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Landscape of emerging and re-emerging infectious diseases in China: impact of ecology, climate, and behavior
Qiyong Liu, Wenbo Xu, Shan Lu, Jiafu Jiang, Jieping Zhou, Zhujun Shao, Xiaobo Liu, Lei Xu, Yanwen Xiong, Han Zheng, Sun Jin, Hai Jiang, Wuchun Cao, Jianguo Xu
Front. Med.    2018, 12 (1): 3-22.
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For the past several decades, the infectious disease profile in China has been shifting with rapid developments in social and economic aspects, environment, quality of food, water, housing, and public health infrastructure. Notably, 5 notifiable infectious diseases have been almost eradicated, and the incidence of 18 additional notifiable infectious diseases has been significantly reduced. Unexpectedly, the incidence of over 10 notifiable infectious diseases, including HIV, brucellosis, syphilis, and dengue fever, has been increasing. Nevertheless, frequent infectious disease outbreaks/events have been reported almost every year, and imported infectious diseases have increased since 2015. New pathogens and over 100 new genotypes or serotypes of known pathogens have been identified. Some infectious diseases seem to be exacerbated by various factors, including rapid urbanization, large numbers of migrant workers, changes in climate, ecology, and policies, such as returning farmland to forests. This review summarizes the current experiences and lessons from China in managing emerging and re-emerging infectious diseases, especially the effects of ecology, climate, and behavior, which should have merits in helping other countries to control and prevent infectious diseases.

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Cited: Crossref(7) WebOfScience(4)
CRISPR-Cas9 mediated LAG-3 disruption in CAR-T cells
Yongping Zhang, Xingying Zhang, Chen Cheng, Wei Mu, Xiaojuan Liu, Na Li, Xiaofei Wei, Xiang Liu, Changqing Xia, Haoyi Wang
Front. Med.    2017, 11 (4): 554-562.
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T cells engineered with chimeric antigen receptor (CAR) have been successfully applied to treat advanced refractory B cell malignancy. However, many challenges remain in extending its application toward the treatment of solid tumors. The immunosuppressive nature of tumor microenvironment is considered one of the key factors limiting CAR-T efficacy. One negative regulator of T cell activity is lymphocyte activation gene-3 (LAG-3). We successfully generated LAG-3 knockout T and CAR-T cells with high efficiency using CRISPR-Cas9 mediated gene editing and found that the viability and immune phenotype were not dramatically changed during in vitro culture. LAG-3 knockout CAR-T cells displayed robust antigen-specific antitumor activity in cell culture and in murine xenograft model, which is comparable to standard CAR-T cells. Our study demonstrates an efficient approach to silence immune checkpoint in CAR-T cells via gene editing.

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Epidemiology of fungal infections in China
Min Chen, Yuan Xu, Nan Hong, Yali Yang, Wenzhi Lei, Lin Du, Jingjun Zhao, Xia Lei, Lin Xiong, Langqi Cai, Hui Xu, Weihua Pan, Wanqing Liao
Front. Med.    2018, 12 (1): 58-75.
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With the increasing number of immunocompromised hosts, the epidemiological characteristics of fungal infections have undergone enormous changes worldwide, including in China. In this paper, we reviewed the existing data on mycosis across China to summarize available epidemiological profiles. We found that the general incidence of superficial fungal infections in China has been stable, but the incidence of tinea capitis has decreased and the transmission route has changed. By contrast, the overall incidence of invasive fungal infections has continued to rise. The occurrence of candidemia caused by Candida species other than C. albicans and including some uncommon Candida species has increased recently in China. Infections caused by Aspergillus have also propagated in recent years, particularly with the emergence of azole-resistant Aspergillus fumigatus. An increasing trend of cryptococcosis has been noted in China, with Cryptococcus neoformans var. grubii ST 5 genotype isolates as the predominant pathogen. Retrospective studies have suggested that the epidemiological characteristics of Pneumocystis pneumonia in China may be similar to those in other developing countries. Endemic fungal infections, such as sporotrichosis in Northeastern China, must arouse research, diagnostic, and treatment vigilance. Currently, the epidemiological data on mycosis in China are variable and fragmentary. Thus, a nationwide epidemiological research on fungal infections in China is an important need for improving the country’s health.

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Transforming bacterial disease surveillance and investigation using whole-genome sequence to probe the trace
Biao Kan, Haijian Zhou, Pengcheng Du, Wen Zhang, Xin Lu, Tian Qin, Jianguo Xu
Front. Med.    2018, 12 (1): 23-33.
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Two decades have passed since the first bacterial whole-genome sequencing, which provides new opportunity for microbial genome. Consequently, considerable genetic diversity encoded by bacterial genomes and among the strains in the same species has been revealed. In recent years, genome sequencing techniques and bioinformatics have developed rapidly, which has resulted in transformation and expedited the application of strategy and methodology for bacterial genome comparison used in dissection of infectious disease epidemics. Bacterial whole-genome sequencing and bioinformatic computing allow genotyping to satisfy the requirements of epidemiological study in disease control. In this review, we outline the significance and summarize the roles of bacterial genome sequencing in the context of bacterial disease control and prevention. We discuss the applications of bacterial genome sequencing in outbreak detection, source tracing, transmission mode discovery, and new epidemic clone identification. Wide applications of genome sequencing and data sharing in infectious disease surveillance networks will considerably promote outbreak detection and early warning to prevent the dissemination of bacterial diseases.

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Molecular classification and precision therapy of cancer: immune checkpoint inhibitors
Yingyan Yu
Front. Med.    2018, 12 (2): 229-235.
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On May 23, 2017, the US Food and Drug Administration (FDA) approved a treatment for cancer patients with positive microsatellite instability-high (MSI-H) markers or mismatch repair deficient (dMMR) markers. This approach is the first approved tumor treatment using a common biomarker rather than specified tumor locations in the body. FDA previously approved Keytruda for treatment of several types of malignancies, such as metastatic melanoma, metastatic non-small-cell lung cancer, recurrent or metastatic head and neck cancer, refractory Hodgkin lymphoma, and urothelial carcinoma, all of which carry positive programmed death-1/programmed death-ligand 1 biomarkers. Therefore, indications of Keytruda significantly expanded. Several types of malignancies are disclosed by MSI-H status due to dMMR and characterized by increased neoantigen load, which elicits intense host immune response in tumor microenvironment, including portions of colorectal and gastric carcinomas. Currently, biomarker-based patient selection remains a challenge. Pathologists play important roles in evaluating histology and biomarker results and establishing detection methods. Taking gastric cancer as an example, its molecular classification is built on genome abnormalities, but it lacks acceptable clinical characteristics. Pathologists are expected to act as “genetic interpreters” or “genetic translators” and build a link between molecular subtypes with tumor histological features. Subsequently, by using their findings, oncologists will carry out targeted therapy based on molecular classification.

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Genomic variations in the counterpart normal controls of lung squamous cell carcinomas
Dalin Zhang, Liwei Qu, Bo Zhou, Guizhen Wang, Guangbiao Zhou
Front. Med.    2018, 12 (3): 280-288.
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Lung squamous cell carcinoma (LUSC) causes approximately 400 000 deaths each year worldwide. The occurrence of LUSC is attributed to exposure to cigarette smoke, which induces the development of numerous genomic abnormalities. However, few studies have investigated the genomic variations that occur only in normal tissues that have been similarly exposed to tobacco smoke as tumor tissues. In this study, we sequenced the whole genomes of three normal lung tissue samples and their paired adjacent squamous cell carcinomas. We then called genomic variations specific to the normal lung tissues through filtering the genomic sequence of the normal lung tissues against that of the paired tumors, the reference human genome, the dbSNP138 common germline variants, and the variations derived from sequencing artifacts. To expand these observations, the whole exome sequences of 478 counterpart normal controls (CNCs) and paired LUSCs of The Cancer Genome Atlas (TCGA) dataset were analyzed. Sixteen genomic variations were called in the three normal lung tissues. These variations were confirmed by Sanger capillary sequencing. A mean of 0.5661 exonic variations/Mb and 7.7887 altered genes per sample were identified in the CNC genome sequences of TCGA. In these CNCs, C:G→T:A transitions, which are the genomic signatures of tobacco carcinogen N-methyl-N-nitro-N-nitrosoguanidine, were the predominant nucleotide changes. Twenty five genes in CNCs had a variation rate that exceeded 2%, including ARSD (18.62%), MUC4 (8.79%), and RBMX (7.11%). CNC variations in CTAGE5 and USP17L7 were associated with the poor prognosis of patients with LUSC. Our results uncovered previously unreported genomic variations in CNCs, rather than LUSCs, that may be involved in the development of LUSC.

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Neuroprotective effects of Ginkgo biloba extract and Ginkgolide B against oxygen–glucose deprivation/reoxygenation and glucose injury in a new in vitro multicellular network model
Xiaohan Yang, Tiezheng Zheng, Hao Hong, Nan Cai, Xiaofeng Zhou, Changkai Sun, Liying Wu, Shuhong Liu, Yongqi Zhao, Lingling Zhu, Ming Fan, Xuezhong Zhou, Fengxie Jin
Front. Med.    2018, 12 (3): 307-318.
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Acute ischemic stroke (AIS), as the third leading cause of death worldwide, is characterized by its high incidence, mortality rate, high incurred disability rate, and frequent reoccurrence. The neuroprotective effects of Ginkgo biloba extract (GBE) against several cerebral diseases have been reported in previous studies, but the underlying mechanisms of action are still unclear. Using a novel in vitro rat cortical capillary endothelial cell-astrocyte-neuron network model, we investigated the neuroprotective effects of GBE and one of its important constituents, Ginkgolide B (GB), against oxygen–glucose deprivation/reoxygenation and glucose (OGD/R) injury. In this model, rat cortical capillary endothelial cells, astrocytes, and neurons were cocultured so that they could be synchronously observed in the same system. Pretreatment with GBE or GB increased the neuron cell viability, ameliorated cell injury, and inhibited the cell apoptotic rate through Bax and Bcl-2 expression regulation after OGD/R injury. Furthermore, GBE or GB pretreatment enhanced the transendothelial electrical resistance of capillary endothelial monolayers, reduced the endothelial permeability coefficients for sodium fluorescein (Na-F), and increased the expression levels of tight junction proteins, namely, ZO-1 and occludin, in endothelial cells. Results demonstrated the preventive effects of GBE on neuronal cell death and enhancement of the function of brain capillary endothelial monolayers after OGD/R injury in vitro; thus, GBE could be used as an effective neuroprotective agent for AIS/reperfusion, with GB as one of its significant constituents.

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Gut microbial balance and liver transplantation: alteration, management, and prediction
Xinyao Tian, Zhe Yang, Fangzhou Luo, Shusen Zheng
Front. Med.    2018, 12 (2): 123-129.
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Liver transplantation is a conventional treatment for terminal stage liver diseases. However, several complications still hinder the survival rate. Intestinal barrier destruction is widely observed among patients receiving liver transplant and suffering from ischemia–reperfusion or rejection injuries because of the relationship between the intestine and the liver, both in anatomy and function. Importantly, the resulting alteration of gut microbiota aggravates graft dysfunctions during the process. This article reviews the research progress for gut microbial alterations and liver transplantation. Especially, this work also evaluates research on the management of gut microbial alteration and the prediction of possible injuries utilizing microbial alteration during liver transplantation. In addition, we propose possible directions for research on gut microbial alteration during liver transplantation and offer a hypothesis on the utilization of microbial alteration in liver transplantation. The aim is not only to predict perioperative injuries but also to function as a method of treatment or even inhibit the rejection of liver transplantation.

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

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New medical risks affecting obstetrics after implementation of the two-child policy in China
Qiang Li, Dongrui Deng
Front. Med.    2017, 11 (4): 570-575.
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China recently instituted a two-child policy in response to its aging population, declining workforce and demographic dividend, and the need to develop asocial economy. Additionally, women generally delay having a second child because of the overwhelming pressure in their lives. With the improvements in assisted fertility technologies in recent years, the number of elderly women attempting to bear children has increased. The quality of woman’s eggs and a man’s sperm declined dramatically with increasing age, leading to an increased risk of pregnancy-related complications among older women. Therefore, the types of fertility problems experienced by elderly females must be provided with considerable attention by obstetricians. This commentary article focuses on the medical problems faced by older second-child pregnant women. This work discusses their increased rates of infertility, spontaneous abortion, fetal malformation, gestational diabetes, cesarean section, placenta previa, postpartum hemorrhage, postpartum depression, and hypertensive disorders, which complicate pregnancy.

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Application of liquid biopsy in precision medicine: opportunities and challenges
Junyun Wang, Shuang Chang, Guochao Li, Yingli Sun
Front. Med.    2017, 11 (4): 522-527.
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Precision medicine for cancer patients aims to adopt the most suitable treatment options during diagnosis and treatment of individuals. Detecting circulating tumor cell (CTC) or circulating tumor DNA (ctDNA) in plasma or serum could serve as liquid biopsy, which would be useful for numerous diagnostic applications. Liquid biopsies can help clinicians screen and detect cancer early, stratify patients to the most suitable treatment and real-time monitoring of treatment response and resistance mechanisms in the tumor, evaluate the risk for metastatic relapse, and estimate prognosis. We summarized the advantages and disadvantages of tissue and liquid biopsies. We also further compared and analyzed the advantages and limitations of detecting CTCs, ctDNAs, and exosomes. Furthermore, we reviewed the literature related with the application of serum or plasma CTCs, ctDNAs, and exosomes for diagnosis and prognosis of cancer. We also analyzed their opportunities and challenges as future biomarkers. In the future, liquid biopsies could be used to guide cancer treatment. They could also provide the ideal scheme to personalize treatment in precision medicine.

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Potential use of serum HBV RNA in antiviral therapy for chronic hepatitis B in the era of nucleos(t)ide analogs
Fengmin Lu, Jie Wang, Xiangmei Chen, Dongping Xu, Ningshao Xia
Front. Med.    2017, 11 (4): 502-508.
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Although the efficacy of nucleos(t)ide analogue (NA) has been confirmed for treatment of chronic hepatitis B, long-term therapy has been recommended due to the high frequency of off-therapy viral DNA rebound and disease relapse. In this review, the RNA virion-like particles of hepatitis B virus (HBV) are integrated into the life cycle of HBV replication, and the potential significance of serum HBV RNA is systematically described. The production of HBV RNA virion-like particles should not be blocked by NA; in this regard, serum HBV RNA is found to be a suitable surrogate marker for the activity of intrahepatic covalently closed circular DNA (cccDNA), particularly among patients receiving NA therapy. Therefore, the concept of virological response is redefined as persistent loss of serum HBV DNA and HBV RNA. In contrast to hepatitis B surface antigen (HBsAg) that can originate from either the cccDNA or the integrated HBV DNA fragment, serum HBV RNA, with pregenomic RNA origination, can only be transcribed from cccDNA. Therefore, the loss of serum HBV RNA would likely be a promising predicator for safe drug discontinuation. The clinical status of consistent loss of serum HBV RNA accompanied with low serum HBsAg levels might be implicated as a “para-functional cure,” a status nearly close to the functional cure of chronic hepatitis B, to distinguish the “functional cure” characterized as serum HBsAg loss with or without anti-HBs seroconversion.

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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.
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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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Cyclospora cayetanensis infections among diarrheal outpatients in Shanghai: a retrospective case study
Yanyan Jiang, Zhongying Yuan, Guoqing Zang, Dan Li, Ying Wang, Yi Zhang, Hua Liu, Jianping Cao, Yujuan Shen
Front. Med.    2018, 12 (1): 98-103.
Abstract   HTML   PDF (156KB)

Cyclospora cayetanensis is a foodborne and waterborne pathogen that causes endemic and epidemic human diarrhea worldwide. A few epidemiological studies regarding C. cayetanensis infections in China have been conducted. During 2013, a total of 291 stool specimens were collected from patients with diarrhea at a hospital in urban Shanghai. C. cayetanensis was not detected in any of the stool specimens by traditional microscopy, whereas five stool specimens (1.72%, 5/291) were positive by PCR. These positive cases confirmed by molecular technology were all in the adult group (mean age 27.8 years; 2.94%, 5/170) with watery diarrhea. Marked infection occurred in the rainy season of May and July. Sequence and phylogenetic analyses of the partial 18S rRNA genes of C. cayetanensis isolated showed intra-species diversity of this parasite. This study showed, for the first time, that C. cayetanensis is a pathogen in outpatients with diarrhea in Shanghai, albeit at a low level. However, the transmission dynamics of this parasite in these patients remain uncertain.

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Trends of foodborne diseases in China: lessons from laboratory-based surveillance since 2011
Jikai Liu, Li Bai, Weiwei Li, Haihong Han, Ping Fu, Xiaochen Ma, Zhenwang Bi, Xiaorong Yang, Xiuli Zhang, Shiqi Zhen, Xiaoling Deng, Xiumei Liu, Yunchang Guo
Front. Med.    2018, 12 (1): 48-57.
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Foodborne disease is one of the most important public health issues worldwide. China faces various and unprecedented challenges in all aspects of the food chain. Data from laboratory-based foodborne disease surveillance systems from 2013 to 2016, as well as different regions and ages, can be found along with differences in the patterns of pathogens detected with diverse characteristics. Vibrio parahaemolyticus has been the leading cause of infectious diarrhea in China, especially among adults in coastal regions. Salmonella has been a serious and widely distributed pathogen responsible for substantial socioeconomic burden. Shigella was mostly identified in Northwest China and the inland province (Henan) with less-developed regions among children under 5 years. Data from foodborne disease outbreak reporting system from 2011 to 2016 showed that poisonous animals and plant factors responsible for most deaths were poisonous mushrooms (54.7%) in remote districts in southwest regions. The biological hazard that caused most cases reported (42.3%) was attributed to V. parahaemolyticus, the leading cause of foodborne outbreaks. In this review, we summarize the recent monitoring approach to foodborne diseases in China and compare the results with those in developed countries.

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Development of small-molecule viral inhibitors targeting various stages of the life cycle of emerging and re-emerging viruses
Xiaohuan Wang, Peng Zou, Fan Wu, Lu Lu, Shibo Jiang
Front. Med.    2017, 11 (4): 449-461.
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In recent years, unexpected outbreaks of infectious diseases caused by emerging and re-emerging viruses have become more frequent, which is possibly due to environmental changes. These outbreaks result in the loss of life and economic hardship. Vaccines and therapeutics should be developed for the prevention and treatment of infectious diseases. In this review, we summarize and discuss the latest progress in the development of small-molecule viral inhibitors against highly pathogenic coronaviruses, including severe acute respiratory syndrome coronavirus and Middle East respiratory syndrome coronavirus, Ebola virus, and Zika virus. These viruses can interfere with the specific steps of viral life cycle by blocking the binding between virus and host cells, disrupting viral endocytosis, disturbing membrane fusion, and interrupting viral RNA replication and translation, thereby demonstrating potent therapeutic effect against various emerging and re-emerging viruses. We also discuss some general strategies for developing small-molecule viral inhibitors.

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High-affinity T cell receptors redirect cytokine-activated T cells (CAT) to kill cancer cells
Synat Kang, Yanyan Li, Yifeng Bao, Yi Li
Front. Med.    2019, 13 (1): 69-82.
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Cytokine-activated T cells (CATs) can be easily expanded and are widely applied to cancer immunotherapy. However, the good efficacy of CATs is rarely reported in clinical applications because CATs have no or very low antigen specificity. The low-efficacy problem can be resolved using T cell antigen receptor-engineered CAT (TCR-CAT). Herein, we demonstrate that NY-ESO-1157–165 HLA-A*02:01-specific high-affinity TCR (HAT)-transduced CATs can specifically kill cancer cells with good efficacy. With low micromolar range dissociation equilibrium constants, HAT-transduced CATs showed good specificity with no off-target killing. Furthermore, the high-affinity TCR-CATs delivered significantly better activation and cytotoxicity than the equivalent TCR-engineered T cells (TCR-Ts) in terms of interferon-g and granzyme B production and in vitro cancer cell killing ability. TCR-CAT may be a very good alternative to the expensive TCR-T, which is considered an effective personalized cyto-immunotherapy.

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Platelet membrane-based and tumor-associated platelet- targeted drug delivery systems for cancer therapy
Yinlong Zhang, Guangna Liu, Jingyan Wei, Guangjun Nie
Front. Med.    2018, 12 (6): 667-677.
Abstract   HTML   PDF (778KB)

Platelets have long been known to play critical roles in hemostasis by clumping and clotting blood vessel injuries. Recent experimental evidence strongly indicates that platelets can also interact with tumor cells by direct binding or secreting cytokines. For example, platelets have been shown to protect circulating cancer cells in blood circulation and to promote tumor metastasis. In-depth understanding of the role of platelets in cancer progression and metastasis provides promising approaches for platelet biomimetic drug delivery systems and functional platelet-targeting strategies for effective cancer treatment. This review highlights recent progresses in platelet membrane-based drug delivery and unique strategies that target tumor-associated platelets for cancer therapy. The paper also discusses future development opportunities and challenges encountered for clinical translation.

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Responses to emerging and re-emerging infectious diseases: One world, One health
Jianqing Xu, Jianguo Xu
Front. Med.    2018, 12 (1): 1-2.
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Recent transmission of Mycobacterium tuberculosis in China: the implication of molecular epidemiology for tuberculosis control
Chongguang Yang, Qian Gao
Front. Med.    2018, 12 (1): 76-83.
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Tuberculosis (TB) has remained an ongoing concern in China. The national scale-up of the Directly Observed Treatment, Short Course (DOTS) program has accelerated the fight against TB in China. Nevertheless, many challenges still remain, including the spread of drug-resistant strains, high disease burden in rural areas, and enormous rural-to-urban migrations. Whether incident active TB represents recent transmission or endogenous reactivation has helped to prioritize the strategies for TB control. Evidence from molecular epidemiology studies has delineated the recent transmission of Mycobacterium tuberculosis (M. tuberculosis) strains in many settings. However, the transmission patterns of TB in most areas of China are still not clear. Studies carried out to date could not capture the real burden of recent transmission of the disease in China because of the retrospective study design, incomplete sampling, and use of low-resolution genotyping methods. We reviewed the implementations of molecular epidemiology of TB in China, the estimated disease burden due to recent transmission of M. tuberculosis strains, the primary transmission of drug-resistant TB, and the evaluation of a feasible genotyping method of M. tuberculosis strains in circulation.

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Current advances in the elimination of hepatitis B in China by 2030
Shuye Zhang, Fusheng Wang, Zheng Zhang
Front. Med.    2017, 11 (4): 490-501.
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With its 78 million chronic carriers, hepatitis B virus (HBV) infection is still one of the leading public health challenges in China. Over the last two decades, China has made great progress on the prevention of HBV transmission through national vaccination programs. Zero transmission from mother to infant has been proposed as the current goal. Available anti-HBV therapy is efficacious in suppressing HBV replication; however, it fails to completely cure patients with chronic hepatitis B and even requires lifelong treatment. To reduce the costs and improve the efficacy, several trials have been recently conducted in China to optimize the current anti-HBV managements. Novel biomarkers were identified to predict treatment outcomes, and new promising treatment strategies were developed. Reports also indicate that coinfections of HBV with other hepatotropic viruses and human immunodeficiency virus are common in China and cause severe liver diseases, which should be recognized early and treated properly. Work is still needed to eliminate hepatitis B in China by 2030.

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Carcinogens that induce the A:T>T:A nucleotide substitutions in the genome
Guangbiao Zhou, Xinchun Zhao
Front. Med.    2018, 12 (2): 236-238.
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Recently, Ng et al. reported that the A:T>T:A substitutions, proposed to be a signature of aristolochic acid (AA) exposure, were detected in 76/98 (78%) of patients with hepatocellular carcinoma (HCC) from the Taiwan Province of China, and 47% to 1.7% of HCCs from the Chinese mainland and other countries harbored the nucleotide changes. However, other carcinogens, e.g., tobacco carcinogens 4-aminobiphenyl and 1,3-butadiene, air toxic vinyl chloride and its reactive metabolites chloroethylene oxide, melphalan and chlorambucil, also cause this signature in the genome. Since tobacco smoke is a worldwide public health threat and vinyl chloride distributes globally and is an air pollutant in Taiwan Province, the estimation of the patients’ exposure history is the key to determine the “culprit” of the A:T>T:A mutations. Apparently, without estimation of the patients’ exposure history, the conclusion of Ng et al. is unpersuasive and misleading.

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Natural killer cells in hepatocellular carcinoma: current status and perspectives for future immunotherapeutic approaches
Min Yu, Zonghai Li
Front. Med.    2017, 11 (4): 509-521.
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Hepatocellular carcinoma (HCC) is currently the fifth most common malignancy and the third leading cause of cancer-related mortalities worldwide. In the last few years, treatments for HCC have significantly improved from a mere surgical resection to a series of minimally invasive therapies and targeted drugs. However, recurrence frequently occurs even upon curative therapeutics, and drug therapies generally produce disappointing results, with the overall prognosis dismal. This challenging clinical scenario warrants new effective and life-prolonging strategies for patients with HCC. Compelling evidence suggests that NK cells play a critical role in the immune function of the liver and in the immune defenses against HCC, indicating that HCC might be an ideal target for NK cell-based immunotherapies. To obtain comprehensive insights into the putative influence of NK cells on HCC, this paper summarizes current knowledge on NK cells in HCC and discusses the usefulness and prospects of NK cell-based immunotherapies. Critical issues that require consideration for the successful clinical translation of NK cell-based therapies are also addressed. If appropriately used and further optimized, NK cell-based therapies could dominate important roles in the future immunotherapeutic market of HCC.

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Characterization of hidden rules linking symptoms and selection of acupoint using an artificial neural network model
Won-Mo Jung, In-Soo Park, Ye-Seul Lee, Chang-Eop Kim, Hyangsook Lee, Dae-Hyun Hahm, Hi-Joon Park, Bo-Hyoung Jang, Younbyoung Chae
Front. Med.    2019, 13 (1): 112-120.
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Comprehension of the medical diagnoses of doctors and treatment of diseases is important to understand the underlying principle in selecting appropriate acupoints. The pattern recognition process that pertains to symptoms and diseases and informs acupuncture treatment in a clinical setting was explored. A total of 232 clinical records were collected using a Charting Language program. The relationship between symptom information and selected acupoints was trained using an artificial neural network (ANN). A total of 11 hidden nodes with the highest average precision score were selected through a tenfold cross-validation. Our ANN model could predict the selected acupoints based on symptom and disease information with an average precision score of 0.865 (precision, 0.911; recall, 0.811). This model is a useful tool for diagnostic classification or pattern recognition and for the prediction and modeling of acupuncture treatment based on clinical data obtained in a real-world setting. The relationship between symptoms and selected acupoints could be systematically characterized through knowledge discovery processes, such as pattern identification.

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

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Low-dose CT for lung cancer screening: opportunities and challenges
Hongbing Shen
Front. Med.    2018, 12 (1): 116-121.
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Lung cancer is among the most frequently diagnosed cancers worldwide and the leading cause of cancer death in both males and females. Screening for lung cancer coupled with earlier intervention has long been studied as an approach to mortality reduction. However, minimal progress was achieved until recently, when low-dose spiral computed tomography (LDCT) screening demonstrated a 20% reduction in mortality from lung cancer in a randomized controlled trial (RCT), the National Lung Screening Trial, from the United States. On the basis of this finding, LDCT has been recommended for lung cancer screening in high-risk populations by several clinical guidelines. However, results from the following independent RCTs in Europe failed to show consistent conclusions. In addition, intractable problems gradually emerged with the progress of LDCT screening. This paper summarizes and discusses the main observations and challenges of LDCT screening for lung cancer. Before spreading implementation of LDCT screening, challenges, including high false-positive rates, overdiagnosis, enormous costs, and radiation risk, must be addressed. Complementary biomarkers and technical improvement are expected in the field of lung cancer screening in the near future.

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Prospects of immunotherapy for cancer
Zhinan Chen
Front. Med.    2019, 13 (1): 1-2.
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Propensity score-matched study and meta-analysis of cumulative outcomes of day 2/3 versus day 5/6 embryo transfers
Ye Yin, Ge Chen, Kezhen Li, Qiuyue Liao, Sijia Zhang, Nieying Ma, Jing Chen, Yan Zhang, Jihui Ai
Front. Med.    2017, 11 (4): 563-569.
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The superiority of the cumulative outcomes of day 5/6 embryo transfer to those of day 2/3 embryo transfer in infertile couples has been debated. This retrospective study included data collected from 1051 patients from July 2011 to June 2014. Multiple maternal baseline covariates were subjected to propensity score matching analysis, and each day 5/6 group woman was matched to one day 2/3 group woman. A systematic meta-analysis was conducted to validate the results. After matching was completed, 217 patients on the day 2/3 group were matched with those on the day 5/6 group, and no significant differences in the baseline characteristics were observed between the two groups. The cumulative pregnancy rate (57.14% vs. 53.46%, OR 1.16, 95% CI 0.79–1.70) and cumulative live birth rate (53.00% vs. 49.77%, OR 1.14, 95% CI 0.78–1.66) of day 5/6 embryo transfers were higher than those of day 2/3 embryo transfers, but this difference was not significant. The mean cycles per live birth and mean days per live birth in the day 5/6 group were significantly lower than those in the day 2/3 group. This study demonstrated that day 5/6 embryo transfer is a more cost-effective and time-efficient policy than day 2/3 embryo transfer to produce a live baby.

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

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Oxidative stress in granulosa cells contributes to poor oocyte quality and IVF-ET outcomes in women with polycystic ovary syndrome
Qiaohong Lai, Wenpei Xiang, Qing Li, Hanwang Zhang, Yufeng Li, Guijin Zhu, Chengliang Xiong, Lei Jin
Front. Med.    2018, 12 (5): 518-524.
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The increased levels of intracellular reactive oxygen species (ROS) in granulosa cells (GCs) may affect the pregnancy results in women with polycystic ovary syndrome (PCOS). In this study, we compared thein vitro fertilization and embryo transfer (IVF-ET) results of 22 patients with PCOS and 25 patients with tubal factor infertility and detected the ROS levels in the GCs of these two groups. Results showed that the PCOS group had significantly larger follicles on the administration day for human chorionic gonadotropin than the tubal factor group (P<0.05); however, the number of retrieved oocytes was not significantly different between the two groups (P>0.05). PCOS group had slightly lower fertilization, cleavage, grade I/II embryo, clinical pregnancy, and implantation rates and higher miscarriage rate than the tubal factor group (P>0.05). We further found a significantly higher ROS level of GCs in the PCOS group than in the tubal factor group (P<0.05). The increased ROS levels in GCs caused GC apoptosis, whereas NADPH oxidase 2 (NOX2) specific inhibitors (diphenyleneiodonium and apocynin) significantly reduced the ROS production in the PCOS group. In conclusion, the increased ROS expression levels in PCOS GCs greatly induced cell apoptosis, which further affected the oocyte quality and reduced the positive IVF-ET pregnancy results of women with PCOS. NADPH oxidase pathway may be involved in the mechanism of ROS production in GCs of women with PCOS.

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