , Evangelista Eric A , Yang Jade , Kelly Edward J , Yeung Catherine K
Published: July 2021

Kidneys are critical for the elimination of many drugs and metabolites via the urine, filtering waste and maintaining proper fluid and electrolyte balance. Emerging technologies incorporating engineered three-dimensional (3D) in vitro cell culture models, such as organoids and microphysiological systems (MPS) culture platforms, have been developed to replicate nephron function, leading to enhanced efficacy, safety, and toxicity evaluation of new drugs and environmental exposures. Organoids are tiny, self-organized three-dimensional tissue cultures derived from stem cells that can include dozens of cell types to replicate the complexity of an organ. In contrast, MPS are highly controlled fluidic culture systems consisting of isolated cell type(s) that can be used to deconvolute mechanism and pathophysiology. Both systems, having their own unique benefits and disadvantages, have exciting applications in the field of kidney disease modeling and therapeutic discovery and toxicology. In this review, we discuss current uses of both hPSC-derived organoids and MPS as pre-clinical models for studying kidney diseases and drug induced nephrotoxicity. Examples such as the use of organoids to model autosomal dominant polycystic kidney disease, and the use of MPS to predict renal clearance and nephrotoxic concentrations of novel drugs are briefly discussed. Taken together, these novel platforms allow investigators to elaborate critical scientific questions. While much work needs to be done, utility of these 3D cell culture technologies has an optimistic outlook and the potential to accelerate drug development while reducing the use of animal testing.
The Dual Dose-Dependent Effects of Corticosterone on Hippocampal Cell Apoptosis After Traumatic Brain Injury Depend on the Activation Ratio of Mineralocorticoid Receptors to Glucocorticoid Receptors
Authors: Zhang Bin , Yang Mengshi , Yan Qiongyu , Xu Xiaojian , Niu Fei , Dong Jinqian , Zhuang Yuan , Lu Shenghua , Ge Qianqian , Liu Baiyun
Published: July 2021

In our recent studies, we reported that mineralocorticoid receptor (MR) had the opposite effects of glucocorticoid receptor (GR) on neural cell survival after traumatic brain injury (TBI). However, whether short-term use of high-dose natural glucocorticoids, which are mixed agonists of both MR and GR, leads to neurotoxic effects by inducing excessive GR activation is unclear, as is the threshold GR activation level and the possible signaling pathways remain unclear. In this study, we examined the dual dose-dependent effects of corticosterone (CORT) on spatial memory, hippocampal cell survival and receptor-mediated downstream signaling pathways after TBI. We found that different doses of CORT exhibited dual effects on hippocampal cell survival and rat spatial memory. Low doses of CORT (0.3 and 3 mg/kg) significantly increased MR activation, upregulated Akt/CREB/Bad phosphorylation and Bcl-2 concentration, reduced the number of apoptotic neural cells, and subsequently improved rat spatial memory. In contrast, a high dose of CORT (30 mg/kg) exerted the opposite effects by overactivating GR, upregulating P53/Bax levels, and inhibiting Erk/CREB activity. The results suggest that the neuroprotective and neurotoxic effects of endogenous GC depend on a threshold level and that a higher dose of GC, even for short-term use, should be avoided after TBI.
Design, Characterisation and Performance of an Improved Portable and Sustainable Low-Field MRI System
Authors: de Vos Bart , Parsa Javad , Abdulrazaq Zaynab , Teeuwisse Wouter M. , Van Speybroeck Camille D. E. , de Gans Danny H. , Remis Rob F. , O’Reilly Tom , Webb Andrew G.
Published: July 2021

Low-field permanent magnet-based MRI systems are finding increasing use in portable, sustainable and point-of-care applications. In order to maximize performance while minimizing cost many components of such a system should ideally be designed specifically for low frequency operation. In this paper we describe recent developments in constructing and characterising a low-field portable MRI system for in vivo imaging at 50 mT. These developments include the design of i) high-linearity gradient coils using a modified volume-based target field approach, ii) phased-array receive coils, and iii) a battery-operated three-axis gradient amplifier for improved portability and sustainability. In addition, we report performance characterisation of the RF amplifier, the gradient amplifier, eddy currents from the gradient coils, and describe a quality control protocol for the overall system.
Heart Rate Variability During a Standard Dive: A Role for Inspired Oxygen Pressure?
Authors: Lafère Pierre , Lambrechts Kate , Germonpré Peter , Balestra Ambre , Germonpré Faye Lisa , Marroni Alessandro , Cialoni Danilo , Bosco Gerardo , Balestra Costantino
Published: July 2021

Introduction: Heart rate variability (HRV) during underwater diving has been infrequently investigated because of environment limitations and technical challenges. This study aims to analyze HRV changes while diving at variable hyperoxia when using open circuit (OC) air diving apparatus or at constant hyperoxia using a closed-circuit rebreather (CCR). We used HRV analysis in time and frequency domain adding nonlinear analysis which is more adapted to short-time analysis and less dependent on respiratory rate (Sinus respiratory arrhythmia).

Materials and Methods: 18 males, 12 using OC (30 mfw for 20 min) and 6 using CCR (30 mfw for 40 min.). HRV was recorded using a polar recorder. Four samples of R-R intervals representing the dive were saved for HRV analysis. Standard deviation of normal-to-normal intervals (SDNN), square root of the mean squared differences between successive RR intervals (rMSSD), and average RR intervals (RR) in time-domain; low frequency (LF) and high frequency (HF) in frequency domain were investigated. Nonlinear analysis included fractal dimension (FrD).

Results: SDNN and rMSSD were significantly increased during descent and at depth with OC, not with CCR. Mean RR interval was longer at depth with OC, but only during ascent and after the dive with CCR. HF power was higher than baseline during the descent both with OC and CCR and remained elevated at depth for OC. The LF/HF ratio was significantly lower than baseline for descent and at depth with both OC and CCR. After 30 min of recovery, the LF/HF ratio was higher than baseline with both OC and CCR. Nonlinear analysis detected differences at depth for OC and CCR.

Discussion: Increased parasympathetic tone was present during diving. RR duration, SDNN; rMSSD, HF spectral power all increased during the dive above pre-dive levels. Conversely, HF power decreased (and the LF/HF increased) 30 min after the dive. Using FrD, a difference was detected between OC and CCR, which may be related to differences in partial pressure of oxygen breathed during the dive.
ETS1, ELK1, and ETV4 Transcription Factors Regulate Angiopoietin-1 Signaling and the Angiogenic Response in Endothelial Cells
Authors: Harel Sharon , Sanchez Veronica , Moamer Alaa , Sanchez-Galan Javier E. , Abid Hussein Mohammad N. , Mayaki Dominique , Blanchette Mathieu , Hussain Sabah N. A.
Published: July 2021

Background

Angiopoietin-1 (Ang-1) is the main ligand of Tie-2 receptors. It promotes endothelial cell (EC) survival, migration, and differentiation. Little is known about the transcription factors (TFs) in ECs that are downstream from Tie-2 receptors.

Objective

The main objective of this study is to identify the roles of the ETS family of TFs in Ang-1 signaling and the angiogenic response.

Methods

In silico enrichment analyses that were designed to predict TF binding sites of the promotors of eighty-six Ang-1-upregulated genes showed significant enrichment of ETS1, ELK1, and ETV4 binding sites in ECs. Human umbilical vein endothelial cells (HUVECs) were exposed for different time periods to recombinant Ang-1 protein and mRNA levels of ETS1, ELK1, and ETV4 were measured with qPCR and intracellular localization of these transcription factors was assessed with immunofluorescence. Electrophoretic mobility shift assays and reporter assays were used to assess activation of ETS1, ELK1, and ETV4 in response to Ang-1 exposure. The functional roles of these TFs in Ang-1-induced endothelial cell survival, migration, differentiation, and gene regulation were evaluated by using a loss-of-function approach (transfection with siRNA oligos).

Results

Ang-1 exposure increased ETS1 mRNA levels but had no effect on ELK1 or ETV4 levels. Immunostaining revealed that in control ECs, ETS1 has nuclear localization whereas ELK1 and ETV4 are localized to the nucleus and the cytosol. Ang-1 exposure increased nuclear intensity of ETS1 protein and enhanced nuclear mobilization of ELK1 and ETV4. Selective siRNA knockdown of ETS1, ELK1, and ETV4 showed that these TFs are required for Ang-1-induced EC survival and differentiation of cells, while ETS1 and ETV4 are required for Ang-1-induced EC migration. Moreover, ETS1, ELK1, and ETV4 knockdown inhibited Ang-1-induced upregulation of thirteen, eight, and nine pro-angiogenesis genes, respectively.

Conclusion

We conclude that ETS1, ELK1, and ETV4 transcription factors play significant angiogenic roles in Ang-1 signaling in ECs.
CRISPR/Cas9-Mediated Targeted Mutagenesis of CYP93E2 Modulates the Triterpene Saponin Biosynthesis in Medicago truncatula
Authors: Confalonieri Massimo , Carelli Maria , Gianoglio Silvia , Moglia Andrea , Biazzi Elisa , Tava Aldo
Published: July 2021

In the Medicago genus, triterpene saponins are a group of bioactive compounds extensively studied for their different biological and pharmaceutical properties. In this work, the CRISPR/Cas9-based approach with two single-site guide RNAs was used in Medicago truncatula (barrel medic) to knock-out the CYP93E2 and CYP72A61 genes, which are responsible for the biosynthesis of soyasapogenol B, the most abundant soyasapogenol in Medicago spp. No transgenic plants carrying mutations in the target CYP72A61 gene were recovered while fifty-two putative CYP93E2 mutant plant lines were obtained following Agrobacterium tumefaciens-mediated transformation. Among these, the fifty-one sequenced plant lines give an editing efficiency of 84%. Sequencing revealed that these lines had various mutation patterns at the target sites. Four T0 mutant plant lines were further selected and examined for their sapogenin content and plant growth performance under greenhouse conditions. The results showed that all tested CYP93E2 knock-out mutants did not produce soyasapogenols in the leaves, stems and roots, and diverted the metabolic flux toward the production of valuable hemolytic sapogenins. No adverse influence was observed on the plant morphological features of CYP93E2 mutants under greenhouse conditions. In addition, differential expression of saponin pathway genes was observed in CYP93E2 mutants in comparison to the control. Our results provide new and interesting insights into the application of CRISPR/Cas9 for metabolic engineering of high-value compounds of plant origin and will be useful to investigate the physiological functions of saponins in planta.
Complex Networks of Prion-Like Proteins Reveal Cross Talk Between Stress and Memory Pathways in Plants
Authors: Garai Sampurna , Citu  , Singla-Pareek Sneh L. , Sopory Sudhir K. , Kaur Charanpreet , Yadav Gitanjali
Published: July 2021

Prions are often considered as molecular memory devices, generating reproducible memory of a conformational change. Prion-like proteins (PrLPs) have been widely demonstrated to be present in plants, but their role in plant stress and memory remains unexplored. In this work, we report the widespread presence of PrLPs in plants through a comprehensive meta-analysis of 39 genomes representing major taxonomic groups. We find diverse functional roles associated with these proteins in various species and term the full complement of PrLPs in a genome as its “prionome.” In particular, we found the rice prionome being significantly enriched in transposons/retrotransposons (Ts/RTRs) and identified over 60 rice PrLPs that were differentially regulated in stress and developmental responses. This prompted us to explore whether and to what extent PrLPs may build stress memory. By integrating the available rice interactome, transcriptome, and regulome data sets, we could find links between stress and memory pathways that would not have otherwise been discernible. Regulatory inferences derived from the superimposition of these data sets revealed a complex network and cross talk between PrLPs, transcription factors (TFs), and the genes involved in stress priming. This integrative meta-analysis connects transient and transgenerational memory mechanisms in plants with PrLPs, suggesting that plant memory may rely upon protein-based signals in addition to chromatin-based epigenetic signals. Taken together, our work provides important insights into the anticipated role of prion-like candidates in stress and memory, paving the way for more focused studies for validating the role of the identified PrLPs in memory acclimation.
Integrated Metabolomics and Transcriptome Analysis of Flavonoid Biosynthesis in Safflower (Carthamus tinctorius L.) With Different Colors
Authors: Wang Rui , Ren Chaoxiang , Dong Shuai , Chen Chao , Xian Bin , Wu Qinghua , Wang Jie , Pei Jin , Chen Jiang
Published: July 2021

Safflower is widely used in dying and in traditional medicine, and C-glucosylquinochalcones are the main metabolic species in the red color of safflower. Various safflower cultivars have flowers with different colors. However, the metabolic and transcriptional differences among safflower cultivars with different-colored flowers and the genes participating in C-glucosylquinochalcone biosynthesis are largely unknown. To provide insights on this issue, we performed integrated metabolomics and transcriptome analyses on the flavonoid biosynthesis of flowers of different colors in safflower (white-W, yellow-Y, light red-LR, and deep red-DR). The metabolic analysis showed that flavonoid metabolites showed great differences among the different colors of safflower. More flavonoid metabolic species were detected in Y and W, while C-glucosylquinochalcones were not detected in W. The content of C-glucosylquinochalcones increased with increasing color. Transcriptional analysis showed that most of the annotated flavonoid biosynthesis genes were significantly increased in W. The expression of genes related to flavonoid biosynthesis decreased with increasing color. We analyzed the candidate genes associated with C-glucosylquinochalcones, and an integration of the metabolic and transcriptional analyses indicated that the differential expression of the chalcone synthase (CHS) gene is one of the main reasons for the difference in flavonoid species and content among the different colors of safflower. Combined with the expression pattern analysis, these results indicated that HH_035319, HH_032689, and HH_018025 are likely involved in C-glucosylquinochalcones biosynthesis. In addition, we found that their expression showed greatly increased after the methyl jasmonate (MeJA) treatment. Therefore, HH_035319, HH_032689, and HH_018025 might participate in C-glucosylquinochalcone biosynthesis, which ultimately leads to the red color in safflower.
Focus on the Beauty of Body: The Mediation Role of Body Appreciation Between Perfectionism and Body-Related Shame and Body-Related Guilt
Authors: Liang Zhang , Lingting Shen , Ying Cai , Xiaoyan Liu , Yan Zhang , Ronghua Ying , Dan Bi , Yanqiang Tao
Published: July 2021

Objectives: According to traditional views, perfectionists are prone to experience shame and guilt. As a relative part of negative body image, body appreciation reflects an appreciation attitude toward physical characteristics, functionality, and health, accepting and appreciating all parts and functions of the body, predicting body-related shame and guilt.

Methods: Therefore, body appreciation was examined for its potential mediating role in the relationship between two dimensions of perfectionism (e.g., healthy perfectionism and unhealthy perfectionism) and body-related shame and body-related guilt among 514 females.

Results: The results highlight that body appreciation partially mediated the relationship between perfectionism and body-related shame and body-related guilt. Implications for enhancing body appreciation among females between experiencing healthy or unhealthy perfectionism and body-related shame and body-related guilt feelings are discussed.

Conclusions: These findings underscore the importance of considering body appreciation in addressing perfectionism dimensions and body-related shame and body-related guilt. Research and clinical implications are also addressed.
COVID-19 Vaccine Acceptance in a Sample From the United Arab Emirates General Adult Population: A Cross-Sectional Survey, 2020
Authors: Albahri Abdulaziz Hussain , Alnaqbi Shahad Ahmed , Alshaali Asma Obaid , Alnaqbi Shatha Ahmed , Shahdoor Shaikha Mohammad
Published: July 2021

Introduction: The COVID-19 pandemic has placed a tremendous stress on economies and healthcare systems worldwide. Having a vaccine is one of the promising solutions. However, vaccination hesitancy is becoming a recognized future challenge. This study aims to evaluate the current vaccine hesitancy in a segment of the United Arab Emirates (UAE) general public and its associated factors.

Methods: This was an online cross-sectional survey that took place from the 14th to the 19th of September 2020 across the UAE. The questionnaire asked the participants about their willingness to receive the COVID-19 vaccine in the future. Multivariable logistic regression analysis was used to assess the association between vaccination willingness and the participants' sociodemographic factors, experiences and beliefs regarding COVID-19, and previous influenza vaccine uptake.

Results: There was a total of 2,705 participants; 72.5% were females, and 69.8% were Emirati nationals. A total of 1,627 (60.1%) participants were willing to take the COVID-19 vaccine in the future. There were statistically significant associations between the following factors and vaccine acceptance: male gender, non-Emiratis, younger age group, residents of Sharjah and the Northern Emirates, having lesser educational attainment, perceived increased personal or public risk of contracting the disease [aOR = 1.71, 95% CI (1.35–2.17), p < 0.0001; aOR = 1.84, 95% CI (1.44–2.36), p < 0.0001, respectively], and increased perception of serious outcome from the disease. Conversely, vaccine hesitancy was associated with unemployment, not receiving the influenza vaccine within the past 2 years [aOR = 0.36, 95% CI (0.30–0.44), p < 0.0001], not believing in the seriousness of the COVID-19 situation or the vaccine's ability to control the pandemic, and not believing that the public authorities are handling the pandemic adequately. Having contracted the disease or knowing someone who has did not show a statistically significant association with vaccine acceptance. Vaccine safety, side effects, and the belief that one needs to develop immunity naturally were the top reasons for vaccination hesitancy.

Conclusion: Given the level of vaccine hesitancy in the study population, this needs to be evaluated in a more representative sample of the whole population. If confirmed, this would signify the need for coordinated local and international initiatives to combat vaccine misinformation and reassure the public regarding vaccine safety and efficacy.
Utilizing Deep Machine Learning for Prognostication of Oral Squamous Cell Carcinoma—A Systematic Review
Authors: Alabi Rasheed Omobolaji , Bello Ibrahim O. , Youssef Omar , Elmusrati Mohammed , Mäkitie Antti A. , Almangush Alhadi
Published: July 2021

The application of deep machine learning, a subfield of artificial intelligence, has become a growing area of interest in predictive medicine in recent years. The deep machine learning approach has been used to analyze imaging and radiomics and to develop models that have the potential to assist the clinicians to make an informed and guided decision that can assist to improve patient outcomes. Improved prognostication of oral squamous cell carcinoma (OSCC) will greatly benefit the clinical management of oral cancer patients. This review examines the recent development in the field of deep learning for OSCC prognostication. The search was carried out using five different databases—PubMed, Scopus, OvidMedline, Web of Science, and Institute of Electrical and Electronic Engineers (IEEE). The search was carried time from inception until 15 May 2021. There were 34 studies that have used deep machine learning for the prognostication of OSCC. The majority of these studies used a convolutional neural network (CNN). This review showed that a range of novel imaging modalities such as computed tomography (or enhanced computed tomography) images and spectra data have shown significant applicability to improve OSCC outcomes. The average specificity, sensitivity, area under receiving operating characteristics curve [AUC]), and accuracy for studies that used spectra data were 0.97, 0.99, 0.96, and 96.6%, respectively. Conversely, the corresponding average values for these parameters for computed tomography images were 0.84, 0.81, 0.967, and 81.8%, respectively. Ethical concerns such as privacy and confidentiality, data and model bias, peer disagreement, responsibility gap, patient-clinician relationship, and patient autonomy have limited the widespread adoption of these models in daily clinical practices. The accumulated evidence indicates that deep machine learning models have great potential in the prognostication of OSCC. This approach offers a more generic model that requires less data engineering with improved accuracy.