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Evidence for lung repair and regeneration in humans: key stem cells and therapeutic functions of fibroblast growth factors
Xuran Chu, Chengshui Chen, Chaolei Chen, Jin-San Zhang, Saverio Bellusci, Xiaokun Li
Front. Med.    https://doi.org/10.1007/s11684-019-0717-5
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Regeneration carries the idea of regrowing partially or completely a missing organ. Repair, on the other hand, allows restoring the function of an existing but failing organ. The recognition that human lungs can both repair and regenerate is quite novel, the concept has not been widely used to treat patients. We present evidence that the human adult lung does repair and regenerate and introduce different ways to harness this power. Various types of lung stem cells are capable of proliferating and differentiating upon injury driving the repair/regeneration process. Injury models, primarily in mice, combined with lineage tracing studies, have allowed the identification of these important cells. Some of these cells, such as basal cells, broncho-alveolar stem cells, and alveolar type 2 cells, rely on fibroblast growth factor (FGF) signaling for their survival, proliferation and/or differentiation. While pre-clinical studies have shown the therapeutic benefits of FGFs, a recent clinical trial for acute respiratory distress syndrome (ARDS) using intravenous injection of FGF7 did not report the expected beneficial effects. We discuss the potential reasons for these negative results and propose the rationale for new approaches for future clinical trials, such as delivery of FGFs to the damaged lungs through efficient inhalation systems, which may be more promising than systemic exposure to FGFs. While this change in the administration route presents a challenge, the therapeutic promises displayed by FGFs are worth the effort.

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New spinal robotic technologies
Bowen Jiang, Tej D. Azad, Ethan Cottrill, Corinna C. Zygourakis, Alex M. Zhu, Neil Crawford, Nicholas Theodore
Front. Med.    https://doi.org/10.1007/s11684-019-0716-6
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Robotic systems in surgery have developed rapidly. Installations of the da Vinci Surgical System® (Intuitive Surgical, Sunnyvale, CA, USA), widely used in urological and gynecological procedures, have nearly doubled in the United States from 2010 to 2017. Robotics systems in spine surgery have been adopted more slowly; however, users are enthusiastic about their applications in this subspecialty. Spinal surgery often requires fine manipulation of vital structures that must be accessed via limited surgical corridors and can require repetitive tasks over lengthy periods of time — issues for which robotic assistance is well-positioned to complement human ability. To date, the United States Food and Drug Administration (FDA) has approved 7 robotic systems across 4 companies for use in spinal surgery. The available clinical data evaluating their efficacy have generally demonstrated these systems to be accurate and safe. A critical next step in the broader adoption of surgical robotics in spine surgery is the design and implementation of rigorous comparative studies to interrogate the utility of robotic assistance. Here we discuss current applications of robotics in spine surgery, review robotic systems FDA-approved for use in spine surgery, summarize randomized controlled trials involving robotics in spine surgery, and comment on prospects of robotic-assisted spine surgery.

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Direct acting antiviral-induced dynamic reduction of serum a fetoprotein in hepatitis C patients without hepatocellular carcinoma
Tung Huynh, Ke-Qin Hu
Front. Med.    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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Unidirectional and stage-dependent roles of Notch1 in Wnt-responsive Lgr5+ cells during mouse inner ear development
Hui Jiang, Shan Zeng, Wenli Ni, Yan Chen, Wenyan Li
Front. Med.    https://doi.org/10.1007/s11684-019-0703-y
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Wnt and Notch signaling play crucial roles in the determination of the prosensory domain and in the differentiation of hair cells (HCs) and supporting cells during mouse inner ear development; however, the relationship between the two signaling pathways in the mouse cochlea remains largely unknown. Here, we investigated the interactions between Notch and Wnt signaling on the basis of the bidirectional regulation of Notch1 specifically in Wnt-responsive Lgr5+ progenitors during different cochlear development stages. We found that the downregulation of Notch1 in Lgr5+ cells from embryonic day (E) 14.5 to E18.5 can drive the quiescent Lgr5+ cells to re-enter the cell cycle and differentiate into extra HCs, whereas the upregulation of Notch1 expression did not affect the proliferation or differentiation of otic progenitor cells. No effect was observed on the upregulation or downregulation of Notch1 in Lgr5+ cells from E10.5 to E14.5. We concluded that the roles of Notch1 in Wnt-responsive Lgr5+ cells are unidirectional and stage dependent and Notch1 serves as a negative regulator for Lgr5+ progenitor activation during cochlear differentiation. Our findings improved the understanding of the interactions between Notch and Wnt signaling in cochlear development.

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Identification of an E3 ligase-encoding gene RFWD3 in non-small cell lung cancer
Yanfei Zhang, Xinchun Zhao, Yongchun Zhou, Min Wang, Guangbiao Zhou
Front. Med.    https://doi.org/10.1007/s11684-019-0708-6
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In order to unveil ubiquitin pathway genes (UPGs) that are essential for non-small cell lung cancer (NSCLC) cell proliferation, we recently conducted a siRNA screening experiment to knockdown the expression of 696 UPGs found in the human genome in A549 and H1975 NSCLC cells. We found that silencing of one of the candidates, RFWD3 that encodes an E3 ubiquitin ligase essential for the repair of DNA interstrand cross-links in response to DNA damage, led to dramatic inhibition of NSCLC cell proliferation with significant Z-scores. Knockdown of RFWD3 suppressed colony forming activity of NSCLC cells. We further evaluated the significance of RFWD3 in NSCLCs and found that this gene was more elevated in tumor samples than in paired normal lung tissues and was inversely associated with the clinical outcome of patients with NSCLC. Moreover, RFWD3 expression was significantly higher in smokers than in non-smokers. These results show for the first time that RFWD3 is required for NSCLC cell proliferation and may have an important role in lung carcinogenesis.

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Risk factors for chronic graft-versus-host disease after anti-thymocyte globulin-based haploidentical hematopoietic stem cell transplantation in acute myeloid leukemia
Meng Lv, Xiaohui Zhang, Lanping Xu, Yu Wang, Chenhua Yan, Huan Chen, Yuhong Chen, Wei Han, Fengrong Wang, Jingzhi Wang, Kaiyan Liu, Xiaojun Huang, Xiaodong Mo
Front. Med.    https://doi.org/10.1007/s11684-019-0702-z
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Chronic graft-versus-host disease (cGVHD) is a major complication following unmanipulated haploidentical hematopoietic stem cell transplantation (haplo-HSCT). We aimed to identify the risk factors for cGVHD in patients who underwent anti-thymocyte globulin-based haplo-HSCT for acute myeloid leukemia (n=280). The diagnosis of cGVHD was in accordance with the National Institutes of Health consensus criteria. A total of 169 patients suffered from cGVHD. The patients who had 3 loci mismatched had a higher 8-year incidence of cGVHD (total, 66.0% vs. 53.7%, P=0.031; moderate to severe, 42.4% vs. 30.1%, P=0.036) than the patients who had 1 to 2 loci mismatched. The patients who had maternal donors had a higher 8-year incidence of moderate to severe cGVHD (49.2% vs. 32.9%, P=0.024) compared with the patients who had other donors. The patients who had grades III to IV acute GVHD (aGVHD) had higher 8-year incidence of cGVHD (total, 88.0% vs. 50.4%, P<0.001; moderate to severe, 68.0% vs. 27.0%, P<0.001) compared with the patients without aGVHD. In multivariate analysis, grades III to IV aGVHD was the only independent risk factor for cGVHD. Thus, further interventions should be considered in patients with severe aGVHD to prevent cGVHD.

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Symptom network topological features predict the effectiveness of herbal treatment for pediatric cough
Mengxue Huang, Jingjing Wang, Runshun Zhang, Zhuying Ni, Xiaoying Liu, Wenwen Liu, Weilian Kong, Yao Chen, Tiantian Huang, Guihua Li, Dan Wei, Jianzhong Liu, Xuezhong Zhou
Front. Med.    https://doi.org/10.1007/s11684-019-0699-3
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Pediatric cough is a heterogeneous condition in terms of symptoms and the underlying disease mechanisms. Symptom phenotypes hold complicated interactions between each other to form an intricate network structure. This study aims to investigate whether the network structure of pediatric cough symptoms is associated with the prognosis and outcome of patients. A total of 384 cases were derived from the electronic medical records of a highly experienced traditional Chinese medicine (TCM) physician. The data were divided into two groups according to the therapeutic effect, namely, an invalid group (group A with 40 cases of poor efficacy) and a valid group (group B with 344 cases of good efficacy). Several well-established analysis methods, namely, statistical test, correlation analysis, and complex network analysis, were used to analyze the data. This study reports that symptom networks of patients with pediatric cough are related to the effectiveness of treatment: a dense network of symptoms is associated with great difficulty in treatment. Interventions with the most different symptoms in the symptom network may have improved therapeutic effects.

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Potential functions of esophageal cancer-related gene-4 in the cardiovascular system
Rui Zhou, Yuanshu Liu, Wenjun Huang, Xitong Dang
Front. Med.    https://doi.org/10.1007/s11684-019-0701-0
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Esophageal cancer-related gene-4 (Ecrg4) is cloned from the normal epithelium of the esophagus. It is constitutively expressed in quiescent epithelial cells and downregulated during tumorigenesis, and Ecrg4 expression levels are inversely correlated with the malignant phenotype of tumor cells, validating that Ecrg4 is a real tumor suppressor gene. Unlike other tumor suppressor genes that usually encode membrane or intracellular proteins, Ecrg4 encodes a 148-amino acid pre-pro-peptide that is tethered on the cell surface in epithelial cells, specialized epithelial cells, and human leukocytes, where it can be processed tissue dependently into several small peptides upon cell activation. Ecrg4 is expressed in a wide variety of other cells/tissues, including cardiomyocytes and conduction system of the heart,, the glomus cells of the carotid body, adrenal glands, choroid plexus, and leukocytes among others, where it exerts distinct functions, such as promoting/suppressing inflammation, inducing neuron senescence, stimulating the hypothalamus–pituitary–adrenal axis, maintaining the stemness of stem cells, participating in the rhythm and rate control of the heart, and possibly gauging the responsiveness of the cardiovascular system (CVS) to hypoxia, in addition to tumor suppression. Here, we briefly review the latest discoveries on Ecrg4 and its underlying molecular mechanisms as a tumor suppressor and focus on the emerging roles of Ecrg4 in the CVS.

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Acetylated HOXB9 at lysine 27 is of differential diagnostic value in patients with pancreatic ductal adenocarcinoma
Xiaoran Sun, Jiagui Song, Jing Zhang, Jun Zhan, Weigang Fang, Hongquan Zhang
Front. Med.    https://doi.org/10.1007/s11684-019-0696-6
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Pancreatic ductal adenocarcinoma (PDAC) is the ninth most common human malignancy and the sixth leading cause of cancer-related death in China. AcK27-HOXB9 is a newly identified HOXB9 post-transcriptional modification that can predict the outcome in lung adenocarcinoma and colon cancer well. However, the role of AcK27-HOXB9 in PDAC is unclear. The present study aims to investigate the differential diagnostic role of patients with AcK27-HOXB9 PDAC. Tissue microarrays consisting of 162 pancreatic tumor tissue samples from patients with PDAC and paired normal subjects were used to examine HOXB9 and AcK27-HOXB9 levels and localizations by immunohistochemical analysis and Western blot assay, respectively. HOXB9 was upregulated (P<0.0001), and AcK27-HOXB9 (P=0.0023) was downregulated in patients with PDAC. HOXB9 promoted (P=0.0115), while AcK27-HOXB9 (P=0.0279) inhibited PDAC progression. AcK27-HOXB9 predicted favorable outcome in patients with PDAC (P=0.0412). AcK27-HOXB9 also suppressed PDAC cell migration in a cell migration assay. The results of this study showed that HOXB9 promoted and AcK27-HOXB9 suppressed PDAC progression. The determination of ratio between HOXB9 and AcK27-HOXB9 exhibited potential diagnostic value in patients with PDAC.

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Detecting genetic hypermutability of gastrointestinal tumor by using a forensic STR kit
Anqi Chen, Suhua Zhang, Jixi Li, Chaoneng Ji, Jinzhong Chen, Chengtao Li
Front. Med.    https://doi.org/10.1007/s11684-019-0698-4
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Growing evidence suggests that somatic hypermutational status and programmed cell death-1 overexpression are potential predictive biomarkers indicating treatment benefits from immunotherapy using immune checkpoint inhibitors. However, biomarker-matched trials are still limited, and many of the genomic alterations remain difficult to target. To isolate the potential somatic hypermutational tumor from microsatellite instability low/microsatellite stability (MSI-L/MSS) cases, we employed two commercial kits to determine MSI and forensic short tandem repeat (STR) alternations in 250 gastrointestinal (GI) tumors. Three types of forensic STR alternations, namely, allelic loss, Aadd, and Anew, were identified. 62.4% (156/250) of the patients with GI exhibited STR alternation, including 100% (15/15) and 60% (141/235) of the microsatellite high instability and MSI-L/MSS cases, respectively. 30% (75/250) of the patients exhibited STR instability with more than 26.32% (26.32%–84.21%) STR alternation. The cutoff with 26.32% of the STR alternations covered all 15 MSI cases and suggested that it might be a potential threshold. Given the similar mechanism of the mutations of MSI and forensic STR, the widely used forensic identifier STR kit might provide potential usage for identifying hypermutational status in GI cancers.

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