Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

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Histone variants: critical determinants in tumour heterogeneity
Tao Wang, Florent Chuffart, Ekaterina Bourova-Flin, Jin Wang, Jianqing Mi, Sophie Rousseaux, Saadi Khochbin
Front. Med.    2019, 13 (3): 289-297.
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Malignant cell transformation could be considered as a series of cell reprogramming events driven by oncogenic transcription factors and upstream signalling pathways. Chromatin plasticity and dynamics are critical determinants in the control of cell reprograming. An increase in chromatin dynamics could therefore constitute an essential step in driving oncogenesis and in generating tumour cell heterogeneity, which is indispensable for the selection of aggressive properties, including the ability of cells to disseminate and acquire resistance to treatments. Histone supply and dosage, as well as histone variants, are the best-known regulators of chromatin dynamics. By facilitating cell reprogramming, histone under-dosage and histone variants should also be crucial in cell transformation and tumour metastasis. Here we summarize and discuss our knowledge of the role of histone supply and histone variants in chromatin dynamics and their ability to enhance oncogenic cell reprogramming and tumour heterogeneity.

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Cytokines and inflammation in adipogenesis: an updated review
Ning Jiang, Yao Li, Ting Shu, Jing Wang
Front. Med.    2019, 13 (3): 314-329.
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The biological relevance of cytokines is known for more than 20 years. Evidence suggests that adipogenesis is one of the biological events involved in the regulation of cytokines, and pro-inflammatory cytokines (e.g., TNFα and IL-1β) inhibit adipogenesis through various pathways. This inhibitory effect can constrain the hyperplastic expandability of adipose tissues. Meanwhile, chronic low-grade inflammation is commonly observed in obese populations. In some individuals, the impaired ability of adipose tissues to recruit new adipocytes to adipose depots during overnutrition results in adipocyte hypertrophy, ectopic lipid accumulation, and insulin resistance. Intervention studies showed that pro-inflammatory cytokine antagonists improve metabolism in patients with metabolic syndrome. This review focuses on the cytokines currently known to regulate adipogenesis under physiological and pathophysiological circumstances. Recent studies on how inhibited adipogenesis leads to metabolic disorders were summarized. Although the interplay of cytokines and lipid metabolism is yet incompletely understood, cytokines represent a class of potential therapeutic targets in the treatment of metabolic disorders.

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HLA and lung transplantation
Liya Ju, Caroline Suberbielle, Xiaofan Li, Nuala Mooney, Dominique Charron
Front. Med.    2019, 13 (3): 298-313.
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Lung transplantation is increasingly practiced for patients with end-stage lung disease. The successful outcome of solid organ transplantation today is severely impeded by the production of alloantibodies, mainly directed against the protein products of the HLA complex of the organ donor. While the association between antibody mediated rejection and allograft damage has been well established in renal and heart transplantation, it has not yet been well characterized in lung transplantation. This review addresses the question of HLA matching in lung transplantation and current knowledge of the allogenicity of different HLA class I and II antigens. The role of the antibody mediated immune response is discussed as well as the importance of pre-transplant or de novo post-transplant circulating antibodies. Finally, potential mechanisms, which may act individually or in combination, of antibody mediated damage to solid organ transplants are considered.

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The FGF metabolic axis
Xiaokun Li
Front. Med.    2019, 13 (5): 511-530.
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Members of the fibroblast growth factor (FGF) family play pleiotropic roles in cellular and metabolic homeostasis. During evolution, the ancestor FGF expands into multiple members by acquiring divergent structural elements that enable functional divergence and specification. Heparan sulfate-binding FGFs, which play critical roles in embryonic development and adult tissue remodeling homeostasis, adapt to an autocrine/paracrine mode of action to promote cell proliferation and population growth. By contrast, FGF19, 21, and 23 coevolve through losing binding affinity for extracellular matrix heparan sulfate while acquiring affinity for transmembrane α-Klotho (KL) or β-KL as a coreceptor, thereby adapting to an endocrine mode of action to drive interorgan crosstalk that regulates a broad spectrum of metabolic homeostasis. FGF19 metabolic axis from the ileum to liver negatively controls diurnal bile acid biosynthesis. FGF21 metabolic axes play multifaceted roles in controlling the homeostasis of lipid, glucose, and energy metabolism. FGF23 axes from the bone to kidney and parathyroid regulate metabolic homeostasis of phosphate, calcium, vitamin D, and parathyroid hormone that are important for bone health and systemic mineral balance. The significant divergence in structural elements and multiple functional specifications of FGF19, 21, and 23 in cellular and organismal metabolism instead of cell proliferation and growth sufficiently necessitate a new unified and specific term for these three endocrine FGFs. Thus, the term “FGF Metabolic Axis,” which distinguishes the unique pathways and functions of endocrine FGFs from other autocrine/paracrine mitogenic FGFs, is coined.

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PD-1/PD-L1 blockade in cervical cancer: current studies and perspectives
Yumeng Wang, Guiling Li
Front. Med.    2019, 13 (4): 438-450.
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Cervical cancer (CC) is the fourth most commonly diagnosed female malignancy and a leading cause of cancer-related mortality worldwide, especially in developing countries. Despite the use of advanced screening and preventive vaccines, more than half of all CC cases are diagnosed at advanced stages, when therapeutic options are extremely limited and side effects are severe. Given these circumstances, new and effective treatments are needed. In recent years, exciting progress has been made in immunotherapies, including the rapid development of immune checkpoint inhibitors. Checkpoint blockades targeting the PD-1/PD-L1 axis have achieved effective clinical responses with acceptable toxicity by suppressing tumor progression and improving survival in several tumor types. In this review, we summarize recent advances in our understanding of the PD-1/PD-L1 signaling pathway, including the expression patterns of PD-1/PD-L1 and potential PD-1/PD-L1-related therapeutic strategies for CC.

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Overexpressed long noncoding RNA CRNDE with distinct alternatively spliced isoforms in multiple cancers
Xuefei Ma, Wei Zhang, Rong Zhang, Jingming Li, Shufen Li, Yunlin Ma, Wen Jin, Kankan Wang
Front. Med.    2019, 13 (3): 330-343.
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Alternative splicing is a tightly regulated process that contributes to cancer development. CRNDE is a long noncoding RNA with alternative splicing and is implicated in the pathogenesis of several cancers. However, whether deregulated expression of CRNDE is common and which isoforms are mainly involved in cancers remain unclear. In this study, we report that CRNDE is aberrantly expressed in the majority of solid and hematopoietic malignancies. The investigation of CRNDE expression in normal samples revealed that CRNDE was expressed in a tissue- and cell-specific manner. Further comparison of CRNDE expression in 2938 patient samples from 15 solid and hematopoietic tumors showed that CRNDE was significantly overexpressed in 11 malignancies, including 3 reported and 8 unreported, and also implicated that the overexpressed isoforms differed in various cancer types. Furthermore, anti-cancer drugs could efficiently repress CRNDE overexpression in cancer cell lines and primary samples, and even had different impacts on the expression of CRNDE isoforms. Finally, experimental profiles of 12 alternatively spliced isoforms demonstrated that the spliced variant CRNDE-g was the most highly expressed isoform in multiple cancer types. Collectively, our results emphasize the cancer-associated feature of CRNDE and its spliced isoforms, and may provide promising targets for cancer diagnosis and therapy.

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Irreversible phenotypic perturbation and functional impairment of B cells during HIV-1 infection
Jingjing Yan, Shuye Zhang, Jun Sun, Jianqing Xu, Xiaoyan Zhang
Front. Med.    2019, 13 (3): 409-409.
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Homoharringtonine synergy with oridonin in treatment of t(8; 21) acute myeloid leukemia
Weina Zhang, Ying Lu, Tao Zhen, Xinjie Chen, Ming Zhang, Ping Liu, Xiangqin Weng, Bing Chen, Yueying Wang
Front. Med.    2019, 13 (3): 388-397.
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Collaboration of c-KIT mutations with AML1–ETO (AE) has been demonstrated to induce t(8; 21) acute myeloid leukemia (AML). Targeted therapies designed to eliminate AE and c-KIT oncoproteins may facilitate effective treatment of t(8; 21) AML. Homoharringtonine (HHT) features activity against tumor cells harboring c-KIT mutations, whereas oridonin can induce t(8; 21) AML cell apoptosis and AE cleavage. Therefore, studies should explore the efficacy of combination therapy with oridonin and HHT in t(8; 21) AML. In this study, we investigated the synergistic effects and mechanism of oridonin combined with HHT in t(8; 21) AML cell line and mouse model. The two drugs synergistically inhibited cell viability and induced significant mitochondrial membrane potential loss and apoptosis. Oridonin and HHT induced significant downregulation of c-KIT and its downstream signaling pathways and promoted AE cleavage. HHT increased intracellular oridonin concentration by modulating the expressions of MRP1 and MDR1, thus enhancing the effects of oridonin. The combination of oridonin and HHT prolonged t(8; 21) leukemia mouse survival. In conclusion, oridonin and HHT exert synergistic effects against t(8; 21) leukemia in vivo and in vitro, thereby indicating that their combination may be an effective therapy for t(8; 21) leukemia.

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Classification and treatment of orbital venous malformations: an updated review
Tianyuan Li, Renbing Jia, Xianqun Fan
Front. Med.    2019, 13 (5): 547-555.
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Orbital venous malformation (OVM) is a congenital vascular disease. As a common type of vascular malformation in the orbit, OVM may result in vision deterioration and cosmetic defect. Classification of orbital vascular malformations, especially OVMs, is carried out on the basis of different categories, such as angiogenesis, hemodynamics, and locations. Management of OVM is complicated and challenging. Treatment approaches include sclerotherapy, laser therapy, embolization, surgical resection, and radiotherapy. A satisfactory outcome can be achieved only by selecting the appropriate treatment according to lesion characteristics and following the sequential multi-method treatment strategy. This article summarizes the current classification and treatment advances in OVM.

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Tprn is essential for the integrity of stereociliary rootlet in cochlear hair cells in mice
Yuqin Men, Xiujuan Li, Hailong Tu, Aizhen Zhang, Xiaolong Fu, Zhishuo Wang, Yecheng Jin, Congzhe Hou, Tingting Zhang, Sen Zhang, Yichen Zhou, Boqin Li, Jianfeng Li, Xiaoyang Sun, Haibo Wang, Jiangang Gao
Front. Med.    2019, 13 (6): 690-704.
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Tprn encodes the taperin protein, which is concentrated in the tapered region of hair cell stereocilia in the inner ear. In humans, TPRN mutations cause autosomal recessive nonsyndromic deafness (DFNB79) by an unknown mechanism. To determine the role of Tprn in hearing, we generated Tprn-null mice by clustered regularly interspaced short palindromic repeat/Cas9 genome-editing technology from a CBA/CaJ background. We observed significant hearing loss and progressive degeneration of stereocilia in the outer hair cells of Tprn-null mice starting from postnatal day 30. Transmission electron microscopy images of stereociliary bundles in the mutant mice showed some stereociliary rootlets with curved shafts. The central cores of the stereociliary rootlets possessed hollow structures with surrounding loose peripheral dense rings. Radixin, a protein expressed at stereocilia tapering, was abnormally dispersed along the stereocilia shafts in Tprn-null mice. The expression levels of radixin and β-actin significantly decreased. We propose that Tprn is critical to the retention of the integrity of the stereociliary rootlet. Loss of Tprn in Tprn-null mice caused the disruption of the stereociliary rootlet, which resulted in damage to stereociliary bundles and hearing impairments. The generated Tprn-null mice are ideal models of human hereditary deafness DFNB79.

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Altered intestinal microbiota associated with colorectal cancer
Hong Zhang, Ying Chang, Qingqing Zheng, Rong Zhang, Cheng Hu, Weiping Jia
Front. Med.    2019, 13 (4): 461-470.
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The gut microbiota plays an important role in the development and progression of colorectal cancer (CRC). To learn more about the dysbiosis of carcinogenesis, we assessed alterations in gut microbiota in patients with CRC. A total of 23 subjects were enrolled in this study: 9 had CRC (CRC group) and 14 had normal colons (normal group). The microbiome of the mucosal--luminal interface of each subject was sampled and analyzed using 16S rRNA gene amplicon sequencing. We also used Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) to predict microbial functional profiles. The microbial composition of the mucosal lumen differed between the groups, and the presence of specific bacteria may serve as a potential biomarker for colorectal carcinogenesis. We identified a significant reduction in Eubacterium, which is a butyrate-producing genera of bacteria, and a significant increase in Devosia in the gut microbiota of CRC patients. Different levels of gut microflora in healthy and CRC samples were identified. The observed abundance of bacterial species belonging to Eubacterium and Devosia may serve as a promising biomarker for the early detection of CRC.

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Genetic and clinical markers for predicting treatment responsiveness in rheumatoid arthritis
Xin Wu, Xiaobao Sheng, Rong Sheng, Hongjuan Lu, Huji Xu
Front. Med.    2019, 13 (4): 411-419.
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Although many drugs and therapeutic strategies have been developed for rheumatoid arthritis (RA) treatment, numerous patients with RA fail to respond to currently available agents. In this review, we provide an overview of the complexity of this autoimmune disease by showing the rapidly increasing number of genes associated with RA. We then systematically review various factors that have a predictive value (predictors) for the response to different drugs in RA treatment, especially recent advances. These predictors include but are certainly not limited to genetic variations, clinical factors, and demographic factors. However, no clinical application is currently available. This review also describes the challenges in treating patients with RA and the need for personalized medicine. At the end of this review, we discuss possible strategies to enhance the prediction of drug responsiveness in patients with RA.

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Clinical risk score for invasive fungal diseases in patients with hematological malignancies undergoing chemotherapy: China Assessment of Antifungal Therapy in Hematological Diseases (CAESAR) study
Ling Wang, Ying Wang, Jiong Hu, Yuqian Sun, He Huang, Jing Chen, Jianyong Li, Jun Ma, Juan Li, Yingmin Liang, Jianmin Wang, Yan Li, Kang Yu, Jianda Hu, Jie Jin, Chun Wang, Depei Wu, Yang Xiao, Xiaojun Huang
Front. Med.    2019, 13 (3): 365-377.
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Invasive fungal disease (IFD) is a major infectious complication in patients with hematological malignancies. In this study, we examined 4889 courses of chemotherapy in patients with hematological diseases to establish a training dataset (n=3500) by simple random sampling to develop a weighted risk score for proven or probable IFD through multivariate regression, which included the following variables: male patients, induction chemotherapy for newly diagnosed or relapsed disease, neutropenia, neutropenia longer than 10 days, hypoalbuminemia, central-venous catheter, and history of IFD. The patients were classified into three groups, which had low (0–10, ~1.2%), intermediate (11–15, 6.4%), and high risk (>15, 17.5%) of IFD. In the validation set (n=1389), the IFD incidences of the groups were ~1.4%, 5.0%, and 21.4%. In addition, we demonstrated that anti-fungal prophylaxis offered no benefits in low-risk patients, whereas benefits were documented in intermediate (2.1% vs. 6.6%, P=0.007) and high-risk patients (8.4% vs. 23.3%, P=0.007). To make the risk score applicable for clinical settings, a pre-chemo risk score that deleted all unpredictable factors before chemotherapy was established, and it confirmed that anti-fungal prophylaxis was beneficial in patients with intermediate and high risk of IFD. In conclusion, an objective, weighted risk score for IFD was developed, and it may be useful in guiding antifungal prophylaxis.

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Glycosylation of dentin matrix protein 1 is critical for fracture healing via promoting chondrogenesis
Hui Xue, Dike Tao, Yuteng Weng, Qiqi Fan, Shuang Zhou, Ruilin Zhang, Han Zhang, Rui Yue, Xiaogang Wang, Zuolin Wang, Yao Sun
Front. Med.    2019, 13 (5): 575-589.
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Fractures are frequently occurring diseases that endanger human health. Crucial to fracture healing is cartilage formation, which provides a bone-regeneration environment. Cartilage consists of both chondrocytes and extracellular matrix (ECM). The ECM of cartilage includes collagens and various types of proteoglycans (PGs), which play important roles in maintaining primary stability in fracture healing. The PG form of dentin matrix protein 1 (DMP1-PG) is involved in maintaining the health of articular cartilage and bone. Our previous data have shown that DMP1-PG is richly expressed in the cartilaginous calluses of fracture sites. However, the possible significant role of DMP1-PG in chondrogenesis and fracture healing is unknown. To further detect the potential role of DMP1-PG in fracture repair, we established a mouse fracture model by using a glycosylation site mutant DMP1 mouse (S89G-DMP1 mouse). Upon inspection, fewer cartilaginous calluses and down-regulated expression levels of chondrogenesis genes were observed in the fracture sites of S89G-DMP1 mice. Given the deficiency of DMP1-PG, the impaired IL-6/JAK/STAT signaling pathway was observed to affect the chondrogenesis of fracture healing. Overall, these results suggest that DMP1-PG is an indispensable proteoglycan in chondrogenesis during fracture healing.

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ECRG4: a new potential target in precision medicine
Xin Qin, Ping Zhang
Front. Med.    2019, 13 (5): 540-546.
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Given the rapid development in precision medicine, tremendous efforts have been devoted to discovering new biomarkers for disease diagnosis and treatment. Esophageal cancer-related gene-4 (ECRG4), which is initially known as a new candidate tumor suppressor gene, is emerging as a sentinel molecule for gauging tissue homeostasis. ECRG4 is unique in its cytokine-like functional pattern and epigenetically-regulated gene expression pattern. The gene can be released from the cell membrane upon activation and detected in liquid biopsy, thus offering considerable potential in precision medicine. This review provides an updated summary on the biology of ECRG4, with emphasis on its important roles in cancer diagnosis and therapy. The future perspectives of ECRG4 as a potential molecular marker in precision medicine are also discussed in detail.

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Four-year follow-up of patients with imatinib-resistant or intolerant chronic myeloid leukemia receiving dasatinib: efficacy and safety
Xiaojun Huang, Qian Jiang, Jianda Hu, Jianyong Li, Jie Jin, Fanyi Meng, Zhixiang Shen, Ting Liu, Depei Wu, Jianmin Wang, Jianxiang Wang
Front. Med.    2019, 13 (3): 344-353.
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Dasatinib is a highly effective second-generation tyrosine kinase inhibitor used to treat chronic myeloid leukemia (CML). In 2007, a pivotal phase-2 study of dasatinib as second-line treatment was initiated in 140 Chinese CML patients. This report from the 4-year follow-up revealed that 73% of 59 patients in chronic phase (CML-CP) and 32% of 25 patients in accelerated phase (CML-AP) remained under treatment. The initial dosage of dasatinib for CML-CP and CML-AP patients were 100 mg once daily and 70 mg twice daily (total= 140 mg/day), respectively. The cumulative major cytogenetic response (MCyR) rate among patients with CML-CP was 66.1% (versus 50.8% at 18 months), and the median time to MCyR was 12.7 weeks. All CML-CP patients who achieved MCyR after a 4-year follow-up also achieved a complete cytogenetic response. The cumulative complete hematological response (CHR) rate among patients with CML-AP was 64% (16/25), with three CML-AP patients achieving CHR between 18 months and 4 years of follow-up; the median time to CHR was 16.4 weeks. The adverse event (AE) profile of dasatinib at 4 years was similar to that at 6 and 18 months. The most frequently reported AEs (any grade) included pleural effusion, headache, and myelosuppression. These long-term follow-up data continue to support dasatinib as a second-line treatment for Chinese patients with CML.

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Changes in public trust in physicians: empirical evidence from China
Dahai Zhao, Zhiruo Zhang
Front. Med.    2019, 13 (4): 504-510.
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Studies examining the trends in public trust in physicians have provided a considerable amount of valuable policy implications for policymakers compared with cross-sectional studies on this topic in many countries. This study investigated changes in public trust in physicians in China based on two cross-sectional national surveys conducted in 2011 and 2016 and identified the determinants of these changes. The results indicated 83.4% of respondents in 2011 reported trust or strong trust in physicians in China, which decreased to 64.2% by 2016. The results of ordinal logistic regression demonstrated that public trust in physicians in China had decreased significantly from 2011 to 2016 (P<0.001) after adjusting for other independent variables. Self-reported health status, self-rated happiness, and self-identified social class were all associated positively with public trust in physicians in China. The results also confirmed that decreasing public satisfaction with the most recent treatment experience was the major determinant of decreasing public trust in physicians in China. The findings of this study suggest that decreasing public trust in physicians deserves considerable attention from national policymakers and that improving satisfaction with treatment experiences would be the most effective strategy for enhancing public trust in physicians in China.

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Comparative analysis of membranous and other nephropathy subtypes and establishment of a diagnostic model
Hanyu Zhu, Bo Fu, Yong Wang, Jing Gao, Qiuxia Han, Wenjia Geng, Xiaoli Yang, Guangyan Cai, Xiangmei Chen, Dong Zhang
Front. Med.    2019, 13 (5): 618-625.
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This study aimed to compare clinical features between membranous nephropathy (MN) and nonmembranous nephropathy (non-MN), to explore the clinically differential diagnosis of these two types, and to establish a diagnostic model of MN. After renal biopsy was obtained, 798 patients were divided into two groups based on their examination results: primary MN group (n = 248) and non-MN group (n = 550). Their data were statistically analyzed. Logistic regression analysis indicated that anti-PLA2R antibodies, IgG, and Cr were independently correlated with MN, and these three parameters were then used to establish the MN diagnostic model. A receiver operating characteristic (ROC) curve confirmed that our diagnostic model could distinguish between patients with and without MN, and their corresponding sensitivity, specificity, and AUC were 79.9%, 89.4%, and 0.917, respectively. The cutoff value for this combination in MN diagnosis was 0.34. The established diagnostic model that combined multiple factors shows a potential for broad clinical applications in differentiating primary MN from other kidney diseases and provides reliable evidence supporting the feasibility of noninvasive diagnosis of kidney diseases.

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Urotensin II receptor antagonist reduces hepatic resistance and portal pressure through enhanced eNOS-dependent HSC vasodilatation in CCl4-induced cirrhotic rats
Ruoxi Zhang, Jing Chen, Diangang Liu, Yu Wang
Front. Med.    2019, 13 (3): 398-408.
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Increased serum urotensin II (UII) levels in human cirrhotic populations have been recently shown, but the long-term effects of UII receptor antagonist on the cirrhosis have not been investigated. To investigate the therapeutic effects of urotensin II receptor (UT) antagonist palosuran on rats with carbon tetrachloride (CCl4)-induced cirrhosis, the hepatic and systemic hemodynamics, liver fibrosis, the metalloproteinase-13 (MMP-13)/ tissue inhibitor of metalloproteinase-1 (TIMP-1) ratio, hepatic Rho-kinase activity, and the endothelial nitric oxide synthase (eNOS) activity are measured in CCl4-cirrhotic rats treated with palosuran or vehicle for 4 weeks. Primary hepatic stellate cells (HSCs) are used to investigate the changes in UII/UT expression and the in vitro effect of palosuran. Compared with the vehicle-treated cirrhotic rats, treatment with palosuran can reduce the portal pressure (PP), decrease the risk of liver fibrosis and the level of α smooth muscle actin, collagen-I (COL-I), and transforming growth factor β expression. However, treatment with palosuran can increase MMP-13/TIMP-1, p-vasodilator-stimulated phosphoprotein (p-VASP), and p-eNOS expression. Moreover, in vitro UII/UT mRNA expression increases during HSC activation. MMP-13/TIMP-1, COL-I, and p-VASP are inhibited after palosuran treatment. Our data indicate that long-term administration of palosuran can decrease PP in cirrhosis, which results from decreased hepatic fibrosis and enhanced eNOS-dependent HSC vasodilatation.

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G protein-coupled receptor LGR6 is an independent risk factor for colon adenocarcinoma
Wenjing Wang, Shigang Ding, Hejun Zhang, Jun Li, Jun Zhan, Hongquan Zhang
Front. Med.    2019, 13 (4): 482-491.
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LGR6 is a member of the G protein-coupled receptor family that plays a tumor-suppressive role in colon cancer. However, the relationship between LGR6 expression in patients and clinicopathological factors remains unclear. This study aimed to clarify whether the expression level of LGR6 is correlated with colon adenocarcinoma progression. Immunohistochemistry was used to detect LGR6 expression in colon adenoma tissues (n = 21), colon adenocarcinoma tissues (n = 156), and adjacent normal tissues (n = 124). The expression levels of LGR6 in colon adenoma and adenocarcinoma were significantly higher than those in normal colon epithelial tissues (P<0.001). Low LGR6 expression predicted a short overall survival in patients with colon adenocarcinoma (log-rank test, P = 0.016). Univariate and multivariate survival analyses showed that, in addition to N and M classification, LGR6 expression served as an independent prognostic factor. Thus, low expression of LGR6 can be used as an independent prognostic parameter in patients with colon adenocarcinoma.

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Deciphering the pharmacological mechanism of Guan-Jie-Kang in treating rat adjuvant-induced arthritis using omics analysis
Hudan Pan, Yanfang Zheng, Zhongqiu Liu, Zhongwen Yuan, Rutong Ren, Hua Zhou, Ying Xie, Liang Liu
Front. Med.    2019, 13 (5): 564-574.
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Traditional Chinese medicine (TCM) formulas have attracted increasing attention worldwide in the past few years for treating complex disease including rheumatoid arthritis. However, their mechanisms are complex and remain unclear. Guan-Jie-Kang (GJK), a prescription modified from “Wu Tou Decoction,” was found to significantly relieve arthritis symptoms in rats with adjuvant-induced arthritis after 30-day treatment, especially in the 24 g/kg/day group. By analyzing 1749 targets related to 358 compounds in the five herbs of GJK, we identified the possible anti-arthritis pathways of GJK, including the calcium signaling and metabolic pathways. Bone damage levels were assessed by micro-computed tomography, and greater bone protective effect was observed with GJK treatment than with methotrexate. Receptor activator of nuclear factor κB ligand (RANKL)–RANK signaling, which is related to calcium signaling, was significantly regulated by GJK. Moreover, a target metabolomics assay of serum was conducted; 17 metabolic biomarkers showed significant correlations with treatment. An integrated pathway analysis revealed that pyruvate metabolism, purine metabolism, and glycolysis metabolism were significantly associated with the effects of GJK in arthritis treatment. Thus, this study establishes a new omics analytical method integrated with bioinformatics analysis for elucidating the multi-pathway mechanisms of TCM.

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NES1/KLK10 and hNIS gene therapy enhanced iodine-131 internal radiation in PC3 proliferation inhibition
Jiajia Hu, Wenbin Shen, Qian Qu, Xiaochun Fei, Ying Miao, Xinyun Huang, Jiajun Liu, Yingli Wu, Biao Li
Front. Med.    2019, 13 (6): 646-657.
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NES1 gene is thought to be a tumor-suppressor gene. Our previous study found that overexpression of NES1 gene in PC3 cell line could slow down the tumor proliferation rate, associated with a mild decrease in BCL-2 expression. The BCL-2 decrease could increase the sensitivity of radiotherapy to tumors. Thus, we supposed to have an “enhanced firepower” effect by combining overexpressed NES1 gene therapy and 131I radiation therapy uptake by overexpressed hNIS protein. We found a weak endogenous expression of hNIS protein in PC3 cells and demonstrated that the low expression of hNIS protein in PC3 cells might be the reason for the low iodine uptake. By overexpressing hNIS in PC3, the radioactive iodine uptake ability was significantly increased. Results of in vitro and in vivo tumor proliferation experiments and 18F-fluorothymidine (18F-FLT) micro-positron emission tomography/computed tomography (micro-PET/CT) imaging showed that the combined NES1 gene therapy and 131I radiation therapy mediated by overexpressed hNIS protein had the best tumor proliferative inhibition effect. Immunohistochemistry showed an obvious decrease of Ki-67 expression and the lowest BCL-2 expression. These data suggest that via inhibition of BCL-2 expression, overexpressed NES1 might enhance the effect of radiation therapy of 131I uptake in hNIS overexpressed PC3 cells.

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Structural shifts in the intestinal microbiota of rats treated with cyclosporine A after orthotropic liver transplantation
Junjun Jia, Xinyao Tian, Jianwen Jiang, Zhigang Ren, Haifeng Lu, Ning He, Haiyang Xie, Lin Zhou, Shusen Zheng
Front. Med.    2019, 13 (4): 451-460.
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Understanding the effect of immunosuppressive agents on intestinal microbiota is important to reduce the mortality and morbidity from orthotopic liver transplantation (OLT). We investigated the relationship between the commonly used immunosuppressive agent cyclosporine A (CSA) and the intestinal microbial variation in an OLT model. The rat samples were divided as follows: (1) N group (normal control); (2) I group (isograft LT, Brown Norway [BN] rat to BN); (3) R group (allograft LT, Lewis to BN rat); and (4) CSA group (R group treated with CSA). The intestinal microbiota was assayed by denaturing gradient gel electrophoresis profiles and by using real-time polymerase chain reaction. The liver histopathology and the alanine/aspartate aminotransferase ratio after LT were both ameliorated by CSA. In the CSA group, the numbers of rDNA gene copies of Clostridium cluster I, Clostridium cluster XIV, and Enterobacteriaceae decreased, whereas those of Faecalibacterium prausnitzii increased compared with the R group. Cluster analysis indicated that the samples from the N, I, and CSA groups were clustered, whereas the other clusters contained the samples from the R group. Hence, CSA ameliorates hepatic graft injury and partially restores gut microbiota following LT, and these may benefit hepatic graft rejection.

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Homoharringtonine is a safe and effective substitute for anthracyclines in children younger than 2 years old with acute myeloid leukemia
Xiaoxiao Chen, Yanjing Tang, Jing Chen, Ru Chen, Longjun Gu, Huiliang Xue, Ci Pan, Jingyan Tang, Shuhong Shen
Front. Med.    2019, 13 (3): 378-387.
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Homoharringtonine (HHT), a plant alkaloid from Cephalotaxus harringtonia, exhibits a unique anticancer mechanism and has been widely used in China to treat patients with acute myeloid leukemia (AML) since the 1970s. Trial SCMC-AML-2009 presented herein was a randomized clinical study designed based on our previous findings that pediatric AML patients younger than two years old may benefit from HHT-containing chemotherapy regimens. Patients randomized to arm A were treated with a standard chemotherapy regimen comprising mainly of anthracyclines and cytarabine (Ara-C), whereas patients in arm B were treated with HHT-containing regimens in which anthracyclines in all but the initial induction therapy were replaced by HHT. From February 2009 to November 2015, 59 patients less than 2 years old with de novo AML (other than acute promyelocytic leukemia) were recruited. A total of 42 patients achieved a morphologic complete remission (CR) after the first course, with similar rates in both arms (70.6% vs.72.0%). At the end of the follow-up period, 40 patients remained in CR and 5 patients underwent hematopoietic stem cell transplantation in CR, which could not be considered as events but censors. The 5-year event-free survival (EFS) was 60.2%±9.6% for arm A and 88.0%±6.5% for arm B (P=0.024). Patients in arm B experienced shorter durations of leukopenia, neutropenia, and thrombocytopenia and had a lower risk of infection during consolidation chemotherapy with high-dosage Ara-C. Consequently, the homoharringtonine-based regimen achieved excellent EFS and alleviated hematologic toxicity for children aged younger than 2 years with de novo AML compared with the anthracycline-based regimen.

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White blood cell count and the incidence of hyperuricemia: insights from a community-based study
Jian Liu, Pingyan Shen, Xiaobo Ma, Xialian Yu, Liyan Ni, Xu Hao, Weiming Wang, Nan Chen
Front. Med.    2019, 13 (6): 741-746.
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Hyperuricemia (HUA) is a risk factor for chronic kidney disease (CKD). The relationship between HUA and white blood cell (WBC) count remains unknown. A sampling survey for CKD was conducted in Sanlin community in 2012 and 2014. CKD was defined as proteinuria in at least the microalbuminuric stage or an estimated GFR of 60 mL/(min·1.73 m2). HUA was defined as serum uric acid>420 µmol/L in men and>360 µmol/L in women. This study included 1024 participants. The prevalence of HUA was 17.77%. Patients with HUA were more likely to have higher levels of WBC count, which was positively associated with HUA prevalence. This association was also observed in participants without CKD, diabetes mellitus, hyperlipidemia, or obesity. Multivariate logistic regression analysis showed that WBC count was independently associated with the risk for HUA in male and female participants. Compared with participants without HUA, inflammatory factors such as high-sensitivity C-reactive protein, tumor necrosis factor-α, and interleukin 6 increased in participants with HUA. Hence, WBC count is positively associated with HUA, and this association is independent of conventional risk factors for CKD.

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Compound C620-0696, a new potent inhibitor targeting BPTF, the chromatin-remodeling factor in non-small-cell lung cancer
Jiahui Xu, Qianqian Wang, Elaine Lai Han Leung, Ying Li, Xingxing Fan, Qibiao Wu, Xiaojun Yao, Liang Liu
Front. Med.    2020, 14 (1): 60-67.
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Bromodomain PHD-finger transcription factor (BPTF) is the largest subunit of the nucleosome remodeling factor and plays an important role in chromatin remodeling for gene activation through its association with histone acetylation or methylation. BPTF is also involved in oncogene transcription in diverse progressions of cancers. Despite clinical trials for inhibitors of bromodomain and extra-terminal family proteins in human cancers, no potent and selective inhibitor targeting the BPTF bromodomain has been discovered. In this study, we identified a potential inhibitor, namely, C620-0696, by computational docking modeling to target bromodomain. Results of biolayer interferometry revealed that compound C620-0696 exhibited high binding affinity to the BPTF bromodomain. Moreover, C620-0696 was cytotoxic in BPTF with a high expression of non-small-cell lung cancer (NSCLC) cells. It suppressed the expression of the BPTF target gene c-MYC, which is known as an oncogenic transcriptional regulator in various cancers. C620-0696 also partially inhibited the migration and colony formation of NSCLC cells owing to apoptosis induction and cell cycle blockage. Thus, our study presents an effective strategy to target a bromodomain factor-mediated tumorigenesis in cancers with small molecules, supporting further exploration of the use of these inhibitors in oncology.

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What will the future hold for artificial organs in the service of assisted reproduction: prospects and considerations
Mara Simopoulou, Konstantinos Sfakianoudis, Petroula Tsioulou, Anna Rapani, Polina Giannelou, Nikolaos Kiriakopoulos, Agni Pantou, Nikolaos Vlahos, George Anifandis, Stamatis Bolaris, Konstantinos Pantos, Michael Koutsilieris
Front. Med.    2019, 13 (6): 627-638.
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Assisted reproduction provides a wide spectrum of treatments and strategies addressing infertility. However, distinct groups of infertile patients with unexplained infertility, congenital disorders, and other complex cases pose a challenge in in vitro fertilization (IVF) practices. This special cohort of patients is associated with futile attempts, IVF overuse, and dead ends in management. Cutting edge research on animal models introduced this concept, along with the development of artificial organs with the aim to mimic the respective physiological functions in reproduction. Extrapolation on clinical application leads to the future use of infertility management in humans. To date, the successful clinical application of artificial reproductive organs in humans is not feasible because further animal model studies are required prior to clinical trials. The application of these artificial organs could provide a solution to infertility cases with no other options. This manuscript presents an overview on the current status, future prospects, and considerations on the potential clinical application of artificial ovary, uterus, and gametes in humans. This paper presents how the IVF practice landscape may be shaped and challenged in the future, along with the subsequent concerns in assisted reproductive treatments.

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Autoimmunity in acute ischemic stroke and the role of blood--brain barrier: the dark side or the light one?
Nikolay V. Tsygan, Alexandr P. Trashkov, Igor V. Litvinenko, Viktoriya A. Yakovleva, Alexandr V. Ryabtsev, Andrey G. Vasiliev, Leonid P. Churilov
Front. Med.    2019, 13 (4): 420-426.
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This article presents a synopsis of the current data on the mechanisms of blood--brain barrier (BBB) alteration and autoimmune response in acute ischemic stroke. Most researchers confirm the relationship between the severity of immunobiochemical changes and clinical outcome of acute ischemic stroke. Ischemic stroke is accompanied by aseptic inflammation, which alters the brain tissue and exposes the co-stimulatory molecules of the immune system and the neuronal antigens. To date, BBB is not considered the border between the immune system and central nervous system, and the local immune subsystems are found within and behind the BBB. BBB disruption contributes to the leakage of brain autoantigens and induction of secondary autoimmune response to neuronal antigens and long-term inflammation. Glymphatic system function is altered and jeopardized both in hemorrhagic and ischemic stroke types. The receptors of innate immunity (toll-like receptor-2 and toll-like receptor-4) are also involved in acute ischemia--reperfusion injury. Immune response is related to the key processes of blood clotting and fibrinolysis. At the same time, the stroke-induced immune activation may promote reparation phenomena in the brain. Subsequent research on the reduction of the acute ischemic brain injury through the target regulation of the immune response is promising.

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Minimal residual disease-directed immunotherapy for high-risk myelodysplastic syndrome after allogeneic hematopoietic stem cell transplantation
Xiaodong Mo, Xiaohui Zhang, Lanping Xu, Yu Wang, Chenhua Yan, Huan Chen, Yuhong Chen, Wei Han, Fengrong Wang, Jingzhi Wang, Kaiyan Liu, Xiaojun Huang
Front. Med.    2019, 13 (3): 354-364.
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The efficacy of minimal residual disease (MRD)-directed immunotherapy, including interferon-α (IFN-α) treatment and chemotherapy plus granulocyte colony-stimulating factor-primed donor leukocyte infusion (chemo-DLI), was investigated in patients with high-risk myelodysplastic syndrome (MDS) who were MRD-positive after allogeneic hematopoietic stem cell transplantation (allo-HSCT). High-risk MDS patients who received non-T-cell-depleted allo-HSCT at the Peking University Institute of Hematology and were MRD-positive after allo-HSCT were studied (n=47). The MRD-positive status was considered if leukemia-associated aberrant immune phenotypes or Wilms’ tumor gene 1 expression is present in a single bone marrow sample. The cumulative incidence of the relapse and non-relapse mortality 2 years after immunotherapy were 14.5% and 21.4% (P=0.377) and 9.1% and 0.0% (P=0.985) for patients in the IFN-α and chemo-DLI groups, respectively. The probability of disease-free and overall survival 2 years after immunotherapy were 76.4% and 78.6% (P=0.891) and 84.3% and 84.6% (P=0.972) for patients in the IFN-α and chemo-DLI groups, respectively. Persistent MRD after immunotherapy was associated with poor survival. Thus, the MRD-directed immunotherapy was effective for patients with high-risk MDS who were MRD-positive after allo-HSCT, and the efficacy was comparable between chemo-DLI and IFN-α treatment.

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A reignited debate over the cell(s) of origin for glioblastoma and its clinical implications
Xiaolin Fan, Yanzhen Xiong, Yuan Wang
Front. Med.    2019, 13 (5): 531-539.
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Glioblastoma (GBM) is the most common and lethal primary neoplasm in the central nervous system. Despite intensive treatment, the prognosis for patients with GBM remains poor, with a median survival of 14--16 months. 90% of GBMs are primary GBMs that are full-blown at diagnosis without evidences of a pre-existing less-malignant precursor lesion. Therefore, identification of the cell(s) of origin for GBM---the normal cell or cell type that acquires the initial GBM-promoting genetic hit(s)---is the key to the understanding of the disease etiology and the development of novel therapies. Neural stem cells and oligodendrocyte precursor cells are the two major candidates for the cell(s) of origin for GBM. Latest data from human samples have reignited the longstanding debate over which cells are the clinically more relevant origin for GBMs. By critically analyzing evidences for or against the candidacy of each cell type, we highlight the most recent progress and debate in the field, explore the clinical implications, and propose future directions toward early diagnosis and preventive treatment of GBMs.

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