bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison Among Endoscopic, Laparoscopic, and Open Resection for Relatively Small Gastric Gastrointestinal Stromal Tumors (<5 cm): A Bayesian Network Meta-Analysis
Authors: Liu Zhen , Zeng Ziyang , Ouyang Siwen , Zhang Zimu , Sun Juan , Wang Xianze , Ye Xin , Kang Weiming , Yu Jianchun
Published: December 2021

Background

Endoscopic resection (ESR) is a novel minimally invasive procedure for superficial tumors. Its safety, efficiency, and outcome for gastric gastrointestinal stromal tumors (gGISTs) less than 5 cm remains unclear compared to laparoscopic resection (LAR) and open resection (ONR). The current network meta-analysis aimed to review and analyze the available evidence of this question.

Methods

PubMed, Embase, Cochrane Library, and Web of Science databases were searched to identify eligible studies published up to July 6, 2020. The perioperative and long-term oncological outcomes among ESR, LAR, and ONR for gGIST (<5 cm) were estimated through the Bayesian network meta-analysis with a random-effect model.

Results

Fifteen studies with 1,631 patients were included. ESR was associated with a shorter operative time [mean difference, MD: -36; 95% confidence interval, CI (-55, -16)], a higher rate of positive margin [odds ratio, OR: 5.1 × 1010, 95% CI (33, 2.5 × 1032)], and less costs [MD: -1 × 104, 95% CI (-1.6 × 104, -4.4 × 103)] but similar time to resume flatus [MD: 0.52, 95% CI (-0.16, 1.1)] and diet [MD: -3.5, 95% CI (-5.6, -1.6)] compared to LAR. A higher rate of total complications [OR: 11, 95% CI (1.2, 140)] was observed in patients who received ESR compared to patients who received LAR. After excluding perforation from the total complication category, the difference of complication between ESR and LAR disappeared [OR: 0.87, 95% CI (0.22, 2.3)]. The recurrence rate [OR: 1.3, 95% CI (0.40, 4.5)] and disease-free survival [hazard ratio: 1.26, 95% CI (0.60, 2.63)] showed no significant difference between ESR and LAR. ESR was associated with better or equivalent perioperative and long-term outcomes compared to ONR, except for positive margin. A subgroup analysis (<2 and 2–5 cm) showed no significantly different results among these three procedures either.

Conclusion

ESR was shown to be a safe and efficient alternative procedure to both LAR and ONR for gGISTs less than 2 cm and within 2–5 cm, respectively, without worsening the oncologic outcomes. However, preoperative assessment of tumor site is of importance for the determination of procedures regarding the increased incidence of a positive margin related to ESR.
Survival Benefit of Pyloric Lymph Node Dissection for Siewert Type II/III Adenocarcinoma of the Esophagogastric Junction Based on Tumor Diameter: A Large Cohort Study
Authors: Lin Xia , Li Zhengyan , Tan Chenjun , Ye Xiaoshuang , Xiong Jie , Liu Jiajia , Mo Ao , Shi Yan , Qian Feng , Yu Peiwu , Zhao Yongliang
Published: December 2021

Background

It is unclear whether the dissection of pyloric lymph nodes (PLNs, No. 5 and No. 6 lymph nodes) is necessary for adenocarcinoma of the esophagogastric junction (AEG) with a tumor diameter >4 cm based on current guidelines. This study aimed at evaluating whether pyloric node lymphadenectomy is essential for patients with Siewert type II/III AEG according to different tumor diameters.

Methods

This study included 300 patients on whom transabdominal total gastrectomy was performed for Siewert type II/III AEG at a high-volume center in China from January 2006 to December 2015. The index of estimated benefit from lymph node dissection (IEBLD) was used to analyze the priority of pyloric lymphadenectomy.

Results

In Siewert type II AEG, the 5-year overall survival (OS) and the 5-year disease-free survival (DFS) were similar between patients with PLN-positive cancer and patients of stage III AEG without PLN metastasis (23.1% vs. 30.6%, p = 0.505; 23.1% vs. 27.1%, p = 0.678). However, in Siewert type III AEG, the OS and the DFS of patients with PLN-positive cancer were significantly lower than that of patients with stage III without PLN metastasis (7.9% vs. 27.8%, p = 0.021; 0 vs. 26.8%, p = 0.005). According to the IEBLD, the dissection of PLNs did not appear to be beneficial in either Siewert type II AEG or type III AEG, whereas a stratified analysis revealed that PLN dissection yielded a high therapeutic benefit for Siewert type II AEG with tumor diameters >4 cm.

Conclusion

We recommended that the PLNs be dissected in Siewert type II AEG when a tumor diameter is >4 cm. Total gastrectomy should be optional for Siewert type II AEG with a tumor diameter >4 cm and Siewert type III AEG.
The Effects of Endocrine Therapies on Lipid Profiles in Chinese Young Women With Early Breast Cancer
Authors: Kang Yi-Kun , Wang Xue , Hu Nan-Lin , Yue Jian , Si Yi-Ran , Ju Jie , Gao Song-Lin , Yuan Peng
Published: December 2021

This study aimed to evaluate and compare the effects of various endocrine therapies on lipid profiles in young patients with breast cancer. A retrospective, single-center study was performed to investigate the effects of tamoxifen (TAM), tamoxifen plus ovarian function suppression (TAM+OFS), and aromatase inhibitors plus ovarian function suppression (AI+OFS) on lipid profiles during the 60 months of endocrine therapy in hormone receptor-positive patients aged <40 with early breast cancer. The primary endpoint was the cumulative incidence of lipid events, and the secondary endpoints were the changes in lipid profiles. A total of 230 young patients were included with the mean age of 35.7 years old. The patients in TAM group had significantly lower incidence of 5-year lipid events than those in TAM+OFS group (7.4% versus 21.3%; P=0.016) and AI+OFS group (7.4% versus 21.6%; P=0.009). The incidence of fatty liver was significantly higher in TAM+OFS group than TAM group (52.5%versus 30.9%; P=0.043). Lipid events were associated with younger age (odds ratio (OR)=0.865, 95% confidence interval (CI): 0.780-0960; P=0.006), higher baseline LDL-C (OR=14.959, 95% CI: 4.379-51.105; P<0.001), and use of OFS (OR=3.557, 95% CI: 1.151-10.989; P=0.027). Therefore, application of OFS, with younger age and higher baseline LDL-C, may increase the incidence of lipid events in premenopausal breast cancer. More care should be taken for lipid profiles during the endocrine therapy for young breast cancer patients.
Upregulation of miR-216a-5p by Lentinan Targeted Inhibition of JAK2/STAT3 Signaling Pathway to Reduce Lung Adenocarcinoma Cell Stemness, Promote Apoptosis, and Slow Down the Lung Adenocarcinoma Mechanisms
Authors: Chen Quan , Zheng Yiming , Chen Xia , Ge Pengfei , Wang Pengcheng , Wu Bingbing
Published: December 2021

To investigate the effect of Lentinan (LNT) on lung adenocarcinoma (LUAD) cell stemness and its mechanism. In this study, we founded that LNT significantly reduce the cell proliferation, activity, migration, invasion, and stemness of LUAD cells, and promote their apoptosis compared with the control group in vitro. Moreover, LNT significantly inhibited the volume and weight of tumors of nude mice in vivo. At the same time, LNT can significantly up-regulate miR-216a-5p levels and reduce the protein expression of phospho-JAK2 (Y1007/1008) and phospho-STAT3 (Tyr705), thereby inhibiting the JAK2/STAT3 signaling pathway. Interfering with miR-216a-5p expression and activating the JAK2/STAT3 signaling pathway can significantly reverse LNT inhibitory effects on LUAD. Collectively, LNT can inhibit the JAK2/STAT3 signaling pathway by up-regulating miR-216a-5p, reducing stemness, and promoting LUAD cells apoptosis, then slow down LUAD occurrence and development, providing concepts and experimental foundation treating patients with LUAD.
PCNA in Cervical Intraepithelial Neoplasia and Cervical Cancer: An Interaction Network Analysis of Differentially Expressed Genes
Authors: Giannos Panagiotis , Kechagias Konstantinos S. , Bowden Sarah , Tabassum Neha , Paraskevaidi Maria , Kyrgiou Maria
Published: December 2021

The investigation of differentially expressed genes (DEGs) and their interactome could provide valuable insights for the development of markers to optimize cervical intraepithelial neoplasia (CIN) screening and treatment. This study investigated patients with cervical disease to identify gene markers whose dysregulated expression and protein interaction interface were linked with CIN and cervical cancer (CC). Literature search of microarray datasets containing cervical epithelial samples was conducted in Gene Expression Omnibus and Pubmed/Medline from inception until March 2021. Retrieved DEGs were used to construct two protein-protein interaction (PPI) networks. Module DEGs that overlapped between CIN and CC samples, were ranked based on 11 topological algorithms. The highest-ranked hub gene was retrieved and its correlation with prognosis, tissue expression and tumor purity in patients with CC, was evaluated. Screening of the literature yielded 9 microarray datasets (GSE7803, GSE27678, GSE63514, GSE6791, GSE9750, GSE29570, GSE39001, GSE63678, GSE67522). Two PPI networks from CIN and CC samples were constructed and consisted of 1704 and 3748 DEGs along 21393 and 79828 interactions, respectively. Two gene clusters were retrieved in the CIN network and three in the CC network. Multi-algorithmic topological analysis revealed PCNA as the highest ranked hub gene between the two networks, both in terms of expression and interactions. Further analysis revealed that while PCNA was overexpressed in CC tissues, it was correlated with favorable prognosis (log-rank P=0.022, HR=0.58) and tumor purity (P=9.86 × 10-4, partial rho=0.197) in CC patients. This study identified that cervical PCNA exhibited multi-algorithmic topological significance among DEGs from CIN and CC samples. Overall, PCNA may serve as a potential gene marker of CIN progression. Experimental validation is necessary to examine its value in patients with cervical disease.
Inhibition of SREBP-1 Activation by a Novel Small-Molecule Inhibitor Enhances the Sensitivity of Hepatocellular Carcinoma Tissue to Radiofrequency Ablation
Authors: Zou Xiao-zheng , Hao Jun-feng , Zhou Xiu-hua
Published: December 2021

Radiofrequency ablation (RFA) is an important strategy for treatment of advanced hepatocellular carcinoma (HCC). However, the prognostic indicators of RFA therapy are not known, and there are few strategies for RFA sensitization. The transcription factor sterol regulatory element binding protein 1 (SREBP)-1 regulates fatty-acid synthesis but also promotes the proliferation or metastasis of HCC cells. Here, the clinical importance of SREBP-1 and potential application of knockdown of SREBP-1 expression in RFA of advanced HCC was elucidated. In patients with advanced HCC receiving RFA, a high level of endogenous SREBP-1 expression correlated to poor survival. Inhibition of SREBP-1 activation using a novel small-molecule inhibitor, SI-1, not only inhibited the aerobic glycolysis of HCC cells, it also enhanced the antitumor effects of RFA on xenograft tumors. Overall, our results: (i) revealed the correlation between SREBP-1 and HCC severity; (ii) indicated that inhibition of SREBP-1 activation could be a promising approach for treatment of advanced HCC.
Comparing the Survival Outcomes of Radical Prostatectomy Versus Radiotherapy for Patients With De Novo Metastasis Prostate Cancer: A Population-Based Study
Authors: Guo Xiaoxiao , Xia Haoran , Su Xiaonan , Hou Huiming , Zhong Qiuzi , Wang Jianye
Published: December 2021

Purpose

The efficacy of local treatments (LTs) in selected patients with metastatic prostate cancer (mPCa) had been demonstrated. However, the comparative effectiveness between LTs is unclear. Here, we compared the impact of radical prostatectomy (RP) and brachytherapy (RT) on the survival outcomes of mPCa patients.

Materials and Methods

mPCa patients who received RT or RP between 2004 and 2016 were identified from the Surveillance, Epidemiology, and End Results (SEER) database. Multivariable Cox proportional hazards analysis was used to evaluate the comparative risk of prostate cancer-specific mortality (CSM) and all-cause mortality (ACM) between LTs. A 1:1 propensity score matching (PSM) and adjusted standardized mortality ratio weighting (SMRW) were performed to balance the clinicopathological characteristics of the groups.

Results

Of 684 mPCa patients, 481 underwent RP and 203 received RT. After PSM, both groups included 148 cases, and RT resulted in comparable CSM versus RP [CSM: hazard ratio (HR) = 0.77, p = 0.325; ACM: HR = 0.73, p = 0.138], which was consistent with the SMRW model [CSM: HR = 0.83, p = 0.138; overall survival (OS): HR = 0.75, p = 0.132]. However, RP was associated with a lower CSM in the T1–2 subgroup (HR = 0.42, p = 0.048) and a lower ACM in the T1–2 (HR = 0.55, p = 0.031) and prostate-specific antigen (PSA) ≤20ng/ml (HR = 0.48, p = 0.022) subgroups. Besides, the results showed that the mortality risk was similar between the two groups in the T3–4, Gleason score (GS) >7, PSA >20 ng/ml, and all metastatic subgroups (all p > 0.100).

Conclusions

RP could confer better survival outcomes than could RT in mPCa patients with favorable primary tumor features, but not in those with advanced primary tumor features. Moreover, the metastatic substage has limited impact on the comparative effectiveness between RP and RT. Further clinical trials are necessary to confirm the present results.
Intermedin Inhibits the Ox-LDL–Induced Inflammation in RAW264.7 Cells by Affecting Fatty Acid–Binding Protein 4 Through the PKA Pathway
Authors: Liu Kai , Shi Rufeng , Wang Si , Liu Qi , Zhang Hengyu , Chen Xiaoping
Published: December 2021

Objectives: Macrophages stimulated by oxidized low-density lipoprotein (ox-LDL) play an important role in the occurrence and progression of atherosclerosis. Fatty acid–binding protein 4 (FABP4), mainly existing in macrophages and adipocytes, can influence lipid metabolism and inflammation regulated by macrophages. Herein, we first established the connection between intermedin (IMD: a new peptide that has versatile biological activities in the cardiovascular system) and FABP4 and then investigated the influence of IMD on ox-LDL-induced changes in RAW264.7 macrophages line.

Methods: The bioinformatics analysis, such as gene ontology enrichment and protein–protein interactions, was performed. For ox-LDL–stimulated assays, RAW264.7 was first pretreated with IMD and then exposed to ox-LDL. To explore the cell signaling pathways of IMD on inflammatory inhibition, main signaling molecules were tested and then cells were co-incubated with relevant inhibitors, and then exposed/not exposed to IMD. Finally, cells were treated with ox-LDL. The protein and gene expression of FABP4, IL-6, and TNF-α were quantified by WB/ELISA and RT-qPCR.

Results: In the ox-LDL-stimulated assays, exposure of the RAW264.7 macrophages line to ox-LDL reduced cell viability and increased the expression of FABP4, as well as induced the release of IL-6 and TNF-α (all p < 0.05). On the other hand, IMD prevented ox-LDL–induced cell toxicity, FABP4 expression, and the inflammatory level in RAW264.7 (all p < 0.05) in a dose-dependent manner. The inhibition of FABP4 and the anti-inflammatory effect of IMD were partially suppressed by the protein kinase A (PKA) inhibitor H-89.

Conclusion: IMD can prevent ox-LDL–induced macrophage inflammation by inhibiting FABP4, whose signaling might partially occur via the PKA pathway.
Interactions Between Ephedra sinica and Prunus armeniaca: From Stereoselectivity to Deamination as a Metabolic Detoxification Mechanism of Amygdalin
Authors: Qin Yan , Wang Shanshan , Wen Qiuyu , Xia Quan , Wang Sheng , Chen Guanjun , Sun Jiayin , Shen Chenlin , Song Shuai
Published: December 2021

Mahuang–Xingren (MX, Ephedra sinica Stapf-Prunus armeniaca L.) is a classic herb pair used in traditional Chinese medicine. This combined preparation reduces the toxicity of Xingren through the stereoselective metabolism of its main active ingredient amygdalin. However, whether stereoselectivity is important in the pharmacokinetic properties of amygdalin either in the traditional decoction or in the dispensing granules is unclear. Amygdalin is hydrolyzed to its metabolite, prunasin, which produces hydrogen cyanide by degradation of the cyano group. A comprehensive study of the metabolic pathway of amygdalin is essential to better understand the detoxification process. In this article, the potential detoxification pathway of MX is further discussed with regard to herb interactions. In this study, the pharmacokinetic parameters and metabolism of amygdalin and prunasin were investigated by comparing the traditional decoction and the dispensing granule preparations. In addition, several potential metabolites were characterized in an incubation system with rat liver microsomes or gut microbial enzymes. The combination of Xingren with Mahuang reduces exposure to D-amygdalin in vivo and contributes to its detoxification, a process that can be further facilitated in the traditional decoction. From the in vitro co-incubation model, 15 metabolites were identified and classified into cyanogenesis and non-cyanogenesis metabolic pathways, and of these, 10 metabolites were described for the first time. The level of detoxified metabolites in the MX traditional decoction was higher than that in the dispensing granules. The metabolism of amygdalin by the gut microbial enzymes occurred more rapidly than that by the rat liver microsomes. These results indicated that combined boiling both herbs during the preparation of the traditional decoction may induce several chemical changes that will influence drug metabolism in vivo. The gut microbiota may play a critical role in amygdalin metabolism. In conclusion, detoxification of MX may result 1) during the preparation of the decoction, in the boiling phase, and 2) from the metabolic pathways activated in vivo. Stereoselective pharmacokinetics and deamination metabolism have been proposed as the detoxification pathway underlying the compatibility of MX. Metabolic detoxification of amygdalin was quite different between the two combinations, which indicates that the MX decoctions should not be completely replaced by their dispensing granules.
Protective Effect of Dictyophora Polysaccharides on Sodium Arsenite-Induced Hepatotoxicity: A Proteomics Study
Authors: Hu Ting , Shen Liming , Huang Qun , Wu Changyan , Zhang Huajie , Zeng Qibing , Wang Guoze , Wei Shaofeng , Zhang Shuling , Zhang Jun , Khan Naseer Ullah , Shen Xiangchun , Luo Peng
Published: December 2021

The purpose of this study is to understand the mechanism of sodium arsenite (NaAsO2)-induced apoptosis of L-02 human hepatic cells, and how Dictyophora polysaccharide (DIP) protects L-02 cells from arsenic-induced apoptosis. The results revealed that DIP pretreatment inhibited NaAsO2 induced L-02 cells apoptosis by increasing anti-apoptotic Bcl-2 expression and decreasing pro-apoptotic Bax expression. Proteomic analysis showed that arsenic treatment disrupted the expression of metabolism and apoptosis associated proteins, including ribosomal proteins (RPs). After pretreatment with DIP, the expression levels of these proteins were reversed or restored. For the first time, it was observed that the significant decrease of cytoplasmic RPs and the increase of mitochondrial RPs were related to human normal cell apoptosis induced by arsenic. This is also the first report that the protective effect of DIP on cells was related to RPs. The results highlight the relationship between RPs and apoptosis, as well as the relationship between RPs and DIP attenuating arsenic-induced apoptosis.
Hemoglobin-Based Oxygen Carriers: Potential Applications in Solid Organ Preservation
Authors: Cao Min , Wang Guoqing , He Hongli , Yue Ruiming , Zhao Yong , Pan Lingai , Huang Weiwei , Guo Yang , Yin Tao , Ma Lina , Zhang Dingding , Huang Xiaobo
Published: December 2021

Ameliorating graft injury induced by ischemia and hypoxia, expanding the donor pool, and improving graft quality and recipient prognosis are still goals pursued by the transplant community. The preservation of organs during this process from donor to recipient is critical to the prognosis of both the graft and the recipient. At present, static cold storage, which is most widely used in clinical practice, not only reduces cell metabolism and oxygen demand through low temperature but also prevents cell edema and resists apoptosis through the application of traditional preservation solutions, but these do not improve hypoxia and increase oxygenation of the donor organ. In recent years, improving the ischemia and hypoxia of grafts during preservation and repairing the quality of marginal donor organs have been of great concern. Hemoglobin-based oxygen carriers (HBOCs) are “made of” natural hemoglobins that were originally developed as blood substitutes but have been extended to a variety of hypoxic clinical situations due to their ability to release oxygen. Compared with traditional preservation protocols, the addition of HBOCs to traditional preservation protocols provides more oxygen to organs to meet their energy metabolic needs, prolong preservation time, reduce ischemia–reperfusion injury to grafts, improve graft quality, and even increase the number of transplantable donors. The focus of the present study was to review the potential applications of HBOCs in solid organ preservation and provide new approaches to understanding the mechanism of the promising strategies for organ preservation.
HPLC-DAD Fingerprints Combined With Multivariate Analysis of Epimedii Folium From Major Producing Areas in Eastern Asia: Effect of Geographical Origin and Species
Authors: Li Ben , Lima Marta R. M. , Nie Yuhao , Xu Long , Liu Xiang , Yuan Hongchao , Chen Chen , Dias Alberto CP , Zhang Xiaoying
Published: December 2021

The growth location and plant variety may influence the active components and biological activities of plants used in phytomedicine. In this study, nine sets of different Epimedii Folium, from different representative cultivation locations and Epimedium species, were collected for comparison, using HPLC-DAD combined with multivariate analysis. The objective was to investigate the influence of geographical origin and Epimedium species on the quality of Epimedii Folium, and provide applicable guidance for cultivation and quality control of Epimedii Folium. Several Epimedium spp. sets were used to establish the HPLC-DAD fingerprints and 91 peaks (compounds) were selected for the multivariate analysis. Major compounds were analyzed by HPLC-DAD combined with principal component analysis (PCA). HPLC quantitative analysis of known bioactive compounds was performed. Application of PCA to HPLC data showed that Epimedium samples sharing the same geographical origin or species clustered together, indicating that both species and geographical origin have impacts on the quality of Epimedii Folium. The major bioactive flavonoid compounds, epimedin C, icariin and baohuoside I, were identified and quantified. The concentration of bioactive compounds was significantly influenced both by species and geographical origin. E. sagittatum from Sichuan showed the highest content of bioactive compounds. The results showed that both Epimedium species and geographical origin have strong impact into quality of Epimedii Folium. HPLC data combined with multivariate analysis is a suitable approach to inform the selection of cultivation areas and choose Epimedium spp. most suitable for different geographical areas, resulting in improved quality of Epimedii Folium.
An Overview of Systematic Reviews of Chinese Herbal Medicine for Alzheimer’s Disease
Authors: Liu Nanyang , Zhang Tingting , Sun Jiahui , Yao Jiuxiu , Ma Lina , Fu Jianhua , Li Hao
Published: December 2021

Background: Multiple systematic reviews (SRs) have been conducted to evaluate the efficacy and safety of Chinese herbal medicine (CHM) in patients with Alzheimer’s disease (AD). Here, we aim to perform an overview to assess the methodological quality and quality of evidence of the SRs to provide convincing data on the treatment of AD with CHM.

Method: Six electronic databases including Chinese and English were searched, until April 31, 2021. Two researchers independently screen documents and extract data according to the predesigned rules. A Measure Tool to Assessment System Reviews 2 (AMSTAR-2) was used to investigate the methodological quality, and the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) was used to determine the quality of evidence for outcomes.

Results: Twelve qualified SRs including 163 randomized controlled trials were reviewed. The methodological quality of the included SRs was considered extremely low assessed through AMSTAR-2. Compared with western medicines (WM) alone, CHM as an adjuvant treatment has shown significant effects in improving Mini-mental State Examination, Alzheimer’s Disease Assessment Scale-Cognitive, and Clinical Dementia Rating scores. The same is true for CHM alone. Regarding the effect on Activities Daily Living, neither the single CHM nor the combination with WM has an obvious effect. For the total effective rate, both single CHM and the combination with WM shown significant effects. Nine SRs suggested that CHM as adjuvant therapy or single-use had fewer adverse events than WM. Additionally, the quality of evidence for the main outcome was reviewed as low or extremely low according to GRADE profiler data.

Conclusion: Current evidence suggests that CHM may be beneficial in improving the cognitive function of AD patients. However, we should be cautious about the evidence due to methodological flaws and low quality. High-quality RCTs are further needed to confirm the efficacy and safety of CHM for AD.
Mechanisms of Peripheral and Central Pain Sensitization: Focus on Ocular Pain
Authors: Puja Giulia , Sonkodi Balazs , Bardoni Rita
Published: December 2021

Persistent ocular pain caused by corneal inflammation and/or nerve injury is accompanied by significant alterations along the pain axis. Both primary sensory neurons in the trigeminal nerves and secondary neurons in the spinal trigeminal nucleus are subjected to profound morphological and functional changes, leading to peripheral and central pain sensitization. Several studies using animal models of inflammatory and neuropathic ocular pain have provided insight about the mechanisms involved in these maladaptive changes. Recently, the advent of new techniques such as optogenetics or genetic neuronal labelling has allowed the investigation of identified circuits involved in nociception, both at the spinal and trigeminal level. In this review, we will describe some of the mechanisms that contribute to the perception of ocular pain at the periphery and at the spinal trigeminal nucleus. Recent advances in the discovery of molecular and cellular mechanisms contributing to peripheral and central pain sensitization of the trigeminal pathways will be also presented.
Can Erythropoietin Reduce Hypoxemic Neurological Damages in Neonates With Congenital Heart Defects?
Authors: Ottolenghi Sara , Milano Giuseppina , Cas Michele Dei , Findley Tina O. , Paroni Rita , Corno Antonio F.
Published: December 2021

Congenital heart defects (CHD), the most common cause of birth defects with increasing birth prevalence, affect nearly 1% of live births worldwide. Cyanotic CHD are characterized by hypoxemia, with subsequent reduced oxygen delivery to the brain, especially critical during brain development, beginning in the fetus and continuing through the neonatal period. Therefore, neonates with CHD carry a high risk for neurological comorbidities, even more frequently when there are associated underlying genetic disorders. We review the currently available knowledge on potential prevention strategies to reduce brain damage induced by hypoxemia during fetal development and immediately after birth, and the role of erythropoietin (EPO) as a potential adjunctive treatment. Maternal hyper-oxygenation had been studied as a potential therapeutic to improve fetal oxygenation. Despite demonstrating some effectiveness, maternal hyper-oxygenation has proven to be impractical for extensive clinical application, thus prompting the investigation of specific pathways for pharmacological intervention. Among those, the role of antioxidant pathways and Hypoxia Inducible Factors (HIF) have been studied for their involvement in the protective response to hypoxic injury. One of the proteins induced by HIF, EPO, has properties of being anti-apoptotic, antioxidant, and protective for neurons, astrocytes, and oligodendrocytes. In human trials, EPO administration in neonates with hypoxic ischemic encephalopathy (HIE) significantly reduced the neurological hypoxemic damages in several reported studies. Currently, it is unknown if the mechanisms of pathophysiology of cyanotic CHD are like HIE. Neonates with cyanotic CHD are exposed to both chronic hypoxemia and episodes of acute ischemia-reperfusion injury when undergo cardiopulmonary bypass surgery requiring aortic cross-clamp and general anesthesia. Our review supports future trials to evaluate the potential efficiency of EPO in reducing the hypoxemic neurologic damages in neonates with CHD. Furthermore, it suggests the need to identify early biomarkers of hypoxia-induced neurological damage, which must be sensitive to the neuroprotective effects of EPO.
Anti-Tumor Effects of Carrimycin and Monomeric Isovalerylspiramycin I on Hepatocellular Carcinoma in Vitro and in Vivo
Authors: Jin Yong , Zuo Hong Xiang , Li Ming Yue , Zhang Zhi Hong , Xing Yue , Wang Jing Ying , Ma Juan , Li Gao , Piao Hongxin , Gu Puqing , Jin Xuejun
Published: December 2021

Hepatocellular carcinoma results in a high risk of second primary malignancies and has prominent morbidity and mortality. There is a lack of effective treatment and prognosis is poor. Therefore, effective drugs need to be discovered. Carrimycin is a 16-member macrolide antibiotic with anticancer activity, and monomeric isovalerylspiramycin I is a main component. The aim of this study was to determine the anti-tumor effects of carrimycin and monomeric isovalerylspiramycin I on hepatocellular carcinoma through in vivo and in vitro experiments. In vitro, changes in cellular proliferation, migration, invasion, and apoptosis were analyzed by MTT, colony formation, EdU labeling, wound-healing, matrigel transwell invasion, and flow cytometric assays using SK-Hep1, Hep3B, SNU-354, SNU-387 hepatocellular carcinoma cell lines. Western blotting and RT-PCR were used to detect the effects of carrimycin and monomeric isovalerylspiramycin I on the expression levels of vascular endothelial growth factor (VEGF) and programmed death ligand 1 (PD-L1). Nude mice were subcutaneously transplanted with SK-Hep1 cells or C57BL/6J mice were orthotopically transplanted with hepatocarcinoma H22 cells. Tumor volume, pathological changes in tumor tissues, and the concentration of VEGF in mouse serum were measured after treatments. Carrimycin and monomeric isovalerylspiramycin I dose-dependently inhibited hepatocellular carcinoma cell viability, colony formation, and DNA replication. These agents markedly suppressed migration and invasion and promoted apoptosis of the cell lines. Western blotting and RT-PCR demonstrated that carrimycin and monomeric isovalerylspiramycin I reduced VEGF and PD-L1 protein and mRNA levels in a dose-dependent manner. In vivo studies further confirmed that carrimycin and monomeric isovalerylspiramycin I could significantly inhibit tumor growth, tumor histopathological alterations, and the concentration of VEGF in both mouse tumor models. These results show that carrimycin and monomeric isovalerylspiramycin I promoted apoptosis and inhibited proliferation, migration, and invasion of hepatocellular carcinoma cells. Therefore, our discovery suggests anti-tumor capacity for carrimycin and monomeric isovalerylspiramycin I and provides data on potential new drugs for inhibiting hepatocellular carcinoma.
Azilsartan Suppresses Osteoclastogenesis and Ameliorates Ovariectomy-Induced Osteoporosis by Inhibiting Reactive Oxygen Species Production and Activating Nrf2 Signaling
Authors: Pan Bin , Zheng Lin , Fang Jiawei , Lin Ye , Lai Hehuan , Gao Jiawei , Pan Wenzheng , Zhang Yejin , Ni Kainan , Lou Chao , He Dengwei
Published: December 2021

Osteoporosis is characterized by a decrease in bone mass and destruction of the bone microarchitecture, and it commonly occurs in postmenopausal women and the elderly. Overactivation of osteoclasts caused by the inflammatory response or oxidative stress leads to osteoporosis. An increasing number of studies have suggested that intracellular reactive oxygen species (ROS) are strongly associated with osteoclastogenesis. As a novel angiotensin (Ang) II receptor blocker (ARB), azilsartan was reported to be associated with the inhibition of intracellular oxidative stress processes. However, the relationship between azilsartan and osteoclastogenesis is still unknown. In this study, we explored the effect of azilsartan on ovariectomy-induced osteoporosis in mice. Azilsartan significantly inhibited the receptor activator of nuclear factor-κB ligand (RANKL)-mediated osteoclastogenesis and downregulated the expression of osteoclast-associated markers (Nfatc1, c-Fos, and Ctsk) in vitro. Furthermore, azilsartan reduced RANKL-induced ROS production by increasing the expression of nuclear factor erythroid 2-related factor 2 (Nrf2). Mechanistically, azilsartan inhibited the activation of MAPK/NF-κB signaling pathways, while Nrf2 silencing reversed the inhibitory effect of azilsartan on MAPK/NF-κB signaling pathways. Consistent with the in vitro data, azilsartan administration ameliorated ovariectomy (OVX)-induced osteoporosis, and decreased ROS levels in vivo. In conclusion, azilsartan inhibited oxidative stress and may be a novel treatment strategy for osteoporosis caused by osteoclast overactivation.
Nanotherapeutics Overcoming the Blood-Brain Barrier for Glioblastoma Treatment
Authors: Tang Lin , Feng Yicheng , Gao Sai , Mu Qingchun , Liu Chaoyong
Published: December 2021

Glioblastoma (GBM) is the most common malignant primary brain tumor with a poor prognosis. The current standard treatment regimen represented by temozolomide/radiotherapy has an average survival time of 14.6 months, while the 5-year survival rate is still less than 5%. New therapeutics are still highly needed to improve the therapeutic outcome of GBM treatment. The blood-brain barrier (BBB) is the main barrier that prevents therapeutic drugs from reaching the brain. Nanotechnologies that enable drug delivery across the BBB hold great promise for the treatment of GBM. This review summarizes various drug delivery systems used to treat glioma and focuses on their approaches for overcoming the BBB to enhance the accumulation of small molecules, protein and gene drugs, etc. in the brain.
Building a Mobile Stroke Unit Based on 5G Technology – A Study Protocol
Authors: Gu Gangfeng , Jiang Junyao , Zheng Bo , Du Xiao , Huang Ke , Yue Qinfang , Wang Jian
Published: December 2021

Background: In-time treatment of acute stroke is critical to saving people’s lives and improving the quality of post-stroke life. A mobile stroke unit (MSU) with fifth-generation (5G) mobile networks strengthens the interaction of patient information and healthcare resources, thereby reducing response times and improving thrombolysis results. However, clinical evidence of better outcomes compared to regular care is still lacking.

Method and Design: In this randomized controlled trial, 484 patients with acute stroke are allocated into the MSU and regular care groups. We establish medical records for each patient and conduct a follow-up of 90 days. The primary outcomes are functional results as defined by utility-weighted modified Rankin Scale (uw-mRS) 90 days after the incidence occurred, whereas secondary outcomes include the alarm to CT scan completed time, the alarm to treatment decision time, the alarm to thrombolytic time, quality of life, and symptomatic intracranial hemorrhage combined with NIHSS score as well as cost-effectiveness.

Discussion: This study establishes an innovative MSU (based on 5G) to manage acute stroke, comparing its clinical and economic outcomes to regular care and informing decision-makers of the effectiveness of the stroke emergency system.

Clinical Trial Registration: [http://www.chictr.org.cn/showproj.aspx?proj=63874], identifier [ChiCTR2000039695].
Heat Balance When Climbing Mount Everest
Authors: Szymczak Robert K. , Błażejczyk Krzysztof
Published: December 2021

Background: Mountaineers must control and regulate their thermal comfort and heat balance to survive the rigors of high altitude environment. High altitudes feature low air pressure and temperatures, strong winds and intense solar radiation, key factors affecting an expedition’s success. All these climatic elements stress human heat balance and survival. We assess components of human heat balance while climbing Mt. Everest.

Materials and Methods: We calculated climbers’ heat balance using the Man-ENvironment heat EXchange model (MENEX-2005) and derived meteorological data from the National Geographic Expedition’s in situ dataset. Three weather stations sited between 3810 and 7945 m a.s.l. provided data with hourly resolution. We used data for summer (1 May–15 August 2019) and winter (16 October 2019–6 January 2020) seasons to analyze heat balance elements of convection, evaporation, respiration and radiation (solar and thermal).

Results: Meteorological and other factors affecting physiology—such as clothing insulation of 3.5–5.5 clo and activity levels of 3–5 MET—regulate human heat balance. Elevation above sea level is the main element affecting heat balance. In summer two to three times more solar radiation can be absorbed at the summit of the mountain than at the foot. Low air pressure reduces air density, which reduces convective heat loss at high altitude by up to half of the loss at lower locations with the same wind speed and air temperature.

Conclusion: 1. Alpinists face little risk of overheating or overcooling while actively climbing Mt. Everest, despite the potential risk of overcooling at extreme altitudes on Mt. Everest in winter. 2. Convection and evaporation are responsible for most of the heat lost at altitude. 3. Levels of physical activity and clothing insulation play the greatest role in counteracting heat loss at high altitude.
Gender Bias in Artificial Intelligence: Severity Prediction at an Early Stage of COVID-19
Authors: Chung Heewon , Park Chul , Kang Wu Seong , Lee Jinseok
Published: December 2021

Artificial intelligence (AI) technologies have been applied in various medical domains to predict patient outcomes with high accuracy. As AI becomes more widely adopted, the problem of model bias is increasingly apparent. In this study, we investigate the model bias that can occur when training a model using datasets for only one particular gender and aim to present new insights into the bias issue. For the investigation, we considered an AI model that predicts severity at an early stage based on the medical records of coronavirus disease (COVID-19) patients. For 5,601 confirmed COVID-19 patients, we used 37 medical records, namely, basic patient information, physical index, initial examination findings, clinical findings, comorbidity diseases, and general blood test results at an early stage. To investigate the gender-based AI model bias, we trained and evaluated two separate models—one that was trained using only the male group, and the other using only the female group. When the model trained by the male-group data was applied to the female testing data, the overall accuracy decreased—sensitivity from 0.93 to 0.86, specificity from 0.92 to 0.86, accuracy from 0.92 to 0.86, balanced accuracy from 0.93 to 0.86, and area under the curve (AUC) from 0.97 to 0.94. Similarly, when the model trained by the female-group data was applied to the male testing data, once again, the overall accuracy decreased—sensitivity from 0.97 to 0.90, specificity from 0.96 to 0.91, accuracy from 0.96 to 0.91, balanced accuracy from 0.96 to 0.90, and AUC from 0.97 to 0.95. Furthermore, when we evaluated each gender-dependent model with the test data from the same gender used for training, the resultant accuracy was also lower than that from the unbiased model.
Plant Copper Metalloenzymes As Prospects for New Metabolism Involving Aromatic Compounds
Authors: Mydy Lisa S. , Chigumba Desnor N. , Kersten Roland D.
Published: December 2021

Copper is an important transition metal cofactor in plant metabolism, which enables diverse biocatalysis in aerobic environments. Multiple classes of plant metalloenzymes evolved and underwent genetic expansions during the evolution of terrestrial plants and, to date, several representatives of these copper enzyme classes have characterized mechanisms. In this review, we give an updated overview of chemistry, structure, mechanism, function and phylogenetic distribution of plant copper metalloenzymes with an emphasis on biosynthesis of aromatic compounds such as phenylpropanoids (lignin, lignan, flavonoids) and cyclic peptides with macrocyclizations via aromatic amino acids. We also review a recent addition to plant copper enzymology in a copper-dependent peptide cyclase called the BURP domain. Given growing plant genetic resources, a large pool of copper biocatalysts remains to be characterized from plants as plant genomes contain on average more than 70 copper enzyme genes. A major challenge in characterization of copper biocatalysts from plant genomes is the identification of endogenous substrates and catalyzed reactions. We highlight some recent and future trends in filling these knowledge gaps in plant metabolism and the potential for genomic discovery of copper-based enzymology from plants.
Dynamic Changes of DNA Methylation During Wild Strawberry (Fragaria nilgerrensis) Tissue Culture
Authors: Cao Qiang , Feng Yuxi , Dai Xiongwei , Huang Lin , Li Jiamin , Tao Pang , Crabbe M. James C. , Zhang Ticao , Qiao Qin
Published: December 2021

Tissue culture is an important tool for asexual propagation and genetic transformation of strawberry plants. In plant tissue culture, variation of DNA methylation is a potential source of phenotypic variation in regenerated plants. However, the genome wide dynamic methylation patterns of strawberry tissue culture remain unclear. In this study, we used whole-genome bisulfite sequencing (WGBS) to study genomic DNA methylation changes of a wild strawberry Fragaria nilgerrensis at six stages: from explants of shoot tips to outplanting and acclimation. Global methylation levels showed that CG sites exhibited the highest methylation level in all stages with an average of 49.5%, followed by CHG (33.2%) and CHH (12.4%). Although CHH accounted for the lowest proportion of total cytosine methylation, it showed the most obvious methylation change and the most of these changes occurred in the transposable element regions. The overall methylation levels alternately decreased and increased during the entire tissue culture process and the distribution of DNA methylation was non-uniform among different genetic regions. Furthermore, much more differentially methylated regions (DMRs) were detected in dedifferentiation and redifferentiation stages and most of them were transposable elements, suggesting these processes involved activating or silencing of amounts of transposons. The functional enrichment of the DMR-related genes indicated that genes involved in hormone metabolic processes, plant development and the stress response changed methylation throughout the tissue culture process. Finally, the quantitative real-time PCR (qRT-PCR) was conducted to examine the association of methylation and gene expression of a set of different methylated genes. Our findings give deeper insight into the epigenetic regulation of gene expression during the plant tissue cultures process, which will be useful in the efficient control of somaclonal variations and in crop improvement.
Structural Diversity of Photosystem I and Its Light-Harvesting System in Eukaryotic Algae and Plants
Authors: Bai Tianyu , Guo Lin , Xu Mingyu , Tian Lirong
Published: December 2021

Photosystem I (PSI) is one of the most efficient photoelectric apparatus in nature, converting solar energy into condensed chemical energy with almost 100% quantum efficiency. The ability of PSI to attain such high conversion efficiency depends on the precise spatial arrangement of its protein subunits and binding cofactors. The PSI structures of oxygenic photosynthetic organisms, namely cyanobacteria, eukaryotic algae, and plants, have undergone great variation during their evolution, especially in eukaryotic algae and vascular plants for which light-harvesting complexes (LHCI) developed that surround the PSI core complex. A detailed understanding of the functional and structural properties of this PSI-LHCI is not only an important foundation for understanding the evolution of photosynthetic organisms but is also useful for designing future artificial photochemical devices. Recently, the structures of such PSI-LHCI supercomplexes from red alga, green alga, diatoms, and plants were determined by X-ray crystallography and single-particle cryo-electron microscopy (cryo-EM). These findings provide new insights into the various structural adjustments of PSI, especially with respect to the diversity of peripheral antenna systems arising via evolutionary processes. Here, we review the structural details of the PSI tetramer in cyanobacteria and the PSI-LHCI and PSI-LHCI-LHCII supercomplexes from different algae and plants, and then discuss the diversity of PSI-LHCI in oxygenic photosynthesis organisms.
Association Between Maternal Body Mass and Physical Activity Counseling During Pregnancy
Authors: Ruart Shelly , Sinnapah Stéphane , Hue Olivier , Janky Eustase , Antoine-Jonville Sophie
Published: December 2021

Aims: The antenatal period provides an important opportunity for giving advice on healthy lifestyle choices. However, the prevalence of maternal obesity is increasing, and women report that they do not receive counseling. We investigated the information given to pregnant women on gestational weight gain, physical activity, and nutrition during pregnancy in relation with their initial weight status, current gestational weight gain and diagnoses of either pre-pregnancy overweight/obesity or excessive gestational weight gain.

Methods: Cross-sectional survey using a questionnaire. Pregnant participants (n = 141) were recruited from a midwife center. They completed a structured questionnaire on the information they received during their pregnancy and we assessed its relationship with their weight.

Results: We found that many pregnant women did not receive advice about physical activity, gestational weight gain and nutrition (37.5, 53.2, and 66.2%, respectively). Women with weight problems (pre-pregnancy overweight/obesity and excessive gestational weight gain) were less targeted for counseling, although more than 80% of the women viewed receiving information on these topics as positive. Also, being informed of a weight problem was associated with a greater chance of receiving information about physical activity, gestational weight gain and nutrition (all p < 0.05). However, verbalization of the weight problems was low (14.0% of women with pre-pregnancy overweight were informed of their status).

Conclusion: Health professionals should dispense more information, especially on PA and particularly for women with weight problems. Verbalization of the weight problem seems associated with more frequent transmission of information.