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Frontiers of Medicine

  • Cover Illustration

    2020, Vol.14  No.3

    Immunohistochemistry result for keratin 5 (marker of keratinocytes) in the skin of Ncstnflox/flox;K5-Cre mice on postnatal day 30. (Courtesy of Drs. Yaping Liu and Xue Zhang. See pages 305‒317 by Jun Yang et al. for more information.)

    Table of Contents

, Volume 14 Issue 3

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REVIEW
Prevention and treatment of pancreatic fistula after pancreatic body and tail resection: current status and future directions
Li Jiang, Deng Ning, Xiao-ping Chen
Front. Med.. 2020, 14 (3): 251-261.  https://doi.org/10.1007/s11684-019-0727-3
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Postoperative pancreatic fistula (POPF) is the most common and critical complication after pancreatic body and tail resection. How to effectively reduce the occurrence of pancreatic fistula and conduct timely treatment thereafter is an urgent clinical issue to be solved. Recent research standardized the definition of pancreatic fistula and stressed the correlation between POPF classification and patient prognosis. According to the literature, identification of the risk factors for pancreatic fistula contributed to lowering the rate of the complication. Appropriate management of the pancreatic stump and perioperative treatment are of great significance to reduce the rate of POPF in clinical practice. After the occurrence of POPF, the treatment of choice should be determined according to the classification of the pancreatic fistula. However, despite the progress and promising treatment approaches, POPF remains to be a clinical issue that warrants further studies in the future.

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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.. 2020, 14 (3): 262-272.  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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Medical oncology management of advanced hepatocellular carcinoma 2019: a reality check
Amy Lee, Fa-Chyi Lee
Front. Med.. 2020, 14 (3): 273-283.  https://doi.org/10.1007/s11684-019-0728-2
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In terms of global cancer-related deaths, hepatocellular carcinoma (HCC) has the fourth highest mortality rate. Up until 2017, treatment of advanced HCC was largely limited to sorafenib, an oral tyrosine kinase inhibitor, with little to no success in the development of alternative treatment options. However, in the past two years, there has been an unprecedented increase in both the number and type of treatment options available for HCC. As of 2019, the US FDA has approved four oral tyrosine kinase inhibitors, two immune checkpoint inhibitors, and one anti-angiogenesis antibody for the treatment of HCC. Even with this new variety, systemic treatment of advanced HCC remains largely unsatisfactory, and the median survival rate stands at approximately one year. The expected breakthrough of using immune checkpoint inhibitors in advanced HCC did not materialize in 2019. The use of immune checkpoint inhibitors in conjunction with oral tyrosine kinase inhibitors or anti-angiogenesis medications is the current clinical research trend, the results of which are eagerly anticipated. Despite limited progress in survival, HCC research is currently experiencing a period of growth and innovation, and there is hope for significant advances in the treatment of advanced HCC as the field continues to develop.

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RESEARCH ARTICLE
Temporal echocardiography findings in patients with fulminant myocarditis: beyond ejection fraction decline
Houjuan Zuo, Rui Li, Fei Ma, Jiangang Jiang, Kun Miao, Haojie Li, Eike Nagel, Marijana Tadic, Hong Wang, Dao Wen Wang
Front. Med.. 2020, 14 (3): 284-292.  https://doi.org/10.1007/s11684-019-0713-9
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The features of myocardial strains from speckle-tracking echocardiography (STE) have not been well defined in fulminant myocarditis (FM) patients. In this study, changes in the left ventricular ejection fraction (LVEF) and global and layer-specific myocardial strains over time were monitored. We aimed to determine the echocardiographic patterns of FM and ascertain their significance in FM treatment. Twenty patients who were clinically diagnosed with FM and received mechanical life support were prospectively enrolled. Conventional echocardiographic measurements were obtained, and serial strain echocardiography was performed from admission to hospital discharge until LVEF recovery (>50%). Global/regional peak systolic longitudinal strains (GLS/RLS) and layer-specific longitudinal strains were quantified, and their changes with time were monitored in 14 FM patients. All patients had severely impaired cardiac function. Steep improvement in LVEF and GLS were observed within 6 days. Layer-specific strain analysis showed that reduction at admission or recovery at discharge in the endocardium and epicardium strains were equal. In conclusion, FM patients who received mechanical circulatory supports exhibited steep improvement in ventricular function within 6 days. The patchy and diffused distribution pattern of reduced RLS and equally and severely impaired strain in the endocardium and epicardium are valuable features in the diagnosis of FM.

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Netrin-1 works with UNC5B to regulate angiogenesis in diabetic kidney disease
Xiaojing Jiao, Dong Zhang, Quan Hong, Lei Yan, Qiuxia Han, Fengmin Shao, Guangyan Cai, Xiangmei Chen, Hanyu Zhu
Front. Med.. 2020, 14 (3): 293-304.  https://doi.org/10.1007/s11684-019-0715-7
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Netrin-1, an axon guidance factor, and its receptor UNC5B play important roles in axonal development and angiogenesis. This study examined netrin-1 and UNC5B expression in kidneys with diabetic kidney disease (DKD) and investigated their roles in angiogenesis. Netrin-1 and UNC5B were upregulated in streptozotocin-induced DKD Wistar rats, and their expression was compared with that in healthy controls. However, exogenous netrin-1 in UNC5B-depleted human renal glomerular endothelial cells (HRGECs) inhibited cell migration and tubulogenesis. This effect was likely associated with SRC pathway deactivation. Netrin-1 treatment also eliminated the pro-angiogenic effects of exogenous VEGF-165 on UNC5B-silenced HRGECs. These results indicate that UNC5B antagonizes netrin-1 and that UNC5B upregulation contributes partly to enhancing angiogenesis in DKD. Therefore, introducing exogenous netrin-1 and depleting endogenous UNC5B are potential strategies for reducing the incidence of early angiogenesis and mitigating kidney injury in DKD.

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Keratin 5-Cre-driven deletion of Ncstn in an acne inversa-like mouse model leads to a markedly increased IL-36a and Sprr2 expression
Jun Yang, Lianqing Wang, Yingzhi Huang, Keqiang Liu, Chaoxia Lu, Nuo Si, Rongrong Wang, Yaping Liu, Xue Zhang
Front. Med.. 2020, 14 (3): 305-317.  https://doi.org/10.1007/s11684-019-0722-8
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Familial acne inversa (AI) is an autoinflammatory disorder that affects hair follicles and is caused by loss-of-function mutations in g-secretase component genes. We and other researchers showed that nicastrin (NCSTN) is the most frequently mutated gene in familial AI. In this study, we generated a keratin 5-Cre-driven epidermis-specific Ncstn conditional knockout mutant in mice. We determined that this mutant recapitulated the major phenotypes of AI, including hyperkeratosis of hair follicles and inflammation. In Ncstnflox/flox;K5-Cre mice, the IL-36a expression level markedly increased starting from postnatal day 0 (P0), and this increase occurred much earlier than those of TNF-α, IL-23A, IL-1b, and TLR4. RNA-Seq analysis indicated that Sprr2d, a member of the small proline-rich protein 2 family, in the skin tissues of the Ncstnflox/flox;K5-Cre mice was also upregulated on P0. Quantitative reverse-transcription polymerase chain reaction showed that other Sprr2 genes had a similar expression pattern. Our findings suggested that IL-36a might be a key inflammatory cytokine in the pathophysiology of AI and implicate malfunction of the skin barrier in the pathogenesis of AI.

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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.. 2020, 14 (3): 318-326.  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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Clinical characteristics and prognostic values of 1p32.3 deletion detected through fluorescence in situ hybridization in patients with newly diagnosed multiple myeloma: a single-center study in China
Huanping Wang, Haitao Meng, Jinghan Wang, Yinjun Lou, Yile Zhou, Peipei Lin, Fenglin Li, Lin Liu, Huan Xu, Min Yang, Jie Jin
Front. Med.. 2020, 14 (3): 327-334.  https://doi.org/10.1007/s11684-019-0712-x
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This study aimed to investigate the prevalence, clinical characteristics, and prognostic impact of 1p32.3 deletion in patients with newly diagnosed multiple myeloma (MM). A retrospective analysis was conducted on 411 patients with newly diagnosed MM; among which, 270 received bortezomib-based therapies, and 141 received thalidomide-based therapies. Fluorescence in situ hybridization (FISH) was performed to detect six cytogenetic abnormalities, namely, del(1p32.3), gain(1q21), del(17p13), del(13q14), t(4;14), and t(11;14). Results showed that 8.3% of patients with MM were detected with del(1p32.3) and had significantly more bone marrow plasma cells (P = 0.025), higher β2-microglobulin levels (P = 0.036), and higher lactate dehydrogenase levels (P = 0.042) than those without del(1p32.3). Univariate analysis showed that patients with del(1p32.3) under thalidomide-based therapies (median PFS 11.6 vs. 31.2 months, P = 0.002; median OS 16.8 vs. 45.9 months, P <0.001) were strongly associated with short progression-free survival (PFS) (P = 0.002) and overall survival (OS) (P <0.001). Multivariate analysis revealed that del(1p32.3) remained a powerful independent factor with worse PFS (P = 0.006) and OS (P = 0.016) for patients under thalidomide-based treatments. Patients with del(1p32.3) under bortezomib-based treatments tended to have short PFS and OS. In conclusion, del(1p32.3) is associated with short PFS and OS in patients with MM who received thalidomide- or bortezomib-based treatments.

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Chinmedomics facilitated quality-marker discovery of Sijunzi decoction to treat spleen qi deficiency syndrome
Qiqi Zhao, Xin Gao, Guangli Yan, Aihua Zhang, Hui Sun, Ying Han, Wenxiu Li, Liang Liu, Xijun Wang
Front. Med.. 2020, 14 (3): 335-356.  https://doi.org/10.1007/s11684-019-0705-9
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Sijunzi decoction (SJZD) is a Chinese classical formula to treat spleen qi deficiency syndrome (SQDS) and has been widely used for thousands of years. However, the quality control (QC) standards of SJZD are insufficient. Chinmedomics has been designed to discover and verify bioactive compounds of a variety of formula rapidly. In this study, we used Chinmedomics to evaluate the SJZD’s efficacy against SQDS to discover the potential quality-markers (q-markers) for QC. A total of 56 compounds in SJZD were characterized in vitro, and 23 compounds were discovered in vivo. A total of 58 biomarkers were related to SQDS, and SJZD can adjust a large proportion of marker metabolites to normal level and then regulate the metabolic profile to the health status. A total of 10 constituents were absorbed as effective ingredients that were associated with overall efficacy. We preliminarily determined malonyl-ginsenoside Rb2 and ginsenoside Ro as the q-markers of ginseng; dehydrotumulosic acid and dihydroxy lanostene-triene-21-acid as the q-markers of poria; glycyrrhizic acid, isoglabrolide, and glycyrrhetnic acid as the q-markers of licorice; and 2-atractylenolide as the q-marker of macrocephala. According to the discovery of the SJZD q-markers, we can establish the quality standard that is related to efficacy.

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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.. 2020, 14 (3): 357-367.  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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