Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

2015 Impact Factor: 1.863

Cover Story   2018, Volume 12 Issue 5
Both the size and number of B cell colonies in Zfyve16KO mice significantly decreased compared with those in wild-type mice. The data demonstrate that Zfyve16 directly regulates the growth of B-lymphoid cells. (Courtesy of Drs. Ping Liu and Ruibao Ren. See pages 559-565 by Xuemei Zhao et al. for more information.)
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REVIEW
Genome editing for the treatment of tumorigenic viral infections and virus-related carcinomas
Lan Yu, Xun Tian, Chun Gao, Ping Wu, Liming Wang, Bei Feng, Xiaomin Li, Hui Wang, Ding Ma, Zheng Hu
Front. Med.. 2018, 12 (5): 497-508.  
https://doi.org/10.1007/s11684-017-0572-1

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Viral infections cause at least 10%–15% of all human carcinomas. Over the last century, the elucidation of viral oncogenic roles in many cancer types has provided fundamental knowledge on carcinogenetic mechanisms and established a basis for the early intervention of virus-related cancers. Meanwhile, rapidly evolving genome-editing techniques targeting viral DNA/RNA have emerged as novel therapeutic strategies for treating virus-related carcinogenesis and have begun showing promising results. This review discusses the recent advances of genome-editing tools for treating tumorigenic viruses and their corresponding cancers, the challenges that must be overcome before clinically applying such genome-editing technologies, and more importantly, the potential solutions to these challenges.

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RESEARCH ARTICLE
Possibility of women treated with fertility-sparing surgery for non-epithelial ovarian tumors to safely and successfully become pregnant---a Chinese retrospective cohort study among 148 cases
Bin Yang, Yan Yu, Jing Chen, Yan Zhang, Ye Yin, Nan Yu, Ge Chen, Shifei Zhu, Haiyan Huang, Yongqun Yuan, Jihui Ai, Xinyu Wang, Kezhen Li
Front. Med.. 2018, 12 (5): 509-517.  
https://doi.org/10.1007/s11684-017-0554-3

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This study was performed to evaluate the oncological and reproductive outcomes of childbearing-age women treated with fertility-sparing surgery (FSS) for non-epithelial ovarian tumors in China. One hundred and forty eight non-epithelial ovarian tumor women treated with FSS between January 1, 2000 and August 31, 2015 from two medical centers in China were identified. Progression-free survival (PFS) was 88.5%, whereas overall survival (OS) was 93.9%. Univariate analysis suggested that delivery after treatment is related to PFS (P=0.023), whereas histology significantly influenced OS. Cox regression analysis suggested that only histology was associated with PFS and OS (P<0.05). Among the 129 women who completed adjuvant chemotherapy (ACT), none developed amenorrhea. Among the 44 women who desired pregnancy, 35 (79.5%) successfully had 51 gestations including 35 live births without birth defects. Non-epithelial ovarian tumors can achieve fulfilling prognosis after FSS and chemotherapy. Histology might be the only independent prognostic factor for PFS and OS. FSS followed by ACT appeared to have little or no effect on fertility. Meanwhile, postoperative pregnancy did not increase the PFS or OS. Use of gonadotropin-releasing hormone agonist was not beneficial for fertility.

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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.  
https://doi.org/10.1007/s11684-017-0575-y

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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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Role of chemerin/CMKLR1 in the maintenance of early pregnancy
Xuezhou Yang, Junning Yao, Qipeng Wei, Jinhai Ye, Xiaofang Yin, Xiaozhen Quan, Yanli Lan, Hui Xing
Front. Med.. 2018, 12 (5): 525-532.  
https://doi.org/10.1007/s11684-017-0577-9

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Chemerin is a cytokine that attracts much attention in the reproductive process. This study aimed to explore the effects of chemerin and its receptor chemokine-like receptor 1 (CMKLR1) on the maintenance of early pregnancy. The expression levels of chemerin and CMKLR1 in the decidua tissues of 20 early normal pregnant women and 20 early spontaneous abortion women were examined by Western blot and real-time polymerase chain reaction analyses. CMKLR1 receptor antagonist (α-NETA) was then intrauterinely injected into normal pregnant mice model to assess its effect on the outcome of pregnancy and the phosphorylation rate of ERK1/2 in decidua tissues. We found that the expression level of chemerin in women who had experienced early spontaneous abortion was lower than in those who had experienced normal early pregnancy (P<0.01); conversely, CMKLR1 expression was higher in the former than in the latter (P<0.01). In a pregnant-mouse model, the embryo resorption rate of α-NETA group was higher than that in the negative control group (61.5% vs. 10.8%) (P<0.001). Compared with the control group, ERK1/2 phosphorylation in decidua tissues decreased in the α-NETA-treated group (P<0.01). These results suggested that the inhibition of the chemerin/CMKLR1 signaling pathway can lead to the abortion of mouse embryos, and that chemerin/CMKLR1 may play an important role in the maintenance of early pregnancy possibly by regulating ERK1/2 phosphorylation.

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Association of maternal depression with dietary intake, growth, and development of preterm infants: a cohort study in Beijing, China
Han Wang, Hong Zhou, Yan Zhang, Yan Wang, Jing Sun
Front. Med.. 2018, 12 (5): 533-541.  
https://doi.org/10.1007/s11684-017-0591-y

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This study aimed to explore the association of maternal depression with nutrient intake, growth, and development of preterm infants. A cohort study of 201 infants was conducted in Beijing. Based on the gestational age of an infant and status of the mother, the infants were divided into four groups: non-depression-fullterm (64), non-depression-preterm (70), depression-fullterm (36), and depression-preterm (31). Data on sociodemographic characteristics, nutritional intake, growth, and developmental status of children at 8 months (corrected ages) were collected using a quantitative questionnaire, a 24-Hour Dietary Recall, anthropometric measurements, and the Bayley-III scale. A multivariate analysis was used to evaluate the effects of maternal depression and preterm birth on infant growth and development. The energy, protein, and carbohydrate intake in the depression group was lower than the recommended amounts. The depression preterm groups indicated the lowest Z-scores for length and weight and the lowest Bayley-III scores. Preterm infants of depressed mothers are at high risks of poor growth and development delay.

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Alteration of heat shock protein 20 expression in preeclamptic patients and its effect in vascular and coagulation function
Fanfan Li, Mengzhou He, Meitao Yang, Yao Fan, Yun Chen, Xi Xia, Yin Xie, Dongrui Deng
Front. Med.. 2018, 12 (5): 542-549.  
https://doi.org/10.1007/s11684-017-0576-x

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Preeclampsia (PE) is a pregnancy-specific, multi-system disorder and the leading cause of maternal and perinatal morbidity and mortality in obstetrics worldwide. Excessive vasoconstriction and dysregulated coagulation function are closely associated with PE. Heat shock protein 20 (HSP20) is ubiquitously expressed under normal physiological conditions and has important roles in vascular dilatation and suppression of platelet aggregation. However, the role of HSP20 in the pathogenesis of PE remains unclear. In this study, we collected chorionic plate resistance arteries (CPAs) and serum from 118 healthy pregnant women and 80 women with PE and detected the levels of HSP20 and its phosphorylated form. Both HSP20 and phosphorylated HSP20 were downregulated in CPAs from women with PE. Comparison of the vasodilative ability of CPAs from the two groups showed impaired relaxation responses to acetyl choline in preeclamptic vessels. In addition to the reduced HSP20 in serum from women with PE, the platelet distribution width and mean platelet volume were also decreased, and the activated partial thromboplastin time and thromboplastin time were elevated. With regard to the vital roles of HSP20 in mediating vasorelaxation and coagulation function, the decreased HSP20 might contribute to the pathogenesis of PE.

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Clinical characterization and diagnosis of cystic fibrosis through exome sequencing in Chinese infants with Bartter-syndrome-like hypokalemia alkalosis
Liru Qiu, Fengjie Yang, Yonghua He, Huiqing Yuan, Jianhua Zhou
Front. Med.. 2018, 12 (5): 550-558.  
https://doi.org/10.1007/s11684-017-0567-y

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Cystic fibrosis (CF) is a fatal autosomal-recessive disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. CF is characterized by recurrent pulmonary infection with obstructive pulmonary disease. CF is common in the Caucasian population but is rare in the Chinese population. The symptoms of early-stage CF are often untypical and may sometimes manifest as Bartter syndrome (BS)-like hypokalemic alkalosis. Therefore, the ability of doctors to differentiate CF from BS-like hypokalemic alkalosis in Chinese infants is a great challenge in the timely and accurate diagnosis of CF. In China, sporadic CF has not been diagnosed in children younger than three years of age to date. Three infants, who were initially admitted to our hospital over the period of June 2013 to September 2014 with BS-like hypokalemic alkalosis, were diagnosed with CF through exome sequencing and sweat chloride measurement. The compound heterozygous mutations of the CFTR gene were detected in two infants, and a homozygous missense mutation was found in one infant. Among the six identified mutations, two are novel point mutations (c.1526G>C and c.3062C>T) that are possibly pathogenic. The three infants are the youngest Chinese patients to have been diagnosed with sporadic CF at a very early stage. Follow-up examination showed that all of the cases remained symptom-free after early intervention, indicating the potential benefit of very early diagnosis and timely intervention in children with CF. Our results demonstrate the necessity of distinguishing CF from BS in Chinese infants with hypokalemic alkalosis and the significant diagnostic value of powerful exome sequencing for rare genetic diseases. Furthermore, our findings expand the CFTR mutation spectrum associated with CF.

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Zfyve16 regulates the proliferation of B-lymphoid cells
Xuemei Zhao, Donghe Li, Qingsong Qiu, Bo Jiao, Ruihong Zhang, Ping Liu, Ruibao Ren
Front. Med.. 2018, 12 (5): 559-565.  
https://doi.org/10.1007/s11684-017-0562-3

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Zfyve16 (a.k.a. endofin or endosome-associated FYVE-domain protein), a member of the FYVE-domain protein family, is involved in endosomal trafficking and in TGF-β, BMP, and EGFR signaling. The FYVE protein SARA regulates the TGF-β signaling pathway by recruiting Smad2/3 and accelerating their phosphorylation, thereby altering their susceptibility to TGF-β-mediated T cell suppression. Zfyve16 binds to Smad4 and their binding affects the formation of Smad2/3-Smad4 complex in TGF-β signaling. However, the in vivo function of Zfyve16 remains unknown. In this study, we generated a Zfyve16 knockout mouse strain (Zfyve16KO) and examined its hematopoietic phenotypes and hematopoietic reconstruction ability. The proportion of T cells in the peripheral blood of Zfyve16KO mice increases compared with that in wild-type mice. This finding is consistent with the role of Zfyve16 in facilitating TGF-β signaling. Unpredictably, B cell proliferation is inhibited in Zfyve16KO mice. The proliferation potential of Zfyve16KO B-lymphoid cells also significantly decreases in vitro. These results suggest that Zfyve16 inhibits the proliferation of T cells, possibly through the TGF-β signaling, but upregulates the proliferation of B-lymphoid cells.

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Cluster analysis for syndromes of real-world coronary heart disease with angina pectoris
Yufeng Zhao, Xueyun Yu, Xinyu Cao, Lin Luo, Liyun He, Shusong Mao, Li Ma, Peijing Rong, Yuxue Zhao, Guozheng Li, Baoyan Liu
Front. Med.. 2018, 12 (5): 566-571.  
https://doi.org/10.1007/s11684-017-0556-1

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Syndromes of coronary heart disease with angina pectoris were analyzed to provide guidance for clinical practice and to improve accuracy of traditional Chinese medicine (TCM) diagnoses and efficacy of TCM treatment. A total of 860 cases with coronary heart disease with angina pectoris were selected from TCM Clinical Research Information Sharing System for TCM clinics and research. Syndromes were automatically extracted with the cluster method and were analyzed to provide objective evidence for clinical studies. Final syndrome classifications were recognized and confirmed by clinical experts. Popular syndromes included Qi and blood deficiency, blood stasis and obstruction collaterals, liver depression and spleen deficiency, and Qi stagnation and blood stasis. Syndromes Qi and blood deficiency and blood stasis and obstruction collaterals accounted for 28.61% of total syndromes, whereas liver depression and spleen deficiency and Qi stagnation and blood stasis accounted for 26.44%. The main syndrome elements comprised Qi deficiency, blood deficiency, blood stasis, and Qi stagnation.

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LETTER TO FRONTIERS OF MEDICINE
Determining “abnormal” levator hiatus distensibility using three-dimensional transperineal ultrasound in Chinese women
Chaoran Dou, Qin Li, Tao Ying, Yulin Yan, Xia Wang, Bing Hu
Front. Med.. 2018, 12 (5): 572-579.  
https://doi.org/10.1007/s11684-017-0561-4

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The dimension of the levator hiatus is a possible predictor of pelvic organ prolapse (POP). This retrospective study investigated 360 women who went to urogynecological clinic for pelvic floor discomfort. Levator hiatus dimensions were obtained by three-dimensional transperineal ultrasound and results were compared between women with and without significantly objective prolapse (International Continence Society POP quantification, grade 2 or higher). Receiver operating characteristic (ROC) curve analyses were performed to determine valid screening index for detecting abnormal levator hiatus distensibility. Women with significantly objective prolapse had significantly higher levator hiatus dimensions than those without (all P <0.001). ROC curve analyses confirmed that hiatal area (HA) of 19.5 cm2 during Valsalva maneuver can be used as single-screening index for abnormal levator hiatus distensibility with sensitivity of 0.80 and specificity of 0.70. In this study, we used a two-step method and achieved higher sensibility (0.80 vs. 0.87) without reducing specificity (0.70 vs. 0.71) compared with a single-screening index method. As a result, we suggest that HA≥19.5 cm2 during Valsalva maneuver is an indicator of abnormal levator hiatus distensibility in Chinese women and that the two-step method has higher sensitivity in detecting abnormal distensibility.

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Sensitivity of supplementation of thyroid hormone on treatment of idiopathic short-stature children during therapy with recombinant human growth hormone
Wei Wang, Shuqin Jiang, Zhirui Cui, Xiangyang Luo, Lingli Shi, Heli Zheng
Front. Med.. 2018, 12 (5): 580-585.  
https://doi.org/10.1007/s11684-017-0585-9

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This study aimed to evaluate the effects of thyroid hormone supplementation on growth rate of children with idiopathic short stature (ISS) and low-normal serum free thyroxine FT4 who were receiving growth hormone therapy. We selected 64 prepubertal children with FT4 levels in the lowest third of the normal range as the lower FT4 group, and these children were divided randomly into two subgroups: L-thyroxine (L-T4)-treated subgroup was treated with L-T4 (0.5–3.0 g/(kg·d)) from the beginning of the study, and the non-L-T4-treated subgroup received placebo. We also selected 39 ISS children with FT4 in the upper two-thirds of the normal range as the higher FT4 group. During the first year, the lower FT4 group featured lower FT3, FT4, thyroid stimulating hormone (TSH), and insulin-like growth factor-I standard deviation score (IGF-I SDS) and significantly lower height velocity (HV) compared with the higher FT4 group. However, in the lower FT4 group, the L-T4-treated subgroup presented higher FT4, FT3, TSH, and IGF-I SDS concentrations and significantly higher HV compared with children in the non-L-T4-treated subgroup. In children with ISS, the negative effect of thyroid hormone deficiency on growth rate should be considered when FT4 level lies in the low-normal range prior to recombinant human growth hormone treatment.

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Learning curve of totally thoracoscopic pulmonary segmentectomy
Weibing Wu, Jing Xu, Wei Wen, Yue Yu, Xinfeng Xu, Quan Zhu, Liang Chen
Front. Med.. 2018, 12 (5): 586-592.  
https://doi.org/10.1007/s11684-017-0566-z

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Totally thoracoscopic pulmonary segmentectomy (TTPS) is a feasible and safe technique that requires advanced thoracoscopic skills and knowledge of pulmonary anatomy. However, data describing the learning curve of TTPS have yet to be obtained. In this study, 128 patients who underwent TTPS between September 2010 and December 2013 were retrospectively analyzed to evaluate the learning curve and were divided chronologically into three phases, namely, ascending phase (A), plateau phase (B), and descending phase (C), through cumulative summation (CUSUM) for operative time (OT). Phases A, B, and C comprised 39, 33, and 56 cases, respectively. OT and blood loss decreased significantly from phases A to C (P <0.01), and the frequency of intraoperative bronchoscopy for target bronchus identification decreased gradually (A, 8/39; B, 4/33; C, 3/56; P = 0.06). No significant differences were observed in demographic factors, conversion, complications, hospital stay, and retrieved lymph nodes among the three phases. Surgical outcomes and techniques improved with experience and volume. CUSUMOT indicated that the learning curve of TTPS should be more than 72 cases.

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CASE REPORT
Venetoclax and low-dose cytarabine induced complete remission in a patient with high-risk acute myeloid leukemia: a case report
Bingshan Liu, Roshni Narurkar, Madhura Hanmantgad, Wahib Zafar, Yongping Song, Delong Liu
Front. Med.. 2018, 12 (5): 593-599.  
https://doi.org/10.1007/s11684-018-0635-y

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Conventional combination therapies have not resulted in considerable progress in the treatment of acute myeloid leukemia (AML). Elderly patients with AML and poor risk factors have grave prognosis. Midostaurin has been recently approved for the treatment of FLT-3-mutated AML. Venetoclax, a BCL-2 inhibitor, has been approved for the treatment of relapsed and/or refractory chronic lymphoid leukemia. Clinical trials on applying venetoclax in combination with cytarabine and other agents to treat various hematological malignancies are currently underway. Here, we present a case of a male patient with poor performance status and who developed AML following allogeneic hematopoietic stem cell transplant for high-risk myelodysplasia. The patient with high risk AML achieved complete response to the combined treatment regimen of low-dose cytarabine and venetoclax. Furthermore, we reviewed current clinical trials on the use of venetoclax for hematological malignancies.

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13 articles