Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

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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.   https://doi.org/10.1007/s11684-018-0667-3
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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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Combination of biomaterial transplantation and genetic enhancement of intrinsic growth capacities to promote CNS axon regeneration after spinal cord injury
Bin Yu, Xiaosong Gu
Front. Med.    2019, 13 (2): 131-137.   https://doi.org/10.1007/s11684-018-0642-z
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The inhibitory environment that surrounds the lesion site and the lack of intrinsic regenerative capacity of the adult mammalian central nervous system (CNS) impede the regrowth of injured axons and thereby the reestablishment of neural circuits required for functional recovery after spinal cord injuries (SCI). To circumvent these barriers, biomaterial scaffolds are applied to bridge the lesion gaps for the regrowing axons to follow, and, often by combining stem cell transplantation, to enable the local environment in the growth-supportive direction. Manipulations, such as the modulation of PTEN/mTOR pathways, can also enhance intrinsic CNS axon regrowth after injury. Given the complex pathophysiology of SCI, combining biomaterial scaffolds and genetic manipulation may provide synergistic effects and promote maximal axonal regrowth. Future directions will primarily focus on the translatability of these approaches and promote therapeutic avenues toward the functional rehabilitation of patients with SCIs.

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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.   https://doi.org/10.1007/s11684-018-0666-4
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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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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.   https://doi.org/10.1007/s11684-019-0695-7
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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.   https://doi.org/10.1007/s11684-018-0659-3
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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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PD-1/PD-L1 blockade in cervical cancer: current studies and perspectives
Yumeng Wang, Guiling Li
Front. Med.    2019, 13 (4): 438-450.   https://doi.org/10.1007/s11684-018-0674-4
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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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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.   https://doi.org/10.1007/s11684-018-0675-3
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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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Direct acting antiviral-induced dynamic reduction of serum α fetoprotein in hepatitis C patients without hepatocellular carcinoma
Tung Huynh, Ke-Qin Hu
Front. Med.    2019, 13 (6): 658-666.   https://doi.org/10.1007/s11684-019-0707-7
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Direct acting antiviral (DAA) treatments may reduce the elevated α fetoprotein (AFP), but data on how these treatments affect elevated AFP in patients with chronic hepatitis C (CHC) remain insufficient. In the present study, the frequency of baseline AFP elevations and their related factors, AFP dynamics during and after DAA treatment, and factors associated with AFP reduction was assessed. This retrospective study included 141 patients with CHC without hepatocellular carcinoma who received DAA and achieved sustained virological response. The details are as follows: mean post-treatment follow-up was 99 weeks (12–213); mean age, 57.8 years old; 52%, males; 79%, genotype (GT) 1; and 47%, cirrhosis. Pre-treatment AFP elevation (>5.5 ng/mL) was seen in 48.2% patients. On multivariate analysis, baseline AFP>5.5 was associated with the presence of cirrhosis (P=0.001), co-existing non-alcoholic steatohepatitis (NASH) (P = 0.035), and GT 1 (P = 0.029). AFP normalization was seen in 28.2% patients at treatment week 2, in 52% at the end of treatment, and in 73.4% at the end of follow-up. Post-treatment week 24 AFP normalization was associated with the absence of cirrhosis (P = 0.003), Child--Pugh score<6 (P = 0.015), and baseline AFP<10 (P = 0.015). AFP elevation is common in patients with CHC and independently associated with NASH, cirrhosis, and GT 1. DAA treatment resulted in AFP normalization as early as treatment week 2. Post-treatment week 24 AFP normalization is independently associated with the absence of cirrhosis, Child--Pugh score<6, and baseline AFP<10.

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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.   https://doi.org/10.1007/s11684-018-0658-4
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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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Antibiotics-mediated intestinal microbiome perturbation aggravates tacrolimus-induced glucose disorders in mice
Yuqiu Han, Xiangyang Jiang, Qi Ling, Li Wu, Pin Wu, Ruiqi Tang, Xiaowei Xu, Meifang Yang, Lijiang Zhang, Weiwei Zhu, Baohong Wang, Lanjuan Li
Front. Med.    2019, 13 (4): 471-481.   https://doi.org/10.1007/s11684-019-0686-8
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Both immunosuppressants and antibiotics (ABX) are indispensable for transplant patients. However, the former increases the risk of new-onset diabetes, whereas the latter impacts intestinal microbiota (IM). It is still unclear whether and how the interaction between immunosuppressants and ABX alters the IM and thus leads to glucose metabolism disorders. This study examined the alterations of glucose and lipid metabolism and IM in mice exposed to tacrolimus (TAC) with or without ABX. We found that ABX further aggravated TAC-induced glucose tolerance and increased insulin secretion. Combined treatment resulted in exacerbated lipid accumulation in the liver. TAC-altered microbial community was further amplified by ABX administration, as characterized by reductions in phylum Firmicutes, family Lachnospiraceae, and genus Coprococcus. Analyses based on the metagenomic profiles revealed that ABX augmented the effect of TAC on microbial metabolic function mostly related to lipid metabolism. The altered components of gut microbiome and predicted microbial functional profiles showed significant correlation with hepatic lipid accumulation and glucose disorders. In conclusion, ABX aggravated the effect of TAC on the microbiome and its metabolic capacities, which might contribute to hepatic lipid accumulation and glucose disorders. These findings suggest that the ABX-altered microbiome can amplify the diabetogenic effect of TAC and could be a novel therapeutic target for patients.

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Mesenchymal stem cells and immune disorders: from basic science to clinical transition
Shihua Wang, Rongjia Zhu, Hongling Li, Jing Li, Qin Han, Robert Chunhua Zhao
Front. Med.    2019, 13 (2): 138-151.   https://doi.org/10.1007/s11684-018-0627-y
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As a promising candidate seed cell type in regenerative medicine, mesenchymal stem cells (MSCs) have attracted considerable attention. The unique capacity of MSCs to exert a regulatory effect on immunity in an autologous/allergenic manner makes them an attractive therapeutic cell type for immune disorders. In this review, we discussed the current knowledge of and advances in MSCs, including its basic biological properties, i.e., multilineage differentiation, secretome, and immunomodulation. Specifically, on the basis of our previous work, we proposed three new concepts of MSCs, i.e., “subtotipotent stem cell” hypothesis, MSC system, and “Yin and Yang” balance of MSC regulation, which may bring new insights into our understanding of MSCs. Furthermore, we analyzed data from the Clinical Trials database (http://clinicaltrials.gov) on registered clinical trials using MSCs to treat a variety of immune diseases, such as graft-versus-host disease, systemic lupus erythematosus, and multiple sclerosis. In addition, we highlighted MSC clinical trials in China and discussed the challenges and future directions in the field of MSC clinical application.

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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.   https://doi.org/10.1007/s11684-019-0688-6
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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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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.   https://doi.org/10.1007/s11684-019-0693-9
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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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Positive stool culture could predict the clinical outcomes of haploidentical hematopoietic stem cell transplantation
Lijuan Hu, Qi Wang, Xiaohui Zhang, Lanping Xu, Yu Wang, Chenhua Yan, Huan Chen, Yuhong Chen, Kaiyan Liu, Hui Wang, Xiaojun Huang, Xiaodong Mo
Front. Med.    2019, 13 (4): 492-503.   https://doi.org/10.1007/s11684-019-0681-0
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We aimed to identify the effect of positive stool cultures (PSCs) on the clinical outcomes of patients undergoing haploidentical hematopoietic stem cell transplantation (haplo-HSCT) (n = 332). PSCs were observed in 61 patients (PSC group, 18.4%). Enterobacteriaceae in stool specimens was associated with a higher risk of bloodstream infection, and Candida in stool specimens was related to a higher risk of platelet engraftment failure. The cumulative incidence of infection-related mortality 1 year after haplo-HSCT in the PSC group was higher than that of the patients who showed persistently negative stool cultures (NSC group; 19.2% vs. 8.9%, P = 0.017). The probabilities of overall survival (71.4% vs. 83.8%, P = 0.031) and disease-free survival (69.6% vs. 81.0%, P = 0.048) 1 year after haplo-HSCT for the PSC group were significantly lower than those for the NSC group, particularly for patients who had Candida in their stool specimens. In multivariate analysis, Candida in stool specimens significantly increased the risk of mortality and was associated with poorer survival. Our results showed that PSC influenced the clinical outcomes after haplo-HSCT, particularly those who had Candida in their stool specimens.

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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.   https://doi.org/10.1007/s11684-018-0633-0
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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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Immunoregulatory effects of Tripterygium wilfordii Hook F and its extracts in clinical practice
Dan Luo, Zhengyun Zuo, Hongyan Zhao, Yong Tan, Cheng Xiao
Front. Med.    2019, 13 (5): 556-563.   https://doi.org/10.1007/s11684-018-0649-5
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Tripterygium wilfordii Hook F (TwHF) and its extracts have long been used for the treatment of rheumatoid arthritis, autoimmune diseases, and kidney disease due to their anti-inflammatory, immunoregulatory, and other pharmacological effects. However, the clinical immunoregulatory effects of TwHF and its extracts remain unclear, so we reviewed their effects for use in clinical practice. This review provides a comprehensive summary of the recent literature on the immunoregulatory effects of TwHF and its extracts in clinical studies. TwHF and its extracts affect the proliferation and activation of T and B cells; ratio of T cell subsets; inflammatory response of monocytes, macrophages, and immunoglobulins; and secretion of many cytokines. Together, these effects dictate immune function in a variety of diseases. TwHF and its extracts can be used alone or in combination with existing therapies against many immune disorders through immunomodulation.

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Targeted therapy of desmoid-type fibromatosis: mechanism, current situation, and future prospects
Zhen Wang, Jianhui Wu, Xiuyun Tian, Chunyi Hao
Front. Med.    2019, 13 (4): 427-437.   https://doi.org/10.1007/s11684-018-0672-6
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Desmoid-type fibromatosis (DF) is a rare monoclonal fibroblastic proliferation that is characterized by locally infiltrative but rarely metastatic lesions. Tyrosine kinase and γ-secretase inhibitors are primarily used in the targeted therapy of DF. The use of these drugs, however, is mainly based on the recommendations of retrospective studies with small sample sizes. Previous studies that focused on the mechanism, efficacy, and safety of targeted therapy for DF were reviewed to provide references for clinical applications and research. The efficacy and safety of targeted therapy were compared with those of other systemic therapy options. Targeted therapy does not provide considerable advantages in efficacy and safety over other medical treatments and is usually applied after the failure of antihormonal therapies, nonsteroidal anti-inflammatory drugs, and chemotherapy. Further studies are required to explore the mechanism, indications, and appropriate drug dosage of the targeted therapy of DF.

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Interferon-α salvage treatment is effective for patients with acute leukemia/myelodysplastic syndrome with unsatisfactory response to minimal residual disease-directed donor lymphocyte infusion 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 (2): 238-249.   https://doi.org/10.1007/s11684-017-0599-3
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The efficacy of salvage interferon-α (IFN-α) treatment was investigated in patients with unsatisfactory response to minimal residual disease (MRD)-directed donor lymphocyte infusion (DLI) (n=24). Patients who did not become MRD-negative at 1 month after DLI were those with unsatisfactory response and were eligible to receive salvage IFN-α treatment within 3 months of DLI. Recombinant human IFN-α-2b injections were subcutaneously administered 2–3 times a week for 6 months. Nine (37.5%), 6 (25.0%), and 3 (12.5%) patients became MRD-negative at 1, 2, and>2 months after the salvage IFN-α treatment, respectively. Two-year cumulative incidences of relapse and non-relapse mortality were 35.9% and 8.3%, respectively. Two-year probabilities of event-free survival, disease-free survival, and overall survival were 51.6%, 54.3%, and 68.0%, respectively. Outcomes of patients subjected to salvage IFN-α treatment after DLI were significantly better than those with persistent MRD without IFN-α treatment. Moreover, clinical outcomes were comparable between the salvage DLI and IFN-α treatment groups. Thus, salvage IFN-α treatment may help improve the outcome of patients with unsatisfactory responses to MRD-directed DLI and could be a potential salvage treatment for these patients after allogeneic hematopoietic stem cell transplantation.

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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.   https://doi.org/10.1007/s11684-019-0697-5
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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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Clinical characteristics in lymphangioleiomyomatosis-related pulmonary hypertension: an observation on 50 patients
Xiuxiu Wu, Wenshuai Xu, Jun Wang, Xinlun Tian, Zhuang Tian, Kaifeng Xu
Front. Med.    2019, 13 (2): 259-266.   https://doi.org/10.1007/s11684-018-0634-z
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Lymphangioleiomyomatosis (LAM) is a rare diffuse cystic lung disease. Knowledge on LAM-related pulmonary hypertension (PH) is limited. This study aimed to analyze the clinical characteristics of LAM with elevated pulmonary artery pressure (PAP) and evaluate the potential efficacy of sirolimus. The study involved 50 LAM patients who underwent echocardiography. According to the tricuspid regurgitation velocity (TRV), these patients were divided into the TRV≤2.8 m/s group and TRV>2.8 m/s group. Both groups comprised 25 females with an average age of 38.6±8.1 and 41.5±8.9 years. In the TRV>2.8 m/s group, the estimated systolic PAP (SPAP) was significantly elevated (52.08±12.45 mmHg vs. 30.24±5.25 mmHg, P<0.01). Linear analysis showed that SPAP was correlated with forced expiratory volume in 1 s (FEV1), diffusing capacity of the lungs for carbon monoxide, alveolar arterial oxygen gradient (PA-aO2), and 6 min walking distance (r = −0.392, −0.351, 0.450, and −0.591, respectively; P<0.05), in which PA-aO2 was a risk factor for SPAP elevation (β = 0.064, OR= 1.066, P<0.05). Moreover, in 10 patients who received sirolimus therapy, SPAP decreased from 57.0±12.6 mmHg to 35.2±11.1 mmHg. The study showed that LAM patients with PH exhibit poor pulmonary function and hypoxemia and may benefit from sirolimus treatment.

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Dental stem cell and dental tissue regeneration
Qiming Zhai, Zhiwei Dong, Wei Wang, Bei Li, Yan Jin
Front. Med.    2019, 13 (2): 152-159.   https://doi.org/10.1007/s11684-018-0628-x
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The teeth are highly differentiated chewing organs formed by the development of tooth germ tissue located in the jaw and consist of the enamel, dentin, cementum, pulp, and periodontal tissue. Moreover, the teeth have a complicated regulatory mechanism, special histologic origin, diverse structure, and important function in mastication,, articulation,, and aesthetics. These characteristics, to a certain extent, greatly complicate the research in tooth regeneration. Recently, new ideas for tooth and tissue regeneration have begun to appear with rapid developments in the theories and technologies in tissue engineering. Numerous types of stem cells have been isolated from dental tissue, such as dental pulp stem cells (DPSCs), stem cells isolated from human pulp of exfoliated deciduous teeth (SHED), periodontal ligament stem cells (PDLSCs), stem cells from apical papilla (SCAPs), and dental follicle cells (DFCs). All these cells can regenerate the tissue of tooth. This review outlines the cell types and strategies of stem cell therapy applied in tooth regeneration, in order to provide theoretical basis for clinical treatments.

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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.   https://doi.org/10.1007/s11684-018-0639-7
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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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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.   https://doi.org/10.1007/s11684-018-0624-1
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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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Mutation profiling of 16 candidate genes in de novo acute myeloid leukemia patients
Yang Zhang, Fang Wang, Xue Chen, Wenjing Liu, Jiancheng Fang, Mingyu Wang, Wen Teng, Panxiang Cao, Hongxing Liu
Front. Med.    2019, 13 (2): 229-237.   https://doi.org/10.1007/s11684-018-0616-1
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This retrospective analysis aimed to investigate the mutation profile of 16 common mutated genes in de novo acute myeloid leukemia (AML) patients. A total of 259 patients who were diagnosed of de novo AML were enrolled in this study. Mutation profiling of 16 candidate genes were performed in bone marrow samples by using Sanger sequencing. We identified at least 1 mutation in 199 of the 259 samples (76.8%), and 2 or more mutations in 31.7% of samples. FLT3-ITD was the most common mutated gene (16.2%, 42/259), followed by CEBPA (15.1%, 39/259), NRAS (14.7%, 38/259), and NPM1 (13.5%, 35/259). Concurrence was observed in 97.1% of the NPM1 mutated cases and in 29.6% of the double mutated CEBPA cases. Distinct patterns of co-occurrence were observed for different hotspot mutations within the IDH2 gene: R140 mutations were associated with NPM1 and/or FLT3-ITD mutations, whereas R172 mutations co-occurred with DNMT3A mutations only. Concurrence was also observed in 86.6% of epigenetic regulation genes, most of which co-occurred with NPM1 mutations. The results showed certain rules in the mutation profiling and concurrence of AML patients, which was related to the function classification of genes. Defining the mutation spectrum and mutation pattern of AML will contribute to the comprehensive assessment of patients and identification of new therapeutic targets.

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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.   https://doi.org/10.1007/s11684-018-0625-0
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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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The FGF metabolic axis
Xiaokun Li
Front. Med.    2019, 13 (5): 511-530.   https://doi.org/10.1007/s11684-019-0711-y
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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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Post-surgical resection prognostic value of combined OPN, MMP7, and PSG9 plasma biomarkers in hepatocellular carcinoma
Weiqi Rong, Yang Zhang, Lei Yang, Lin Feng, Baojun Wei, Fan Wu, Liming Wang, Yanning Gao, Shujun Cheng, Jianxiong Wu, Ting Xiao
Front. Med.    2019, 13 (2): 250-258.   https://doi.org/10.1007/s11684-018-0632-1
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Biomarkers for hepatocellular carcinoma (HCC) following curative resection are not currently sufficient for prognostic indication of overall survival (OS) and disease-free survival (DFS). The aim of this study was to investigate the prognostic performance of osteopontin (OPN), matrix metalloproteinase 7 (MMP7), and pregnancy specific glycoprotein 9 (PSG9) in patients with HCC. A total of 179 prospective patients with HCC provided plasma before hepatectomy. Plasma OPN, MMP7, and PSG9 levels were determined by enzyme-linked immunosorbent assay. Correlations between plasma levels, clinical parameters, and outcomes (OS and DFS) were overall analyzed. High OPN (≥149.97 ng/mL), MMP7 (≥2.28 ng/mL), and PSG9 (≥45.59 ng/mL) were prognostic indicators of reduced OS (P<0.001, P<0.001, and P=0.007, respectively). Plasma PSG9 protein level was an independent factor in predicting OS (P=0.008) and DFS (P=0.038). Plasma OPN+MMP7+PSG9 elevation in combination was a prognostic factor for OS (P<0.001). OPN was demonstrated to be a risk factor-associated OS in stage I patients with HCC and patients with low α-fetoprotein levels (<20 ng/mL). These findings suggested that OPN, MMP7, PSG9 and their combined panels may be useful for aiding in tumor recurrence and mortality risk prediction of patients with HCC, particularly in the early stage of HCC carcinogenesis.

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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.   https://doi.org/10.1007/s11684-017-0557-0
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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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Current advances for bone regeneration based on tissue engineering strategies
Rui Shi, Yuelong Huang, Chi Ma, Chengai Wu, Wei Tian
Front. Med.    2019, 13 (2): 160-188.   https://doi.org/10.1007/s11684-018-0629-9
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Bone tissue engineering (BTE) is a rapidly developing strategy for repairing critical-sized bone defects to address the unmet need for bone augmentation and skeletal repair. Effective therapies for bone regeneration primarily require the coordinated combination of innovative scaffolds, seed cells, and biological factors. However, current techniques in bone tissue engineering have not yet reached valid translation into clinical applications because of several limitations, such as weaker osteogenic differentiation, inadequate vascularization of scaffolds, and inefficient growth factor delivery. Therefore, further standardized protocols and innovative measures are required to overcome these shortcomings and facilitate the clinical application of these techniques to enhance bone regeneration. Given the deficiency of comprehensive studies in the development in BTE, our review systematically introduces the new types of biomimetic and bifunctional scaffolds. We describe the cell sources, biology of seed cells, growth factors, vascular development, and the interactions of relevant molecules. Furthermore, we discuss the challenges and perspectives that may propel the direction of future clinical delivery in bone regeneration.

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Cholera: an overview with reference to the Yemen epidemic
Ali A. Rabaan
Front. Med.    2019, 13 (2): 213-228.   https://doi.org/10.1007/s11684-018-0631-2
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Cholera is a secretory diarrhoeal disease caused by infection with Vibrio cholerae, primarily the V. cholerae O1 El Tor biotype. There are approximately 2.9 million cases in 69 endemic countries annually, resulting in 95 000 deaths. Cholera is associated with poor infrastructure and lack of access to sanitation and clean drinking water. The current cholera epidemic in Yemen, linked to spread of V. cholerae O1 (Ogawa serotype), is associated with the ongoing war. This has devastated infrastructure and health services. The World Health Organization had estimated that 172 286 suspected cases arose between 27th April and 19th June 2017, including 1170 deaths. While there are three oral cholera vaccines prequalified by the World Health Organization, there are issues surrounding vaccination campaigns in conflict situations, exacerbated by external factors such as a global vaccine shortage. Major movements of people complicates surveillance and administration of double doses of vaccines. Cholera therapy mainly depends on rehydration, with use of antibiotics in more severe infections. Concerns have arisen about the rise of antibiotic resistance in cholera, due to mobile genetic elements. In this review, we give an overview of cholera epidemiology, virulence, antibiotic resistance, therapy and vaccines, in the light of the ongoing epidemic in Yemen.

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