Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

2018 Impact Factor: 1.847

Cover Story   2021, Volume 15 Issue 2
Scanning electron microscopy micrographs of typical bent head malformation of sperm in Dcaf8 knockout mice. (Courtesy of Dr. Ruibao Ren. See pages 302-312 by Xiuli Zhang et al. for more information.)
   Online First

Administered by

, Volume 15 Issue 2

For Selected: View Abstracts Toggle Thumbnails
REVIEW
Adjuvant treatment strategy after curative resection for hepatocellular carcinoma
Wei Zhang, Bixiang Zhang, Xiao-ping Chen
Front. Med.. 2021, 15 (2): 155-169.  
https://doi.org/10.1007/s11684-021-0848-3

Abstract   HTML   PDF (226KB)

Hepatic resection represents the first-line treatment for patients with resectable hepatocellular carcinoma (HCC). However, the 5-year recurrence rates of HCC after surgery have been reported to range from 50% to 70%. In this review, we evaluated the available evidence for the efficiency of adjuvant treatments to prevent HCC recurrence after curative liver resection. Antiviral therapy has potential advantages in terms of reducing the recurrence rate and improving the overall survival (OS) and/or disease-free survival of patients with hepatitis-related HCC. Postoperative adjuvant transarterial chemoembolization can significantly reduce the intrahepatic recurrence rate and improve OS, especially for patients with a high risk of recurrence. The efficacy of molecular targeted drugs as an adjuvant therapy deserves further study. Adjuvant adoptive immunotherapy can significantly improve the clinical prognosis in the early stage. Randomized controlled trial (RCT) studies evaluating adjuvant immune checkpoint inhibitors are ongoing, and the results are highly expected. Adjuvant hepatic artery infusion chemotherapy might be beneficial in patients with vascular invasion. Huaier granule, a traditional Chinese medicine, has been proved to be effective in prolonging the recurrence-free survival and reducing extrahepatic recurrence. The efficiency of other adjuvant treatments needs to be further confirmed by large RCT studies.

Figures and Tables | References | Related Articles | Metrics
Immune response triggered by the ablation of hepatocellular carcinoma with nanosecond pulsed electric field
Jianpeng Liu, Xinhua Chen, Shusen Zheng
Front. Med.. 2021, 15 (2): 170-177.  
https://doi.org/10.1007/s11684-020-0747-z

Abstract   HTML   PDF (309KB)

Nanosecond pulsed electric field (nsPEF) is a novel, nonthermal, and minimally invasive modality that can ablate solid tumors by inducing apoptosis. Recent animal experiments show that nsPEF can induce the immunogenic cell death of hepatocellular carcinoma (HCC) and stimulate the host’s immune response to kill residual tumor cells and decrease distant metastatic tumors. nsPEF-induced immunity is of great clinical importance because the nonthermal ablation may enhance the immune memory, which can prevent HCC recurrence and metastasis. This review summarized the most advanced research on the effect of nsPEF. The possible mechanisms of how locoregional nsPEF ablation enhances the systemic anticancer immune responses were illustrated. nsPEF stimulates the host immune system to boost stimulation and prevail suppression. Also, nsPEF increases the dendritic cell loading and inhibits the regulatory responses, thereby improving immune stimulation and limiting immunosuppression in HCC-bearing hosts. Therefore, nsPEF has excellent potential for HCC treatment.

Figures and Tables | References | Related Articles | Metrics
Metabolism and immunity in breast cancer
Deyu Zhang, Xiaojie Xu, Qinong Ye
Front. Med.. 2021, 15 (2): 178-207.  
https://doi.org/10.1007/s11684-020-0793-6

Abstract   HTML   PDF (1533KB)

Breast cancer is one of the most common malignancies that seriously threaten women’s health. In the process of the malignant transformation of breast cancer, metabolic reprogramming and immune evasion represent the two main fascinating characteristics of cancer and facilitate cancer cell proliferation. Breast cancer cells generate energy through increased glucose metabolism. Lipid metabolism contributes to biological signal pathways and forms cell membranes except energy generation. Amino acids act as basic protein units and metabolic regulators in supporting cell growth. For tumor-associated immunity, poor immunogenicity and heightened immunosuppression cause breast cancer cells to evade the host’s immune system. For the past few years, the complex mechanisms of metabolic reprogramming and immune evasion are deeply investigated, and the genes involved in these processes are used as clinical therapeutic targets for breast cancer. Here, we review the recent findings related to abnormal metabolism and immune characteristics, regulatory mechanisms, their links, and relevant therapeutic strategies.

Figures and Tables | References | Related Articles | Metrics
Overcoming resistance to endocrine therapy in hormone receptor-positive human epidermal growth factor receptor 2-negative (HR+/HER2--) advanced breast cancer: a meta-analysis and systemic review of randomized clinical trials
Wenjie Zhu, Binghe Xu
Front. Med.. 2021, 15 (2): 208-220.  
https://doi.org/10.1007/s11684-020-0795-4

Abstract   HTML   PDF (1149KB)

New targeted therapies have been developed to overcome resistance to endocrine therapy (ET) and improve the outcome of HR+/HER2-- advanced breast cancer (ABC). We conducted a meta-analysis and systemic review on randomized controlled trials evaluating various targeted therapies in combination with ET in HR+/HER2-- ABC. PUBMED and EMBASE databases were searched for eligible trials. Hazard ratios (HRs) for progression-free survival (PFS), odds ratios (ORs) for objective response rate (ORR), clinical benefit rate (CBR), and toxicity were meta-analyzed. Twenty-six studies with data on 10 347 patients were included and pooled. The addition of cyclin-dependent kinase 4/6 inhibitors to ET significantly improved median PFS (pooled HR= 0.547, P<0.001), overall survival (pooled HR= 0.755, P<0.001), and tumor response rates (ORR, pooled OR= 1.478, P<0.001; CBR, pooled OR= 1.201, P<0.001) with manageable toxicities (pooled OR= 3.280, P<0.001). The mammalian targets of rapamycin inhibitors and exemestane were not clinically beneficial for this pooled population including ET-naïve and ET-resistant patients. Moderate improvement in PFS (pooled HR= 0.686, P<0.001) yet pronounced toxicities (pooled OR=2.154, P<0.001) were noted in the combination of phosphatidylinositol-4,5-bisphosphate 3-kinase inhibitors with fulvestrant. Future studies are warranted to optimize the population and the dosing sequence of these available options.

Figures and Tables | References | Supplementary Material | Related Articles | Metrics
mTOR-targeted cancer therapy: great target but disappointing clinical outcomes, why?
Shi-Yong Sun
Front. Med.. 2021, 15 (2): 221-231.  
https://doi.org/10.1007/s11684-020-0812-7

Abstract   HTML   PDF (984KB)

The mammalian target of rapamycin (mTOR) critically regulates several essential biological functions, such as cell growth, metabolism, survival, and immune response by forming two important complexes, namely, mTOR complex 1 (mTORC1) and complex 2 (mTORC2). mTOR signaling is often dysregulated in cancers and has been considered an attractive cancer therapeutic target. Great efforts have been made to develop efficacious mTOR inhibitors, particularly mTOR kinase inhibitors, which suppress mTORC1 and mTORC2; however, major success has not been achieved. With the strong scientific rationale, the intriguing question is why cancers are insensitive or not responsive to mTOR-targeted cancer therapy in clinics. Beyond early findings on induced activation of PI3K/Akt, MEK/ERK, and Mnk/eIF4E survival signaling pathways that compromise the efficacy of rapalog-based cancer therapy, recent findings on the essential role of GSK3 in mediating cancer cell response to mTOR inhibitors and mTORC1 inhibition-induced upregulation of PD-L1 in cancer cells may provide some explanations. These new findings may also offer us the opportunity to rationally utilize mTOR inhibitors in cancer therapy. Further elucidation of the biology of complicated mTOR networks may bring us the hope to develop effective therapeutic strategies with mTOR inhibitors against cancer.

Figures and Tables | References | Related Articles | Metrics
Recent advances in myeloid-derived suppressor cell biology
Mahmoud Mohammad Yaseen, Nizar Mohammad Abuharfeil, Homa Darmani, Ammar Daoud
Front. Med.. 2021, 15 (2): 232-251.  
https://doi.org/10.1007/s11684-020-0797-2

Abstract   HTML   PDF (2899KB)

In recent years, studying the role of myeloid-derived suppressor cells (MDSCs) in many pathological inflammatory conditions has become a very active research area. Although the role of MDSCs in cancer is relatively well established, their role in non-cancerous pathological conditions remains in its infancy resulting in much confusion. Our objectives in this review are to address some recent advances in MDSC research in order to minimize such confusion and to provide an insight into their function in the context of other diseases. The following topics will be specifically focused upon: (1) definition and characterization of MDSCs; (2) whether all MDSC populations consist of immature cells; (3) technical issues in MDSC isolation, estimation and characterization; (4) the origin of MDSCs and their anatomical distribution in health and disease; (5) mediators of MDSC expansion and accumulation; (6) factors that determine the expansion of one MDSC population over the other; (7) the Yin and Yang roles of MDSCs. Moreover, the functions of MDSCs will be addressed throughout the text.

Figures and Tables | References | Related Articles | Metrics
RESEARCH ARTICLE
Degradation of SARS-CoV-2 receptor ACE2 by the E3 ubiquitin ligase Skp2 in lung epithelial cells
Guizhen Wang, Qun Zhao, Hui Zhang, Fan Liang, Chen Zhang, Jun Wang, Zhenyin Chen, Ran Wu, Hong Yu, Beibei Sun, Hua Guo, Ruie Feng, Kaifeng Xu, Guangbiao Zhou
Front. Med.. 2021, 15 (2): 252-263.  
https://doi.org/10.1007/s11684-021-0837-6

Abstract   HTML   PDF (4402KB)

An unexpected observation among the COVID-19 pandemic is that smokers constituted only 1.4%−18.5% of hospitalized adults, calling for an urgent investigation to determine the role of smoking in SARS-CoV-2 infection. Here, we show that cigarette smoke extract (CSE) and carcinogen benzo(a)pyrene (BaP) increase ACE2 mRNA but trigger ACE2 protein catabolism. BaP induces an aryl hydrocarbon receptor (AhR)-dependent upregulation of the ubiquitin E3 ligase Skp2 for ACE2 ubiquitination. ACE2 in lung tissues of non-smokers is higher than in smokers, consistent with the findings that tobacco carcinogens downregulate ACE2 in mice. Tobacco carcinogens inhibit SARS-CoV-2 spike protein pseudovirions infection of the cells. Given that tobacco smoke accounts for 8 million deaths including 2.1 million cancer deaths annually and Skp2 is an oncoprotein, tobacco use should not be recommended and cessation plan should be prepared for smokers in COVID-19 pandemic.

Figures and Tables | References | Supplementary Material | Related Articles | Metrics
Clinical characteristics and risk factors for mortality in cancer patients with COVID-19
Junnan Liang, Guannan Jin, Tongtong Liu, Jingyuan Wen, Ganxun Li, Lin Chen, Wei Wang, Yuwei Wang, Wei Liao, Jia Song, Zeyang Ding, Xiao-ping Chen, Bixiang Zhang
Front. Med.. 2021, 15 (2): 264-274.  
https://doi.org/10.1007/s11684-021-0845-6

Abstract   HTML   PDF (523KB)

Patients with cancer are at increased risk of severe infections. From a cohort including 3060 patients with confirmed COVID-19, 109 (3.4%) cancer patients were included in this study. Among them, 23 (21.1%) patients died in the hospital. Cancer patients, especially those with hematological malignancies (41.6%), urinary carcinoma (35.7%), malignancies of the digestive system (33.3%), gynecological malignancies (20%), and lung cancer (14.3%), had a much higher mortality than patients without cancer. A total of 19 (17.4%) cancer patients were infected in the hospital. The clinical characteristics of deceased cancer patients were compared with those of recovered cancer patients. Multivariate Cox regression analysis indicated that a Nutritional Risk Screening (NRS2002) score≥3 (adjusted hazard ratio (HR) 11.00; 95% confidence interval (CI) 4.60–26.32; P <0.001), high-risk type (adjusted HR 18.81; 95% CI 4.21–83.93; P <0.001), tumor stage IV (adjusted HR 4.26; 95% CI 2.34–7.75; P <0.001), and recent adjuvant therapy (<1 month) (adjusted HR 3.16; 95% CI 1.75–5.70; P <0.01) were independent risk factors for in-hospital death after adjusting for age, comorbidities, D-dimer, and lymphocyte count. In conclusion, cancer patients showed a higher risk of COVID-19 infection with a poorer prognosis than patients without cancer. Cancer patients with high-risk tumor, NRS2002 score≥3, advanced tumor stage, and recent adjuvant therapy (<1 month) may have high risk of mortality.

Figures and Tables | References | Supplementary Material | Related Articles | Metrics
Comprehensive functional annotation of susceptibility variants identifies genetic heterogeneity between lung adenocarcinoma and squamous cell carcinoma
Na Qin, Yuancheng Li, Cheng Wang, Meng Zhu, Juncheng Dai, Tongtong Hong, Demetrius Albanes, Stephen Lam, Adonina Tardon, Chu Chen, Gary Goodman, Stig E. Bojesen, Maria Teresa Landi, Mattias Johansson, Angela Risch, H-Erich Wichmann, Heike Bickeboller, Gadi Rennert, Susanne Arnold, Paul Brennan, John K. Field, Sanjay Shete, Loic Le Marchand, Olle Melander, Hans Brunnstrom, Geoffrey Liu, Rayjean J. Hung, Angeline Andrew, Lambertus A. Kiemeney, Shan Zienolddiny, Kjell Grankvist, Mikael Johansson, Neil Caporaso, Penella Woll, Philip Lazarus, Matthew B. Schabath, Melinda C. Aldrich, Victoria L. Stevens, Guangfu Jin, David C. Christiani, Zhibin Hu, Christopher I. Amos, Hongxia Ma, Hongbing Shen
Front. Med.. 2021, 15 (2): 275-291.  
https://doi.org/10.1007/s11684-020-0779-4

Abstract   HTML   PDF (1761KB)

Although genome-wide association studies have identified more than eighty genetic variants associated with non-small cell lung cancer (NSCLC) risk, biological mechanisms of these variants remain largely unknown. By integrating a large-scale genotype data of 15 581 lung adenocarcinoma (AD) cases, 8350 squamous cell carcinoma (SqCC) cases, and 27 355 controls, as well as multiple transcriptome and epigenomic databases, we conducted histology-specific meta-analyses and functional annotations of both reported and novel susceptibility variants. We identified 3064 credible risk variants for NSCLC, which were overrepresented in enhancer-like and promoter-like histone modification peaks as well as DNase I hypersensitive sites. Transcription factor enrichment analysis revealed that USF1 was AD-specific while CREB1 was SqCC-specific. Functional annotation and gene-based analysis implicated 894 target genes, including 274 specifics for AD and 123 for SqCC, which were overrepresented in somatic driver genes (ER=1.95, P=0.005). Pathway enrichment analysis and Gene-Set Enrichment Analysis revealed that AD genes were primarily involved in immune-related pathways, while SqCC genes were homologous recombination deficiency related. Our results illustrate the molecular basis of both well-studied and new susceptibility loci of NSCLC, providing not only novel insights into the genetic heterogeneity between AD and SqCC but also a set of plausible gene targets for post-GWAS functional experiments.

Figures and Tables | References | Supplementary Material | Related Articles | Metrics
Bioactive hyaluronic acid fragments inhibit lipopolysaccharide- induced inflammatory responses via the Toll-like receptor 4 signaling pathway
Na You, Sasa Chu, Binggang Cai, Youfang Gao, Mizhou Hui, Jin Zhu, Maorong Wang
Front. Med.. 2021, 15 (2): 292-301.  
https://doi.org/10.1007/s11684-020-0806-5

Abstract   HTML   PDF (883KB)

The high- and the low-molecular weight hyaluronic acids (HMW-HA and LMW-HA, respectively) showed different biological activities in inflammation. However, the role of LMW-HA in inflammatory response is controversial. In this study, we aimed to investigate the effect of bioactive hyaluronan (B-HA) on lipopolysaccharide (LPS)-induced inflammatory responses in human macrophages and mice. B-HA was produced from HA treated with glycosylated recombinant human hyaluronidase PH20. Human THP-1 cells were induced to differentiate into macrophages. THP-1-derived macrophages were treated with B-HA, LPS, or B-HA+LPS. The mRNA expression and the production of inflammatory cytokines were determined using quantitative real-time PCR and enzyme-linked immunosorbent assay. The phosphorylation levels of proteins in the nuclear factor-kB (NF-kB), mitogen-activated protein kinase (MAPK), and IRF-3 signaling pathways were measured using Western blot. The in vivo efficacy of B-HA was assessed in a mouse model of LPS-induced inflammation. Results showed that B-HA inhibited the expression of TNF-α, IL-6, IL-1, and IFN-β, and enhanced the expression of the anti-inflammatory cytokine IL-10 in LPS-induced inflammatory responses in THP-1-derived macrophages and in vivo. B-HA significantly suppressed the phosphorylation of the TLR4 signaling pathway proteins p65, IKKα/β, IkBα, JNK1/2, ERK1/2, p38, and IRF-3. In conclusion, our results demonstrated that the B-HA attenuated the LPS-stimulated inflammatory response by inhibiting the activation of the TLR4 signaling pathway. B-HA could be a potential anti-inflammatory drug in the treatment of inflammatory disease.

Figures and Tables | References | Related Articles | Metrics
DDB1- and CUL4-associated factor 8 plays a critical role in spermatogenesis
Xiuli Zhang, Zhizhou Xia, Xingyu Lv, Donghe Li, Mingzhu Liu, Ruihong Zhang, Tong Ji, Ping Liu, Ruibao Ren
Front. Med.. 2021, 15 (2): 302-312.  
https://doi.org/10.1007/s11684-021-0851-8

Abstract   HTML   PDF (1778KB)

Cullin-RING E3 ubiquitin ligase (CRL)-4 is a member of the large CRL family in eukaryotes. It plays important roles in a wide range of cellular processes, organismal development, and physiological and pathological conditions. DDB1- and CUL4-associated factor 8 (DCAF8) is a WD40 repeat-containing protein, which serves as a substrate receptor for CRL4. The physiological role of DCAF8 is unknown. In this study, we constructed Dcaf8 knockout mice. Homozygous mice were viable with no noticeable abnormalities. However, the fertility of Dcaf8-deficient male mice was markedly impaired, consistent with the high expression of DCAF8 in adult mouse testis. Sperm movement characteristics, including progressive motility, path velocity, progressive velocity, and track speed, were significantly lower in Dcaf8 knockout mice than in wild-type (WT) mice. However, the total motility was similar between WT and Dcaf8 knockout sperm. More than 40% of spermatids in Dcaf8 knockout mice showed pronounced morphological abnormalities with typical bent head malformation. The acrosome and nucleus of Dcaf8 knockout sperm looked similar to those of WT sperm. In vitro tests showed that the fertilization rate of Dcaf8 knockout mice was significantly reduced. The results demonstrated that DCAF8 plays a critical role in spermatogenesis, and DCAF8 is a key component of CRL4 function in the reproductive system.

Figures and Tables | References | Supplementary Material | Related Articles | Metrics
H. sinensis mycelium inhibits epithelial--mesenchymal transition by inactivating the midkine pathway in pulmonary fibrosis
Li Lu, Haiyan Zhu, Hailin Wang, Huaping Liang, Yayi Hou, Huan Dou
Front. Med.. 2021, 15 (2): 313-329.  
https://doi.org/10.1007/s11684-020-0737-1

Abstract   HTML   PDF (10974KB)

The medical fungus Hirsutella sinensis has been used as a Chinese folk health supplement because of its immunomodulatory properties. Our previous studies established the antifibrotic action of Hirsutella sinensis mycelium (HSM) in the lung. The epithelial–mesenchymal transition (EMT) is involved in the pathogenesis of idiopathic pulmonary fibrosis. The present study investigates the role of HSM in mediating EMT during the development of pulmonary fibrosis. HSM significantly inhibits bleomycin (BLM)-induced pulmonary fibrosis by blocking the EMT. In addition, the expression levels of midkine are increased in the lungs of the BLM-induced group. Further analysis of the results indicates that the mRNA level of midkine correlated positively with EMT. HSM markedly abrogates the transforming growth factor β-induced EMT-like phenotype and behavior in vitro. The activation of midkine related signaling pathway is ameliorated following HSM treatment, whereas this extract also caused an effective attenuation of the induction of EMT (caused by midkine overexpression) in vitro. Results further confirm that oral medication of HSM disrupted the midkine pathway in vivo. Overall, findings suggest that the midkine pathway and the regulation of the EMT may be considered novel candidate therapeutic targets for the antifibrotic effects caused by HSM.

Figures and Tables | References | Supplementary Material | Related Articles | Metrics
ERRATUM
Screening for main components associated with the idiosyncratic hepatotoxicity of a tonic herb, Polygonum multiflorum
Chunyu Li, Ming Niu, Zhaofang Bai, Congen Zhang, Yanling Zhao, Ruiyu Li, Can Tu, Huifang Li, Jing Jing, Yakun Meng, Zhijie Ma, Wuwen Feng, Jinfa Tang, Yun Zhu, Jinjie Li, Xiaoya Shang, Zhengsheng Zou, Xiaohe Xiao, Jiabo Wang
Front. Med.. 2021, 15 (2): 330-332.  
https://doi.org/10.1007/s11684-020-0819-0

Abstract   HTML   PDF (4428KB)
Figures and Tables | References | Related Articles | Metrics
13 articles