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A pilot study of hydroxychloroquine in treatment of patients with moderate COVID-19
CHEN Jun,LIU Danping,LIU Li,LIU Ping,XU Qingnian,XIA Lu,LING Yun,HUANG Dan,SONG Shuli,ZHANG Dandan,QIAN Zhiping,LI Tao,SHEN Yinzhong,LU Hongzhou
J Zhejiang Univ (Med Sci)    2020, 49 (2): 215-219.   DOI: 10.3785/j.issn.1008-9292.2020.03.03
Abstract   HTML PDF (1044KB) ( 26145 )  

Objective: To evaluate the efficacy and safety of hydroxychloroquine (HCQ) in the treatment of patients with moderate coronavirus disease 2019 (COVID-19). Methods: We prospectively enrolled 30 treatment-naïve patients with confirmed COVID-19 after informed consent at Shanghai Public Health Clinical Center. The patients were randomized 1:1 to HCQ group and the control group. Patients in HCQ group were given HCQ 400 mg per day for 5 days plus conventional treatments, while those in the control group were given conventional treatment only. The primary endpoint was negative conversion rate of SARS-CoV-2 nucleic acid in respiratory pharyngeal swab on days 7 after randomization. This study has been approved by the Ethics Committee of Shanghai Public Health Clinical Center and registered online (NCT04261517). Results: One patient in HCQ group developed to severe during the treatment. On day 7, nucleic acid of throat swabs was negative in 13 (86.7%) cases in the HCQ group and 14 (93.3%) cases in the control group (P>0.05). The median duration from hospitalization to virus nucleic acid negative conservation was 4 (1, 9) days in HCQ group, which is comparable to that in the control group [2 (1, 4) days, Z=1.27, P>0.05]. The median time for body temperature normalization in HCQ group was 1 (0, 2) day after hospitalization, which was also comparable to that in the control group [1 (0, 3) day]. Radiological progression was shown on CT images in 5 cases (33.3%) of the HCQ group and 7 cases (46.7%) of the control group, and all patients showed improvement in follow-up examinations. Four cases (26.7%) of the HCQ group and 3 cases (20%) of the control group had transient diarrhea and abnormal liver function (P>0.05). Conclusions: The prognosis of COVID-19 moderate patients is good. Larger sample size study are needed to investigate the effects of HCQ in the treatment of COVID-19. Subsequent research should determine better endpoint and fully consider the feasibility of experiments such as sample size.

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Management of COVID-19: the Zhejiang experience
XU Kaijin,CAI Hongliu,SHEN Yihong,NI Qin,CHEN Yu,HU Shaohua,LI Jianping,WANG Huafen,YU Liang,HUANG He,QIU Yunqing,WEI Guoqing,FANG Qiang,ZHOU Jianying,SHENG Jifang,LIANG Tingbo,LI Lanjuan
J Zhejiang Univ (Med Sci)    2020, 49 (2): 147-157.   DOI: 10.3785/j.issn.1008-9292.2020.02.02
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The current epidemic situation of coronavirus disease 2019 (COVID-19) still remained severe. As the National Clinical Research Center for Infectious Diseases, the First Affiliated Hospital of Zhejiang University School of Medicine is the primary medical care center for COVID-19 in Zhejiang province. Based on the present expert consensus carried out by National Health Commission and National Administration of Traditional Chinese Medicine, our team summarized and established an effective treatment strategy centered on "Four-Anti and Two-Balance" for clinical practice. The "Four-Anti and Two-Balance" strategy included antivirus, anti-shock, anti-hyoxemia, anti-secondary infection, and maintaining of water, electrolyte and acid base balance and microecological balance. Meanwhile, integrated multidisciplinary personalized treatment was recommended to improve therapeutic effect. The importance of early viralogical detection, dynamic monitoring of inflammatory indexes and chest radiograph was emphasized in clinical decision-making. Sputum was observed with the highest positive rate of RT-PCR results. Viral nucleic acids could be detected in 10%patients' blood samples at acute period and 50%of patients had positive RT-PCR results in their feces. We also isolated alive viral strains from feces, indicating potential infectiousness of feces.Dynamic cytokine detection was necessary to timely identifying cytokine storms and application of artificial liver blood purification system. The "Four-Anti and Two-Balance" strategy effectively increased cure rate and reduced mortality. Early antiviral treatment could alleviate disease severity and prevent illness progression, and we found lopinavir/ritonavir combined with abidol showed antiviral effects in COVID-19. Shock and hypoxemia were usually caused by cytokine storms. The artificial liver blood purification system could rapidly remove inflammatory mediators and block cytokine storm.Moreover, it also favored the balance of fluid, electrolyte and acid-base and thus improved treatment efficacy in critical illness. For cases of severe illness, early and also short period of moderate glucocorticoid was supported. Patients with oxygenation index below 200 mmHg should be transferred to intensive medical center. Conservative oxygen therapy was preferred and noninvasive ventilation was not recommended. Patients with mechanical ventilation should be strictly supervised with cluster ventilator-associated pneumonia prevention strategies. Antimicrobial prophylaxis was not recommended except for patients with long course of disease, repeated fever and elevated procalcitonin (PCT), meanwhile secondary fungal infection should be concerned.Some patients with COVID-19 showed intestinal microbial dysbiosis with decreased probiotics such as Lactobacillus and Bifidobacterium, so nutritional and gastrointestinal function should be assessed for all patients.Nutritional support and application of prebiotics or probiotics were suggested to regulate the balance of intestinal microbiota and reduce the risk of secondary infection due to bacterial translocation. Anxiety and fear were common in patients with COVID-19. Therefore, we established dynamic assessment and warning for psychological crisis. We also integrated Chinese medicine in treatment to promote disease rehabilitation through classification methods of traditional Chinese medicine. We optimized nursing process for severe patients to promote their rehabilitation. It remained unclear about viral clearance pattern after the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Therefore, two weeks' quarantine for discharged patients was required and a regular following up was also needed.The Zhejiang experience and suggestions have been implemented in our center and achieved good results. However, since COVID-19 was a newly emerging disease, more work was warranted to improve strategies of prevention, diagnosis and treatment for COVID-19.

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Diagnosis and treatment recommendation for pediatric COVID-19 (the second edition)
CHEN Zhimin,FU Junfen,SHU Qiang,WANG Wei,CHEN Yinghu,HUA Chunzhen,LI Fubang,LIN Ru,TANG Lanfang,WANG Tianlin,WANG Yingshuo,XU Weize,YANG Zihao,YE Sheng,YUAN Tianming,ZHANG Chenmei,ZHANG Yuanyuan
J Zhejiang Univ (Med Sci)    2020, 49 (2): 139-146.   DOI: 10.3785/j.issn.1008-9292.2020.02.01
Abstract   HTML PDF (1074KB) ( 1015 )  

The coronavirus disease 2019 (COVID-19) has caused a global pandemic. All people including children are generally susceptible to COVID-19, but the condition is relatively mild for children. The diagnosis of COVID-19 is largely based on the epidemiological evidence and clinical manifestations, and confirmed by positive detection of virus nucleic acid in respiratory samples. The main symptoms of COVID-19 in children are fever and cough; the total number of white blood cell count is usually normal or decreased; the chest imaging is characterized by interstitial pneumonia, which is similar to other respiratory virus infections and Mycoplasma pneumoniae infections. Early identification, early isolation, early diagnosis and early treatment are important for clinical management. The treatment of mild or moderate type of child COVID-19 is mainly symptomatic. For severe and critical ill cases, the oxygen therapy, antiviral drugs, antibacterial drugs, glucocorticoids, mechanical ventilation or even extracorporeal membrane oxygenation (ECMO) may be adopted, and the treatment plan should be adjusted timely through multi-disciplinary cooperation.

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Study on the epidemic development of COVID-19 in Hubei province by a modified SEIR model
CAO Shengli,FENG Peihua,SHI Pengpeng
J Zhejiang Univ (Med Sci)    2020, 49 (2): 178-184.   DOI: 10.3785/j.issn.1008-9292.2020.02.05
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Objective: To establish a SEIR epidemic dynamics model that can be used to evaluate the COVID-19 epidemic, and to predict and evaluate the COVID-19 epidemic in Hubei province using the proposed model. Methods: COVID-19 SEIR transmission dynamics model was established, which took transmission ability in latent period and tracking quarantine interventions into consideration. Based on the epidemic data of Hubei province from January 23, 2020 to February 24, 2020, the parameters of the newly established modified SEIR model were fitted. By using Euler integral algorithm to solve the modified SEIR dynamics model, the epidemic situation in Hubei province was analyzed, and the impact of prevention and control measures such as quarantine and centralized treatment on the epidemic development was discussed. Results: The theoretical estimation of the epidemic situation by the modified SEIR epidemic dynamics model is in good agreement with the actual situation in Hubei province. Theoretical analysis showed that prevention and control quarantine and medical follow-up quarantine played an important inhibitory effect on the outbreak of the epidemic.The centralized treatment played a key role in the rapid decline in the number of infected people. In addition, it is suggested that individuals should improve their prevention awareness and take strict self-protection measures to curb the increase in infected people. Conclusion: The modified SEIR model is reliable in the evaluation of COVID-19 epidemic in Hubei province, which provides a theoretical reference for the decision-making of epidemic interventions.

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Dynamic changes of chest CT imaging in patients with COVID-19
WANG Jincheng,LIU Jinpeng,WANG Yuanyuan,LIU Wei,CHEN Xiaoqun,SUN Chao,SHEN Xiaoyong,WANG Qidong,WU Yaping,LIANG Wenjie,RUAN Lingxiang
J Zhejiang Univ (Med Sci)    2020, 49 (2): 191-197.   DOI: 10.3785/j.issn.1008-9292.2020.02.03
Abstract   HTML PDF (12251KB) ( 474 )  

Objective: To analyze the dynamic changes of chest CT images of patients with coronavirus disease 2019 (COVID-19). Methods: Fifty-two cases of COVID-19 were admitted in the First Affiliated Hospital of Zhejiang University School of Medicine. The consecutive chest CT scans were followed up for all patients with an average of 4 scans performed per patient during the hospitalization. The shortest interval between each scan was 2 days and the longest was 7 days. The shape, number and distribution of lung shadows, as well as the characteristics of the lesions on the CT images were reviewed. Results: The obvious shadows infiltrating the lungs were shown on CT images in 50 cases, for other 2 cases there was no abnormal changes in the lungs during the first CT examination. Ground-glass opacities (GGO) were found in 48 cases (92.3%), and 19 cases (36.5%) had patchy consolidation and sub-consolidation, which were accompanied with air bronchi sign in 17 cases (32.7%). Forty one cases (78.8%) showed a thickened leaflet interval, 4 cases (7.6%) had a small number of fibrous stripes. During hospitalization, GGO lesions in COVID-19 patients gradually became rare, the fibrous strip shadows increased and it became the most common imaging manifestation. The lesions rapidly progressed in 39 cases (75.0%) within 6-9 days after admission. On days 10-14 of admission, the lesions distinctly resolved in 40 cases (76.9%). Conclusion: The chest CT images of patients with COVID-19 have certain characteristics with dynamic changes, which are of value for monitoring disease progress and clinical treatment.

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Progress on cancer associated fibroblasts in tumor immunoregulation
LI Gaopeng,HE Jia,WANG Qingqing
J Zhejiang Univ (Med Sci)    2018, 47 (5): 558-563.   DOI: 10.3785/j.issn.1008-9292.2018.10.17
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Cancer associated fibroblasts (CAFs) are important components of the tumor microenvironment. Through secreting of multiple growth factors, cytokines and proteases, CAFs play a significant role in regulating the recruitment and function of various innate immune cells and adaptive immune cells in tumor microenvironment. In addition, extracellular matrix secreted by CAFs can also promote the formation of immunosuppression and hypoxia of tumor microenvironment. Here, we review the progress on CAFs in regulation of immune cells and tumor immunity.

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Pharmaceutical care for severe and critically ill patients with COVID-19
JIANG Saiping,LI Lu,RU Renping,ZHANG Chunhong,RAO Yuefeng,LIN Bin,WANG Rongrong,CHEN Na,WANG Xiaojuan,CAI Hongliu,SHENG Jifang,ZHOU Jianying,LU Xiaoyang,QIU Yunqing
J Zhejiang Univ (Med Sci)    2020, 49 (2): 158-169.   DOI: 10.3785/j.issn.1008-9292.2020.03.01
Abstract   HTML PDF (1156KB) ( 365 )  

Severe and critically ill patients with coronavirus disease 2019 (COVID-19) were usually with underlying diseases, which led to the problems of complicated drug use, potential drug-drug interactions and medication errors in special patients. Based on Diagnosis and treatment of novel coronavirus pneumonia (trial version 6), and Management of COVID-19: the Zhejiang experience, we summarized the experience in the use of antiviral drugs, corticosteroids, vascular active drugs, antibacterial, probiotics, nutrition support schemes in severe and critically ill COVID-19 patients. It is also suggested to focus on medication management for evaluation of drug efficacy and duration of treatment, prevention and treatment of adverse drug reactions, identification of potential drug-drug interactions, individualized medication monitoring based on biosafety protection, and medication administration for special patients.

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Anesthesia management in cesarean section for patient with COVID-19: a case report
KANG Xianhui,ZHANG Rong,HE Huiliang,YAO Yongxing,ZHENG Yueying,WEN Xiaohong,ZHU Shengmei
J Zhejiang Univ (Med Sci)    2020, 49 (2): 249-252.   DOI: 10.3785/j.issn.1008-9292.2020.03.04
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Since the coronavirus disease 2019 (COVID-19) affects the cardio-pulmonary function of pregnant women, the anesthetic management and protection of medical staff in the cesarean section is significantly different from that in ordinary surgical operation. This paper reports a case of cesarean section for a woman with COVID-19, which was successfully performed in the First Affiliated Hospital of Zhejiang University School of Medicine on February 8, 2020. Anesthetic management, protection of medical staff and psychological intervention for the pregnant woman during the operation were discussed. Importance has been attached to the preoperative evaluation of pregnant women with COVID-19 and the implementation of anesthesia plan. For moderate patients, intraspinal anesthesia is preferred in cesarean section, and try to reduce its influence in respiration and circulation in both maternal and infant; general anesthesia with endotracheal intubation should be adopted for severe or critically ill patients. Ensure the safety of medical environment, and anesthetists should carry out level-Ⅲ standard protection. Special attention and support should be paid to maternal psychology: fully explanation before operation to reduce anxiety; relieve the discomfort during operation, so as to reduce tension; avoid the bad mood due to pain after operation.

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Clinical observation of 6 severe COVID-19 patients treated with plasma exchange or tocilizumab
LUO Song,YANG Lijuan,WANG Chun,LIU Chuanmiao,LI Dianming
J Zhejiang Univ (Med Sci)    2020, 49 (2): 227-231.   DOI: 10.3785/j.issn.1008-9292.2020.03.06
Abstract   HTML PDF (1042KB) ( 331 )  

Objective: To observe the clinical effect of plasma exchange and tocilizumab in treatment of patients with severe coronavirus disease 2019 (COVID-19). Methods: Six patients with severe COVID-19 admitted in First Affiliated Hospital of Bengbu Medical College from January 25 to February 25, 2020. Three patients were treated with plasma exchange and three patients were treated with tocilizumab. The effect on excessive inflammatory reaction of plasma exchange and tocilizumab was observed. Results: The C-reactive protein (CRP) and IL-6 levels were significantly decreased and the lymphocyte and prothrombin time were improved in 3 patients after treatment with plasma exchange; while inflammation level was not significantly decreased, and lymphocyte and prothrombin time did not improve in 3 patients treated with tocilizumab. Conclusion: For severe COVID-19 patients with strong inflammatory reaction, plasma exchange may be preferred.

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Principles and suggestions on biosafety protection of biological specimen preservation during prevalence of COVID-19
ZHANG Xiaoyan, SUN Wei, SHANG Shiqiang, MAO Jianhua, FU Junfen, SHU Qiang, JIANG Kewen
J Zhejiang Univ (Med Sci)    2020, 49 (2): 170-177.   DOI: 10.3785/j.issn.1008-9292.2020.02.04
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Coronavirus disease 2019 (COVID-19) is a grade B infectious disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). In pace with the spreading of the disease, biosafety risk of the biological specimen preservation in biobanks has been significantly increased and biosafety protection during biological specimen preservation become increasingly important. According to the related national rules and the corresponding guidelines of Chinese Medical Association, this paper introduced the etiology about SARS-CoV-2, epidemiology about COVID-19, and the biosafety protection principles of individuals and biological specimen storage places in the process of personal protection, protection of collection, transport, handling, preservation, detection, post-detection disposal and emergencies of biological specimen. Emphasized to carry out a strict biosafety-risk assessment on biological specimen basing on virus load information, infectivity, and sample type (possible contact transmission, aerosol transmission, and fecal oral transmission).

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Progress on structural biology of voltage-gated ion channels
SONG Fangjun,GUO Hongtao
J Zhejiang Univ (Med Sci)    2019, 48 (1): 25-33.   DOI: 10.3785/j.issn.1008-9292.2019.02.05
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Ion channels mediate ion transport across membranes, and play vital roles in processes of matter exchange, energy transfer and signal transduction in living organisms. Recently, structural studies of ion channels have greatly advanced our understanding of their ion selectivity and gating mechanisms. Structural studies of voltage-gated potassium channels elucidate the structural basis for potassium selectivity and voltage-gating mechanism; structural studies of voltage-gated sodium channels reveal their slow and fast inactivation mechanisms; and structural studies of transient receptor potential (TRP) channels provide complex and diverse structures of TRP channels, and their ligand gating mechanisms. In the article we summarize recent progress on ion channel structural biology, and outlook the prospect of ion channel structural biology in the future.

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Frontiers in structural biology
YANG Fan,YANG Wei
J Zhejiang Univ (Med Sci)    2019, 48 (1): 1-4.   DOI: 10.3785/j.issn.1008-9292.2019.02.01
Abstract   HTML PDF (459KB) ( 249 )  
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Follow-up testing of viral nucleic acid in discharged patients with moderate type of COVID-19
LI Youjiang,HU Yingying,ZHANG Xiaodong,YU Yuanyuan,LI Bin,WU Jianguo,WU Yingping,XIA Xiaoping,XU Jian
J Zhejiang Univ (Med Sci)    2020, 49 (2): 270-274.   DOI: 10.3785/j.issn.1008-9292.2020.03.11
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Objective: To investigate the clinical outcome of patients with moderate type of coronavirus disease 2019 (COVID-19) after discharge by retesting viral nucleic acid. Methods: Seven patients with moderate COVID-19 met the discharge criteria enacted by National Health Commission were quarantined in hospital for 7 days, then continuously quarantined at home for 4 weeks after discharged. During the quarantined period, the symptoms and signs were documented, and sputum or nasal swab and feces samples were collected to test SARS-CoV-2 nucleic acid by RT-PCR method. Results: There was no symptoms and signs during the quarantine period in all 7 patients. However, respiratory swabs from 3 patients were confirmed positive of SARS-CoV-2 nucleic acid at 5 to 7 days after they met the discharge criteria. Conclusion: There is a relatively high incidence of positive viral nucleic acid in patients met the discharge criteria, and it is suggested that patients met the current discharge criteria should be quarantined in hospital for another 7 days and the follow-up viral testing is necessary.

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Pregnant women complicated with COVID-19: a clinical analysis of 3 cases
CHEN Xu,LI Yang,WANG Jinxi,CAI Hongliu,CAO Hongcui,SHENG Jifang
J Zhejiang Univ (Med Sci)    2020, 49 (2): 240-244.   DOI: 10.3785/j.issn.1008-9292.2020.03.08
Abstract   HTML PDF (2811KB) ( 232 )  

Objective: To analyze the clinical characteristics and pregnancy outcomes of pregnant women complicated with coronavirus disease 2019 (COVID-19). Methods: The clinical data of 3 pregnant women with COVID-19 admitted to the First Affiliated Hospital of Zhejiang University School of Medicine from January 19 to February 10, 2020 were retrospectively analyzed. Results: There was one case in the first-trimester pregnancy (case 1), one in the second-trimester pregnancy (case 2) and one in third-trimester pregnancy (case 3). Cough, fever, fatigue, lung imaging changes were the main manifestations. The white cell count, lymphocyte percentage had no significantly changes in case 1 and case 3, while the levels of C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), IL-6 and IL-10 elevated. The lymphocyte count and lymphocyte percentage decreased and the inflammatory indicators significantly increased in case 2. All patients were treated with antiviral, antitussive, oxygen inhalation; case 3 received glucocorticoids, case 2 with severe illness received glucocorticoids and additionally gamma globulin. All three cases were cured and discharged. Case 1 with early pregnancy chose to terminate pregnancy after discharge; case 2 chose to continue pregnancy without obstetric complications; and case 3 had cesarean section delivery due to abnormal fetal heart monitoring. Conclusion: The report shows that COVID-19 in pregnancy women could be cured with active treatment, and the maternal and fetal outcomes can be satisfactory.

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Advances in newborn screening and immune system reconstitution of severe combined immunodeficiency
HUANG Shumin,ZHAO Zhengyan
J Zhejiang Univ (Med Sci)    2019, 48 (4): 351-357.   DOI: 10.3785/j.issn.1008-9292.2019.08.01
Abstract   HTML PDF (913KB) ( 193 )  

Severe combined immunodeficiency disease (SCID) is a group of rare congenital diseases characterized by severe deficiencies in T lymphocyte counts and/or function. The recurrent, persistent and severe infections are its clinical manifestations. Neonatal screening and immune system reconstruction would improve the prognosis of SCID children. Newborn screening programs based on T-cell receptor excision circles (TRECs) quantitative detection have been carried out in clinical practice, however, the methods still have some limitations. Other new methods such as mass spectrometry and T lymphocyte-specific biomarker assays are still under investigation. Hematopoietic stem cell transplantation and gene therapy are the two main methods for reconstructing immune function in SCID children. Through improving the success rate of transplantation and the long-term safety and stability of viral vectors, some achievements have been made by many centers already. However, large-scale prospective studies are needed for evaluation of the long-term efficacy. In this article, the recent progress in newborn screening and immune reconstitution of SCID is reviewed.

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CT imaging features of patients with different clinical types of COVID-19
ZHONG Qi,LI Zhi,SHEN Xiaoyong,XU Kaijin,SHEN Yihong,FANG Qiang,CHEN Feng,LIANG Tingbo
J Zhejiang Univ (Med Sci)    2020, 49 (2): 198-202.   DOI: 10.3785/j.issn.1008-9292.2020.03.05
Abstract   HTML PDF (4462KB) ( 190 )  

Objective: To investigate the CT findings of patients with different clinical types of coronavirus disease 2019 (COVID-19). Methods: A total of 67 patients diagnosed as COVID-19 by nucleic acid testing were collected and divided into 4 groups according to the clinical stages based on Diagnosis and treatment of novel coronavirus pneumonia (trial version 6). The CT imaging characteristics were analyzed among patients with different clinical types. Results: Among 67 patients, 3(4.5%) were mild, 35 (52.2%) were moderate, 22 (32.8%) were severe, and 7(10.4%) were critical ill. No significant abnormality in chest CT imaging in mild patients. The 35 cases of moderate type included 3 (8.6%) single lesions, the 22 cases of severe cases included 1 (4.5%) single lesion and the rest cases were with multiple lesions. CT images of moderate patients were mainly manifested by solid plaque shadow and halo sign (18/35, 51.4%); while fibrous strip shadow with ground glass shadow was more frequent in severe cases (7/22, 31.8%). Consolidation shadow as the main lesion was observed in 7 cases, and all of them were severe or critical ill patients. Conclusion: CT images of patients with different clinical types of COVID-19 have characteristic manifestations, and solid shadow may predict severe and critical illness.

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Advances in molecular mechanism of vascular remodeling in pulmonary arterial hypertension
XIAO Li,TONG Xiaoyong
J Zhejiang Univ (Med Sci)    2019, 48 (1): 102-110.   DOI: 10.3785/j.issn.1008-9292.2019.02.15
Abstract   HTML PDF (881KB) ( 189 )  

Pulmonary arterial hypertension (PAH) is a clinical hemodynamic syndrome characterized by elevated pulmonary arterial pressure and pulmonary vascular resistance leading to right heart failure and death. Vascular remodeling is the most prominent histopathological feature of PAH, which is regulated by many factors. Endoplasmic reticulum stress, calcium disorder and mitochondrial dysfunction are involved in the vascular cell proliferation and apoptosis by regulating intracellular calcium homeostasis and cellular metabolism. Epigenetic phenomenon such as DNA damage and abnormal expression of miRNA are also involved in the regulation of abnormal proliferation of vascular cells. Vascular cell phenotype switching including endothelial-mesenchymal transition and smooth muscle cell phenotype switching play an important role in abnormal proliferation of vascular cells. Vascular remodeling is produced by a variety of cells and molecular pathways, and aiming at multiple targets which is expected to find a new breakthrough in the treatment of PAH, and to improve abnormal vascular remodeling, delay or even reverse the progression of PAH.

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Application of mechanosensitive channels in sonogenetics
HONG Feifan,LI Yuezhou
J Zhejiang Univ (Med Sci)    2019, 48 (1): 34-38.   DOI: 10.3785/j.issn.1008-9292.2019.02.06
Abstract   HTML PDF (725KB) ( 179 )  

As a non-invasive approach, sonogenetics is applied to control neuronal activity. The mechanosensitive channel(MSC), which has low threshold of responding to ultrasound, may be the alternative solution. Sonogenetics is the technique that activates the MSC expressed in targeted neurons by low intensity ultrasound, thus achieve the neuromodulation. In this review, we introduce the mechanosensitive channel of large conductance, transient receptor potential, channels of the two-pore-domain potassium family, Piezo and the recent progress on their application in sonogenetics.

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Diagnostic efficacy of three test kits for SARS-CoV-2 nucleic acid detection
SHEN Lihua,HUANG Fei,CHEN Xiang,XIONG Zuan,YANG Xiaoyu,LI Hui,CHENG Feng,GUO Jian,GONG Guofu
J Zhejiang Univ (Med Sci)    2020, 49 (2): 185-190.   DOI: 10.3785/j.issn.1008-9292.2020.03.09
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Objective: To compare the diagnostic efficacy among three RT-PCR test kits for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleic acid detection. Methods: The throat swab samples from 40 hospitalized patients clinically diagnosed as coronavirus disease 2019 (COVID-19) and 16 hospitalized non-COVID-19 patients were recruited. The SARS-CoV-2 nucleic acid was detected in throat swab samples with RT-PCR test kits from Sansure Biotech ("Sansure" for short), Jiangsu Bioperfectus Technologies ("Bioperfectus" for short) and BGI Genomics ("BGI" for short). The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and Kappa value were analyzed. The viral nucleic acid was extracted from the throat swab samples by one-step cleavage and magnetic bead methods, and the efficacy of two extraction methods was also compared. The results of magnetic bead method for nucleic acid extraction by two different extractors (Sansure Natch CS S12C Fully Automated Nucleic Acid Extraction System vs. Tianlong NP968-C Nucleic Acid Extractor) were also compared. Results: The sensitivity, specificity, PPV, NPV and kappa value were 95.00%, 87.50%, 95.00%, 87.50%and 0.825 for Sansure kit; 90.00%, 87.50%, 94.74%, 77.78%and 0.747 for the Bioperfectus kit, and 82.50%, 81.25%, 91.67%, 65.00%and 0.593 for the BGI kit, respectively. The positive, negative and total coincident rates and kappa value of viral nucleic acid detection results using the samples extracted by one-step cleavage and magnetic bead methods were 95.24%, 100.00%, 96.43%and 0.909, respectively, but the one-step cleavage method took only 25 min, while the magnetic bead method required 180 min. The positive, negative and total coincident rates and kappa value of viral nucleic acid detection results using the samples extracted by the two different nucleic acid extractors were 85.00%, 100.00%, 89.29% and 0.764, respectively. Conclusion: The detection efficacy for SARS-CoV-2 nucleic acid by the Sansure kit is relatively higher and the one-step cleavage method has advantages of convenient operation and less time consuming.

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Clinical analysis of suspected COVID-19 patients with anxiety and depression
LI Xin,DAI Tian,WANG Hong,SHI Junnian,YUAN Wei,LI Jing,CHEN Lijun,ZHANG Tianming,ZHANG Shanshan,KONG Yan,YUE Ning,SHI Hui,HE Yuping,HU Huifang,LIU Furong,YANG Caixia
J Zhejiang Univ (Med Sci)    2020, 49 (2): 203-208.   DOI: 10.3785/j.issn.1008-9292.2020.03.02
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Objective: To explore the risk factors of anxiety and depression in patients with suspected coronavirus disease 2019 (COVID-19) so as to achieve early intervention and better clinical prognosis. Methods: Seventy-six patients with suspected COVID-19 in fever isolation wards of Second Hospital of Lanzhou University were enrolled From January 31, 2020 to February 22, 2020. Their clinical baseline data were collected. The anxiety of patients was assessed by Hamilton Anxiety Scale, and the depression of patients was assessed by Hamilton Depression Scale. Multivariate Logistic regression analysis was performed to explore the risk factors of anxiety and depression in these patients. Results: Female patients are more likely to have anxiety (OR=3.206, 95%CI:1.073-9.583, P < 0.05) and depression (OR=9.111, 95%CI:2.143-38.729, P < 0.01) than male patients; patients with known contact history of epidemic area and personnel in epidemic area are more likely to have depression (OR=3.267, 95%CI:1.082-9.597, P < 0.05). Conclusion: During the isolation treatment of suspected COVID-19 patients, early psychological intervention should be carried out for the female patients with known contact history of epidemic area and personnel in epidemic area, and drug treatment should be given in advance if necessary.

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Mechanisms of herpes simplex virus latency and reactivation
SUN Boqiang,WANG Qiongyan,PAN Dongli
J Zhejiang Univ (Med Sci)    2019, 48 (1): 89-101.   DOI: 10.3785/j.issn.1008-9292.2019.02.14
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Herpes simplex virus (HSV), including HSV-1 and HSV-2, is an important pathogen that can cause many diseases. Usually these diseases are recurrent and incurable. After lytic infection on the surface of peripheral mucosa, HSV can enter sensory neurons and establish latent infection during which viral replication ceases. Moreover, latent virus can re-enter the replication cycle by reactivation and return to peripheral tissues to start recurrent infection. This ability to escape host immune surveillance during latent infection and to spread during reactivation is a viral survival strategy and the fundamental reason why no drug can completely eradicate the virus at present. Although there are many studies on latency and reactivation of HSV, and much progress has been made, many specific mechanisms of the process remain obscure or even controversial due to the complexity of this process and the limitations of research models. This paper reviews the major results of research on HSV latency and reactivation, and discusses future research directions in this field.

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Dynamic inflammatory response in a critically ill COVID-19 patient treated with corticosteroids
ZHAGN Sheng,LI Danping,CHEN Huazhong,ZHENG Dan,ZHOU Yiping,CHEN Baoguo,SHI Weiwu,LIN Ronghai
J Zhejiang Univ (Med Sci)    2020, 49 (2): 220-226.   DOI: 10.3785/j.issn.1008-9292.2020.03.10
Abstract   HTML PDF (4582KB) ( 143 )  

Objective: To investigate the effect of corticosteroids therapy on the inflammatory response in a critically ill coronavirus disease 2019 (COVID-19) patient. Methods: A 55-year old female patient with critical ill COVID-19 was admitted in Taizhou Hospital on January 19, 2020. The patient was treated with methylprednisolone 80 mg on the 2nd day after admission. Thereafter, the dose was adjusted in a timely manner and the therapy lasted for 13 days. The peripheral lymphocyte subsets (CD3+T, CD4+ T, CD8+ T, NK cells, B cells), as well as serum levels of lymphocyte factors (IL-2, IL-4, IL-6, IL-10, TNF-α, IFN-γ) were dynamically monitored. Results: On D1 of admission, the numbers of peripheral blood CD3+ T, CD4+ T, CD8+ T, and NK cells were significantly lower than the normal range. With the improvement of the disease, the numbers of CD3+ T, CD8+ T and CD4 + T cells gradually recovered and showed a linear growth trend (linear fitting equation: Y=18.59X+109.4, P < 0.05). On D2 of admission, the patient's IL-6 and IL-10 levels were significantly higher than normal values, IFN-γ was at a normal high value, and then rapidly decreased; IL-2, IL-4, and TNF-α were all in the normal range. On the D6 and D7, the IL-6 and IL-10 decreased to the normal range for the first time. On the D18, the sputum virus nucleic acid test was negative for the first time, and the fecal virus nucleic acid test was still positive; on the D20 the sputum and fecal virus nucleic acid test were both negative. On D34, the patient recovered and was discharged. At the discharge the muscle strength score of the patient was 44 and the daily life ability evaluation was 90. Conclusion: In the absence of effective antiviral drugs, early use of appropriate doses of corticosteroids in critically ill patient with COVID-19 can quickly alleviate inflammatory response and improve clinical symptoms, however, it may reduce the number of T cells, and to adjust the dose in time is necessary.

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Management of a colon cancer patient complicated with COVID-19
YE Ziqi,HONG Yun,WU Xiuhua,HONG Dongsheng,ZHANG Yanfang,DONG Xihao,RAO Yuefeng,LU Xiaoyang
J Zhejiang Univ (Med Sci)    2020, 49 (2): 245-248.   DOI: 10.3785/j.issn.1008-9292.2020.03.12
Abstract   HTML PDF (1028KB) ( 141 )  

Objective: To explore the feasibility of radical resection for cancer patients complicated with coronavirus disease 2019 (COVID-19). Methods: The management and clinical outcome of a sigmoid cancer patient with COVID-19 were analyzed. Results: The inflammation indicators and fever of this patient were effectively controlled and the lung lesions remained stable after active anti-viral treatment, then the radical colorectomy was performed after the viral negative conversion for twice. Conclusion: The case indicates that radical resection can be performed in SARS-CoV-2 patients with twice-negative SARS-CoV-2 nucleic acid testing results.

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Single-particle cryo-electron microscopy opens new avenues in structural biology of G protein-coupled receptor
LI Chuntao,ZHANG Huibing,ZHANG Yan
J Zhejiang Univ (Med Sci)    2019, 48 (1): 39-43.   DOI: 10.3785/j.issn.1008-9292.2019.02.07
Abstract   HTML PDF (1360KB) ( 141 )  

G protein-coupled receptors (GPCRs) represent the largest class of cell surface receptors, mediating wide range of cellular and physiological processes through their transducers, G proteins and the-arrestins participate in almost all pathological processes. Recent technological advances are revolutionizing the utility of cryo-electron microscopy (cryo-EM), leading to a tremendous progress in the structural studies of biological macromolecules and cryo-EM has played a leading role in the structural biology of GPCR signaling complex. New discoveries of high-resolution three-dimensional structures of GPCR signaling complexes based on cryo-EM have emerged vigorously, which depict the common structural characteristics of intermolecular interaction between GPCR and G protein complex-the conformational changes of the transmembrane helix 6 of receptors, and also demonstrate the structural basis of G protein subtype selectivity. Single-particle cryo-EM becomes an efficient tool for identifying the molecular mechanism of receptor-ligand interaction, providing important information for understanding GPCR signaling and the structure-based drug design.

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Progress on evaluation, diagnosis and management of disorders of sex development
CHEN Guangjie,WANG Xiaohao,TANG Daxing
J Zhejiang Univ (Med Sci)    2019, 48 (4): 358-366.   DOI: 10.3785/j.issn.1008-9292.2019.08.02
Abstract   HTML PDF (928KB) ( 139 )  

Disorders of sex development (DSD) refer to a group of diseases characterized by abnormal congenital development of chromosomes, gonad or genitals with different pathophysiological changes and clinical manifestations. DSD is more common in neonates and adolescents, and neonates often show genital abnormalities while adolescents show abnormal sexual development during puberty. It is the international consensus that the scope of DSD should include basic clinical evaluation (internal and external genitalia and endocrine hormones), diagnostic confirmation (chromosome, genetic diagnosis), psychological assessment for children and family, treatment (sex assignment, hormone replacement and surgical intervention), potential fertility protection and long-term follow-up, which require the expertise of pediatric endocrinology, pediatric urology, clinical psychology, genetic disciplines, medical images and other related disciplines; that is, individualized management of children with DSD requires an experienced multidisciplinary team (MDT). This article reviews the recent progress on the evaluation, diagnosis and management of disorders of sex development.

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What is narrative medicine?
GUO Liping
J Zhejiang Univ (Med Sci)    2019, 48 (5): 467-473.   DOI: 10.3785/j.issn.1008-9292.2019.10.01
Abstract   HTML PDF (1081KB) ( 134 )  

Narrative medicine first entered China in 2011 and has developed rapidly since then. The patient-centered care, shared decision making and relational medicine in the medical sphere, together with patients narrating their illness and narratology contributed to the rise of narrative medicine. Through listening to patients' narratives, paying attention to their emotions, and representing their stories in various ways, clinicians can connect with patients and empathize with them. In this way, affiliation and mutual trust with patients can be established. Patients will feel good in the doctor-patient encounter because of such humane care, and clinicians may get satisfaction from their work. Narrative medicine courses characterized by close reading of literature and writing should be added to the curriculum of medical education as the major content of medical humanities, so as to train narrative competence for the future doctors.

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Application of mesenchymal stem cells in antineoplastic drugs delivery for tumor-targeted therapy
WANG Xiaoling,OUYANG Xumei,SUN Xiaoyi
J Zhejiang Univ (Med Sci)    2018, 47 (5): 525-533.   DOI: 10.3785/j.issn.1008-9292.2018.10.13
Abstract   HTML PDF (914KB) ( 127 )  

In recent years, a large number of studies have achieved tumor targeting by mesenchymal stem cells (MSC)-based delivery system attributed to the tumor tropism of MSCs. Biomacromolecules and antineoplastic drugs loaded on MSC via internalization or cell membrane anchoring can be released or expressed at tumor site to perform their antitumor effects. The genetically modified MSC are extensively studied, however, the applications of MSCs in targeted delivery of antineoplastic drug with small molecules are not well summarized. In this review, MSCs homing mechanism and the distribution of injected MSCs in vivo is introduced; the examples of antitumor drug-primed MSCs and drug loaded MSCs are presented; the drug loading and releasing process from MSCs is also illustrated; finally, challenges and future perspectives of MSCs-based drug delivery system on realizing its full potential are prospected.

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Noninvasive prenatal screening for twin pregnancy: an analysis of 2057 cases
YIN Yixuan,ZHU Hui,QIAN Yeqing,JIN Jinglei,MEI Jin,DONG Minyue
J Zhejiang Univ (Med Sci)    2019, 48 (4): 403-408.   DOI: 10.3785/j.issn.1008-9292.2019.08.09
Abstract   HTML PDF (905KB) ( 126 )  

Objective: To analyze the results of noninvasive prenatal screening (NIPS) for fetal chromosome aneuploidy in twin pregnancy. Methods: A total of 2057 women with twin-pregnancy between 12-26+6 weeks were recruited from Women's Hospital, Zhejiang University School of Medicine, Hangzhou Municipal Women's Hospital and Jiaxing Maternal and Child Health Hospital during February 2015 to August 2018. The cell-free DNA was extracted from the peripheral blood sample for DNA library, and non-invasive prenatal testing (NIPT) was performed by high-throughput sequencing technique. The fetal karyotype analysis or neonatal karyotype analysis was performed in pregnant women with fetal chromosome aneuploidy, and all subjects were followed up. The efficiency of NIPS testing for twin aneuploidy was calculated. Results: NIPS revealed chromosome abnormalities in 11 out of 2057 twin pregnant women, 9 cases were confirmed chromosome abnormalities, 2 cases were normal and no false negative cases. In this screening, the detection rate, sensitivity, specificity, positive predictive value, false positive rate of NIPS were 100.00%, 100.00%, 99.90%, 81.82%, 0.10%. Those were 100.00%, 100.00%, 99.95%, 87.50% and 0.05% for trisomy 21, 100.00%, 100.00%, 100.00%, 100.00%, 0.00% for trisomy18, and the specificity and false positive rate for trisomy13 were 99.95% and 0.05%, respectively. Conclusion: NIPS can detect fetal chromosomal aneuploidy rapidly and accurately in twin pregnancies, and it is of value in clinical application.

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Stratified treatment and management of adenomyosis
ZHANG Xinmei,XU Ping
J Zhejiang Univ (Med Sci)    2019, 48 (2): 123-129.   DOI: 10.3785/j.issn.1008-9292.2019.04.01
Abstract   HTML PDF (1005KB) ( 124 )  

In recent years, surgical and non-surgical excision and drug therapy have replaced hysterectomy as the main therapeutic modalities for adenomyosis. It is suggested that the precise clinical diagnosis should be based on the reconstruction of digitized three-dimensional model with original image data of adenomyosis. Patients' age and clinical manifestations should also be considered, and the patients should be stratified according to reproductive requirements, so as to determine the best treatment. In view of the infiltration and diffuse growth of adenomyosis lesions in the myometrium of the uterus, it is suggested that long-term drug management should be adopted after surgical or non-surgical lesion resection.Gonadotropin releasing hormone agonists, levonorgestrel-releasing intrauterine system, dienogest and short-acting oral contraceptives should be recommended to consolidate the curative effect in order to delay the progress of the disease and prevent recurrence.

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Anti-inflammatory effect of interleukin-35 in mice with colitis and its mechanism
LU Zhanjun,HU Yangyang,LI Sisi,ZANG Lijuan,JIANG Weiliang,WU Jianjiong,WU Xiening,ZENG Yue,WANG Xingpeng
J Zhejiang Univ (Med Sci)    2018, 47 (5): 499-506.   DOI: 10.3785/j.issn.1008-9292.2018.10.09
Abstract   HTML PDF (1635KB) ( 122 )  

Objective: To investigate the anti-inflammatory effect and mechanisms of interleukin-35 (IL-35) in inflammatory bowel disease. Methods: BALB/c mice were divided into three groups with 10 mice in each group:control group, model group (oral administration of 4% glucan sodium sulfate for 7 d) and IL-35-treated group (oral administration of 4% glucan sodium sulfate for 7 d, intraperitoneal injection of 2 μg IL-35 at d2-5). Disease activity index (DAI) was scored every day. After 7 d, the mice were sacrificed, and the serum and intestinal tissue samples were collected. The gross morphology of the colon was observed; HE staining was used to observe the pathological changes of colon tissue; flow cytometry was employed to detect the change of macrophage polarization ratio in colon tissue; the mRNA expression levels of cytokines IL-6, TNF-α, IFN-γ, IL-10 and SHIP1 in colon tissue were determined by real-time quantitative RT-PCR; the expression and distribution of SHIP1 in colon tissue was measured by immunohistochemistry; Western blotting was adopted to detect the expression level of SHIP1 protein in colonic intestinal tissues of each group. Results: The DAI scores of the mice in the model group were higher than those in the control group, while the DAI scores in the IL-35-treated group were lower than those in the model group (all P < 0.01). Compared with the control group, the colon length was significantly shortened in the model group (P < 0.05), while the colon length of the IL-35-treated group had an increasing trend compared with the model group, but the difference was not statistically significant (P > 0.05). Compared with the model group, microscopic inflammatory infiltration score was decreased and microscopic crypt destruction and score was significantly lower in IL-35-treated group (all P < 0.05). The relative expression of proinflammatory cytokines IL-6, TNF-α and IFN-γ in the colon tissue of IL-35-treated group was decreased compared with the model group, while the relative expression of IL-10 mRNA was higher than that of the model group (all P < 0.05). Compared with the control group, the proportion of M1 macrophages in the model group increased (P < 0.05), while the proportion of M1 macrophages in the IL-35-treated group was lower than that in the model group (P < 0.05). The relative expression of SHIP1 mRNA and protein in the colon tissue of IL-35-treated group was higher than that in the model group (all P < 0.05). Conclusion: IL-35 can inhibit the polarization of M1 macrophages and regulate inflammatory cytokines to promote anti-inflammatory effect on mice with colitis.

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Relationship between temperament, parenting style and resilience of children aged 3-5 years
NIU Yubai,ZHANG Lingyan,HAO Zesheng,JI Yuzhu
J Zhejiang Univ (Med Sci)    2019, 48 (1): 75-82.   DOI: 10.3785/j.issn.1008-9292.2019.02.12
Abstract   HTML PDF (642KB) ( 122 )  
Objective

To investigate the developmental characteristics of resilience in children aged 3-5, and to explore the relationship between temperament, parenting style and resilience.

Methods

A total of 570 preschoolers aged 3-5 years in Hangzhou participated in this study. The children’s teachers completed the assessment of the resilience scale of DECA-P2 (Devereux Early Childhood Assessment for Preschoolers Second Edition); the children’s parents completed assessment of temperament questionnaire CBQ (Children’s Behavior Questionnaire) and parenting style questionnaire PSDQ (Parenting Styles and Dimensions Questionnaire).

Results

Totally 432 valid questionnaires were retrieved with a recovery rate of 75.79%. The levels of initiative and self-regulation of 5-y children were higher than those of children aged 3 or 4 (all P<0.01); the level of attachment/relationship of 5-y children was higher than that of children aged 4 (P<0.01); the levels of initiative and self-regulation of girls were higher than those of boys (P<0.05 or P<0.01). The negative affect dimension of temperament was negatively correlated with resilience (all P<0.05), while the effortful control and authoritative parenting styles were positively correlated with resilience (all P<0.05). The negative affect and effortful control were able to partially predict resilience of children through authoritative parenting style (mediating effect were -0.0143 and 0.0363).

Conclusion

Preschoolers aged 3-5 years with different age and gender show differences in resilience, and parenting styles may play a mediating effect between temperament and resilience.

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Relative security of health care big data protection
LIU Chunfu,CHEN Hongmin
J Zhejiang Univ (Med Sci)    2018, 47 (6): 563-576.   DOI: 10.3785/j.issn.1008-9292.2018.12.01
Abstract   HTML PDF (1185KB) ( 114 )  

With China's implementing big data strategy, health care becomes one of the key areas in which the national big data strategy is highly promoted. However, as the health care big data industry grows rapidly, the security risk is increasingly prominent and the internet plus medical care makes the protection of health care big data more complicated. By analyzing the current situation of health care big data security protection, the article proposes the viewpoint of relative security and suggests the strategies and key issues of health care big data protection. From the aspects of legal supervision, talents cultivation, publicity and education, and key data protection, it is necessary to build the prevention and control system for health care big data security, so that the security risk can be reduced and the data utility can be maximized.

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Extraction and purification of NUDT9 homology domain of human transient receptor potential melastatin 2 channel
YE Peiwu,YU Xiafei,MA Cheng,YANG Wei
J Zhejiang Univ (Med Sci)    2019, 48 (1): 5-11.   DOI: 10.3785/j.issn.1008-9292.2019.02.02
Abstract   HTML PDF (1227KB) ( 109 )  
Objective

To develop methods of extraction and purification of C-terminal NUDT9 homology domain of human transient receptor potential melastatin 2 (TRPM2) channel.

Methods

After sonication and centrifuge of Escherichia coli strain Rosetta (DE3) which was induced by isopropylthio-β-D-galactoside, GST-NUDT9-H was collected after the binding of supernatant with GST beads and eluted with reduced glutathione. Then the elution buffer containing fusion protein was purified by size exclusion chromatography after concentration and centrifuge. Finally, with the cleavage of thrombin and binding with the GST beads, NUDT9-H with high purity in supernatant was collected.

Results

The GST-NUDT9-H fusion protein was stabilized with lysis buffer containing 0.5% n-dodecyl-β-d-maltoside (DDM), and wash buffer containing 0.025% DDM in size-exclusion chromatography system, and finally the NUDT9-H with high purity was obtained after cleaved by thrombin (1 U/2 mg fusion protein) for 24 h.

Conclusion

Due to the poor stability of NUDT9-H, it is necessary to add DDM in extraction and purification buffer to stabilize the conformation of NUDT9-H, so as to increase its yields and purity.

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Genetic analysis and prenatal diagnosis of a sporadic family with neurofibromatosis type 1
LIU Bei,YANG Yanmei,YAN Kai,CHEN Min,WANG Liya,HUANG Yingzhi,QIAN Yeqing,DONG Minyue
J Zhejiang Univ (Med Sci)    2019, 48 (4): 367-372.   DOI: 10.3785/j.issn.1008-9292.2019.08.03
Abstract   HTML PDF (1079KB) ( 109 )  

Objective: To identify pathogenic mutation for a family with neurofibromatosis type 1(NF1) and provide prenatal diagnosis for them. Methods: Mutation analysis of the sporadic family with NF1 was performed with target captured next generation sequencing and Sanger sequencing. RNA samples were extracted from the lymphocytes of NF1 patient and her parents. RT-PCR and Sanger sequencing were performed to analyze the relative mRNA expression in the samples. Prenatal diagnosis of the pathogenic mutation was offered to the fetus. Results: A novel splicing mutation c.1260+4A>T in the NF1 gene was found in the proband of the family, but was not found in her parents.cDNA sequencing showed that 13 bases inserted into the 3' end of exon 11 in the NF1 gene lead to a frameshift mutation. Prenatal diagnosis suggested that the fetus did not carried the mutant. Conclusion: The NF1: c.1260+4A>T mutation found in the NF1 patient is considered to be pathogenic, which provides information for family genetic counseling and prenatal diagnosis.

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Key anatomies of DeLancey's three levels of vaginal support theory: an observation in laparoscopic surgery
ZHAO Xiaofeng,CHEN Gongli,LEI Ling,WU Xiaomei,LIU Shikai,WANG Juntao,HU Bin,LYU Weiguo
J Zhejiang Univ (Med Sci)    2018, 47 (4): 329-337.   DOI: 10.3785/j.issn.1008-9292.2018.08.01
Abstract   HTML PDF (1321KB) ( 108 )  

Objective: To observe and verify the key anatomies of DeLancey's three levels of vaginal support theory through laparoscopic surgery by space dissection technique. Methods: The features and stress performance of related anatomies were observed and analyzed in laparoscopic type C hysterectomy and pelvic lymphadenectomy for cervical cancer by natural space exposures. Results: The main ligament-like structure at level Ⅰ was the uterosacral ligament, which acted as the main apical fixation in the sacral direction, while the cardinal ligament was mainly composed of vascular system, lymph-vessels and loose connective tissue around them, lacking the tough connective tissue structures, which was connected to the internal iliac vascular system. There were no strong ligaments connected to the tendinous arch of pelvic fascia (ATFP) at the lateral side of vaginal wall at level Ⅱ. ATFP was the edge of the superior fascia of pelvic diaphragm, which was bounded by the fascia of the obturator. Its surface was smooth and close to the levator ani muscle and fuses with the vaginal fascia in about one thirds of middle lower segments of the vagina. When the ureter tunnel is separated, dense connective structures can be found in both anterior and posterior walls near the intersection of the ureter across uterine artery, fixing the bilateral angle of the bladder triangle, starting from the cervix and vagina and ending in the tunica muscularis vesicae urinariae. Conclusion: Based on the laparoscopic anatomy, the pelvic floor fascia ligament support above the levator ani muscle can be considered mainly around the vagina, and fascial ligament above the levator ani muscle can be simply considered as two parallel planes forming a "double hammock" structure, which may provide more anatomic data for pelvic floor reconstruction.

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Neuroprotective effect of rapamycin against Parkinson's disease in mice
ZHU Feng,FAN Miao,XU Ziwei,CAI Yiting,CHEN Yizhen,YU Shuang,ZENG Linghui
J Zhejiang Univ (Med Sci)    2018, 47 (5): 465-472.   DOI: 10.3785/j.issn.1008-9292.2018.10.04
Abstract   HTML PDF (1247KB) ( 107 )  

Objective: To investigate the effect of rapamycin on Parkinson's disease (PD) and its underlying mechanism in mice. Methods: Sixty SPF adult male C57BL/6 mice were randomly divided into control group, model group and treatment group. 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine(MPTP) was used to induce Parkinson's disease in model group and treatment group. All mice were trained to cross the runway and were subjected to computer-assisted CatWalk. The numbers of tyrosine hydroxylase positive (TH+) neurons in the substantia nigra (SN) were assessed by unbiased stereology using the optical fractionator method; protein expression was detected by Western blot analysis; and glutathione peroxidase (GSH-Px), malondialdehyde (MDA) and superoxide dismutase (SOD) were detected by spectrophotometry. Results: In the model group, a decrease in stride rate and an increase in variation of stance and swing were noted by CatWalk system (P < 0.05 or P < 0.01); the numbers of TH+ neurons decreased (P < 0.01); expression of p-Akt, p-S6K, p-S6 and p-ULK increased (all P < 0.01); LC3-Ⅱ/Ⅰ ratio decreased (P < 0.01); MDA level was elevated while the levels of SOD and GSH-PX were reduced (all P < 0.01). Compared with the model group, after treated with rapamycin, the abnormal behavior including the stride length, variation of stance and swing and step patterns induced by MPTP were all improved (P < 0.05 or P < 0.01); the numbers of TH+ neurons increased (P < 0.05); the expression of p-Akt, p-S6K, p-S6 and p-ULK was suppressed (all P < 0.01); the LC3-Ⅱ/Ⅰ ratio was upregulated (P < 0.05); MDA level decreased while the levels of GSH-Px and SOD increased (all P < 0.01). Conclusion: Rapamycin inhibits the activation of mTOR pathway, which contributes to protect against the loss of dopaminergic neurons and provide behavioral improvements in mice with Parkinson's disease. These results are partially related to the ability of rapamycin in inducing autophagy and reducing oxidative stress.

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Identification of dynamic co-expression networks in peripheral blood of rats after middle cerebral artery occlusion
PAN Zongfu,HU Xiaoping,ZHANG Yiwen,LI Li,HUANG Ping
J Zhejiang Univ (Med Sci)    2019, 48 (6): 587-593.   DOI: 10.3785/j.issn.1008-9292.2019.12.01
Abstract   HTML PDF (1095KB) ( 107 )  

Objective: To identify the time dependent profiles of gene expression and featured co-expression network modules in peripheral blood of rats after middle cerebral artery occlusion (MCAO). Methods: Microarray GSE119121 from GEO database was analyzed by R language to identify the significantly changed genes in peripheral blood at different time points (0, 1, 2, 3, 6 and 24 h) after MCAO. Gene expression patterns at different time courses were screened by STEM tools. Then, function annotation and pathway enrichment of differentially expressed genes (DEGs) were performed using the Gene Ontology (GO) database and the Kyoto Gene and Genomic Encyclopedia (KEGG) database. Depending on CEMiTool package, gene expression profile matrix was inputted into R to construct the co-expression networks and to analyze modules, and enrichment analysis was conducted to evaluate the correlation between the modules and different time points. Results: Comparing with gene at 0 h, the numbers of DEGs in peripheral blood at different time points after MCAO were 163 (1 h), 502 (2 h), 527 (3 h), 550 (6 h), and 75 (24 h), respectively. Moreover, a total of 38 gene expression patterns were enriched, and pattern 65 and pattern 34 were specifically up-regulated or down-regulated at 2-6 h. Hp, Nos2, P2ry10, and Klf12 were representative genes of these two models. The co-expression network module analysis showed that the gene status in the early acute phase (1-6 h) was positively correlated with the Module 2. Module 3 and Module 4 was positively correlated with phase phase 1-3 h and 2-6 h, respectively. Noteworthy, Module 6 gradually changed from positive correlation (0-2 h) to negative correlation (3-24 h) with the MCAO time course, and Module 6 was mainly related to viral response and innate immune response. The hub genes of Module 6 included Mx1, Mx2, and Rtp4. Conclusion: Our study has identified the featured genes and dynamic co-expression network modules in peripheral blood after acute ischemic stroke, which provides a potential basis for judging the onset time of ischemic stroke.

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Association of maternal age with fetal sex chromosome aneuploidies
LEI Yu,DONG Minyue
J Zhejiang Univ (Med Sci)    2019, 48 (4): 409-413.   DOI: 10.3785/j.issn.1008-9292.2019.08.10
Abstract   HTML PDF (897KB) ( 106 )  

Objective: To analyze the impact of maternal age on sex chromosome aneuploidies (SCA). Methods: Pregnant women who had karyotype analysis of amniotic fluid in Women's Hospital, Zhejiang University School of Medicine from January 2014 to July 2018 were recruited. The association of the maternal age with fetal SCAs was analyzed. Results: The incidence of 45, X in age group >34- < 38 was lower than that of ≤ 28 age group (P < 0.05). For the incidences of total sex chromosome trisomy and 47, XXY in age groups 34- < 38 and ≥38 were higher than age groups ≤28 and >28-34 (P < 0.05 or P < 0.01). The incidence of 47, XXX in age group ≥ 38 was higher than that in age group>28-34 (P < 0.05). However, the incidence of 47, XYY had no differences among the four groups (P>0.05). After excluding the high risk of sex chromosome abnormalities by non-invasive prenatal testing (NIPT), we found that for 45, X, the incidences of two groups with advanced age were lower than that of ≤ 28 year-old group of age group (P < 0.05 or P < 0.01), and incidence in age group >34- < 38 was also lower than that in age group >28-34 (P < 0.05). The other results were consistent with those without excluding the high risk of sex chromosome abnormalities by NIPT. Conclusion: Advanced age decreases the incidence of 45, X, but increases the risk of sex chromosome trisomy, especially 47, XXX and 47, XXY.

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New inhibitors targeting bacterial RNA polymerase
SHI Jing,FENG Jue
J Zhejiang Univ (Med Sci)    2019, 48 (1): 44-49.   DOI: 10.3785/j.issn.1008-9292.2019.02.08
Abstract   HTML PDF (1296KB) ( 104 )  

Rifamycins, a group of bacterial RNA polymerase inhibitors, are the first-line antimicrobial drugs to treat tuberculosis. In light of the emergence of rifamycin-resistant bacteria, development of new RNA polymerase inhibitors that kill rifamycin-resistant bacteria with high bioavailability is urgent. Structural analysis of bacterial RNA polymerase in complex with inhibitors by crystallography and cryo-EM indicates that RNA polymerase inhibitors function through five distinct molecular mechanisms: inhibition of the extension of short RNA; competition with substrates; inhibition of the conformational change of the ‘bridge helix’; inhibition of clamp opening; inhibition of clamp closure. This article reviews the research progress of these five groups of RNA polymerase inhibitors to provide references for the modification of existing RNA polymerase inhibitors and the discovery of new RNA polymerase inhibitors.

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Graft failure in allogeneic hematopoietic stem cell trans-plantation
CAO Liqin,SHI Jimin
J Zhejiang Univ (Med Sci)    2018, 47 (6): 651-658.   DOI: 10.3785/j.issn.1008-9292.2018.12.14
Abstract   HTML PDF (1027KB) ( 102 )  

With the progress of medical technology, the development of new drugs and the improvement of the therapeutic effect of graft-versus host disease in the last two decades, the outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT) have been greatly improved. However, graft failure is still a rare but serious complication of allo-HSCT. HLA incompatibility, virus infection, elderly donor, uncontrolled primary disease, damage of bone marrow hematopoietic microenvironment, ABO blood group incompatibility, T cell depletion, reduced intensity conditioning, and low nucleated cell number are all risk factors for graft failure. In recent years, with the implementation of HLA haplo-identical hematopoietic stem cell transplantation, the role of donor-specific antibodies in graft failure has attracted attention increasingly. This article reviews the recent studies involving the mechanism, risk factors and prevention measures of graft failure in allo-HSCT.

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Rapamycin treatment starting at 24 h after cerebral ischemia/reperfusion exhibits protective effect on brain injury in rats
LIANG Gang, NIU Yumiao, LI Yihan, Wei Anyi, DONG Jingyin, ZENG Linghui
J Zhejiang Univ (Med Sci)    2018, 47 (5): 443-449.   DOI: 10.3785/j.issn.1008-9292.2018.10.01
Abstract   HTML PDF (1093KB) ( 100 )  

Objective: To investigate whether rapamycin treatment starting at 24 h after cerebral ischemia/reperfusion(I/R) has protective effect on brain injury in rats. Methods: The rat I/R model was established by middle cerebral artery occlusion according to Longa's method. A total of 104 Sprague Dawley rats were randomly divided into sham group, model group, and rapamycin-treated groups (6 h or 24 h after modeling). Neurological function was assessed with neurological severity score (NSS). Triphenyl tetrazolium chloride (TTC) staining and Fluoro-Jade B (FJB) staining were used to examine the infarct volume and neuronal apoptosis, respectively. The expression of p-S6 protein in mTOR signaling pathway was detected by Western blot analysis. Results: Compared with sham group, NSS of the model group was significantly increased and TTC staining indicated obvious infarct area (all P < 0.01). Furthermore, significantly increased number of FJB-positive cells and p-S6 expression in the penumbra area were shown in the model group (all P < 0.01). Compared with the model group, both rapamycin-treated groups demonstrated decreased NSS, infarction volume and FJB positive cells as well as p-S6 expression in the penumbra area (P < 0.05 or P < 0.01). There was no significant difference between the groups of rapamycin administrated 6 h and 24 h after modeling (all P > 0.05). Conclusion: Rapamycin treatment starting at 24 h after I/R exhibits protective effect on brain injury in rats.

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Research advances on the role of exosomes in chemotherapy resistance of ovarian cancer
SHEN Xiameng,LYU Weiguo
J Zhejiang Univ (Med Sci)    2019, 48 (1): 116-120.   DOI: 10.3785/j.issn.1008-9292.2019.02.17
Abstract   HTML PDF (514KB) ( 100 )  

Chemotherapy resistance is one of the biggest challenges in treatment of ovarian cancer. Mounting evidence shows that the exosomes shedding from tumor cells are considered to be involved in chemotherapy resistance of ovarian cancer by enhanced exosomal export of drugs, transferring RNAs or proteins and interfering with the bioactivity of therapeutic anti-tumor antibodies. In this review, we display the correlation between exosomes and chemotherapy resistance of ovarian cancer, the mechanism of exosomes involved in chemotherapy resistance of ovarian cancer, and discuss the potential clinical values of exosomes in chemotherapy resistance of ovarian cancer.

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Precision screening and treatment of human papilloma virus related cervical cancer
HU Zheng,MA Ding
J Zhejiang Univ (Med Sci)    2018, 47 (4): 338-343.   DOI: 10.3785/j.issn.1008-9292.2018.08.02
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Cervical cancer is a complex disease caused by both genetic susceptibility and environmental factors. Inherited genomic variance, high-risk human papilloma virus (HPV) infection/integration, genome methylation and somatic mutation could all constitute one machine learning model, laying the ground for molecular classification and the precision medicine of cervical cancer. Therefore, for cervical screening, next generation sequencing (NGS)-based HPV DNA and other molecular tests as well as dynamic machine learning models would accurately predict patients with potential to develop the cancer, thereby reducing the burden of repeated screening. Meantime, genome-editing tools targeting HPV would emerge as the next generation gene therapy for HPV-related cervical lesions. In this article, we review the substantial progress on molecular mechanism of cervical cancer development and suggest the future for precise prevention and early treatment of cervical cancer.

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Prenatal diagnosis and pregnancy outcomes of 22q11.2 duplication syndrome: analysis of 8 cases
MEI Jin,LIU Jiao,WANG Min,ZHANG Wen,WANG Hao,LU Sha,HE Chaying,JIN Chunlei
J Zhejiang Univ (Med Sci)    2019, 48 (4): 429-433.   DOI: 10.3785/j.issn.1008-9292.2019.08.13
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Objective: To investigate the relationship between 22q11.2 duplication and clinical phenotype. Methods: Eight fetuses with 22q11.2 duplication syndrome diagnosed by chromosome microarray analysis (CMA) through amniocentesis from February 2015 to March 2017 were enrolled in the study. The prenatal diagnostic indications, fetal ultrasound, chromosome karyotype, peripheral blood CMA results of parents, pregnancy outcomes and follow-up of postnatal growth and development were retrospectively analyzed. Results: Prenatal serological screening indicated 6 cases with high risk of trisomy 21, 1 case with nuchal fold (NF) thickening and 1 case of maternal chromosomal balanced translocation. Fetal ultrasonography showed 1 case of NF thickening, 1 case of fetal cerebral ventriculomegaly and 6 cases with normal ultrasound. CMA demonstrated that the size of duplication was between 651 kb and 3.26 Mb, and 22q11.2 duplication. Parents' CMA results revealed that 6 cases inherited from one of the parents with normal phenotype, and the parents of 2 cases refused the CMA test. Two couples chose induced labor; 6 cases of continued pregnancy had normal phenotypes at birth. All 6 cases were followed up with longest of 3.5 years. The growth and psychological development were normal in 5 cases, and one case was growth retardation. Conclusion: There were no specific clinical phenotypes in 22q11.2 duplication syndrome, and most of them were inherited from one parent who has normal phenotype.

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Research progress on selective immunoproteasome inhibitors
KONG Limin,LU Jingyi,ZHU Huajian,ZHANG Jiankang
J Zhejiang Univ (Med Sci)    2019, 48 (6): 688-694.   DOI: 10.3785/j.issn.1008-9292.2019.12.15
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Immunoproteasome is associated with various diseases such as hematologic malignancies, inflammatory, autoimmune and central nervous system diseases, and over expression of immunoproteasome is observed in all of these diseases. Immunoproteasome inhibitors can reduce the expression of immunoproteasome by inhibiting the production of related cell-inducing factors and the activity of T lymphocyte for treating related diseases. In order to achieve good efficacy and reduce the toxic effects, key for development of selective immunoproteasome inhibitors is the high selectivity and potent activity of the three active subunits of the proteasome. This review summarizes the structure and functions of immunoproteasome and the associated diseases. Besides, structure, activity and status of selective immunoproteasome inhibitors are also been highlighted.

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Advances in serum biomarkers for early diagnosis of gastric cancer
ZHANG Yunzhu, ZHU Chunpeng, LU Xinliang
J Zhejiang Univ (Med Sci)    2019, 48 (3): 326-333.   DOI: 10.3785/j.issn.1008-9292.2019.06.14
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Early diagnosis is the key to improve the prognosis of gastric cancer. How to screen out high-risk subjects of gastric cancer in population is a hot spot. Serum-based early detection of gastric cancer is suitable for high-risk population screening, which is more convenient and safer. This article reviews the diagnostic value of serum biomarkers for gastric cancer, including serum DNA methylation, various RNAs, pepsinogen, gastrin, osteopontin, MG7-Ag and CA724. Until now, there is still lack of ideal biomarkers for gastric cancer, and searching for specific RNAs may be promising for early diagnosis and screening of gastric cancer.

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Involvement of PML proteins in treatment of acute promyelocytic leukemia with arsenic trioxide
HAO Rui,SU Lide,SHAO Yiming,BU Na,MA Liya,NARANMAN DURAHua
J Zhejiang Univ (Med Sci)    2018, 47 (5): 541-551.   DOI: 10.3785/j.issn.1008-9292.2018.10.15
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Promyelocytic leukemia (PML) protein, a tumor suppressor, plays an important role in patients with acute promyelocytic leukemia (APL) receiving arsenic trioxide (As2O3) therapy. APL is a M3 subtype of acute myeloid leukemia (AML), which is characterized by expression of PML-RARα (P/R) fusion protein, leading to the oncogenesis. As2O3 is currently used as the first-line drug for patients with APL, and the mechanism may be:As2O3 directly binds to PML part of P/R protein and induces multimerization of related proteins, which further recruits different functional proteins to reform PML nuclear bodies (PML-NBs), and finally it degraded by SUMOylation and ubiquitination proteasomal pathway. Gene mutations may lead to relapse and drug resistance after As2O3 treatment. In this review, we discuss the structure and function of PML proteins; the pathogenesis of APL induced by P/R fusion protein; the involvement of PML protein in treatment of APL patient with As2O3; and explain how PML protein mutations could cause resistance to As2O3 therapy.

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Structural modeling of selectivity filter in transient receptor pontential melastatin 8 ion channel
XU Lizhen,YANG Fan
J Zhejiang Univ (Med Sci)    2019, 48 (1): 19-24.   DOI: 10.3785/j.issn.1008-9292.2019.02.04
Abstract   HTML PDF (4528KB) ( 94 )  
Objective

To construct a three-dimensional structural model for the selectivity filter in the transient receptor pontential melastatin 8 (TRPM8) ion channel.

Methods

In the Rosetta computational structural biology suite, multiple rounds of de novo modeling with the kinematic loop closure algorithm were performed.

Results

After nine rounds of computational modeling, we obtained the models of the selectivity filter within the TRPM8 channel with the lowest energy and high convergence. The model showed that the sidechain of D918 points were away from the central ion permeation pathway, while the sidechains of Q914, D920 and T923 pointed towards it.The glycosylation site N934 was located outside the pore region and its side chain directed to the extracellular water environment.

Conclusion

A three-dimensional structural model for the selectivity filter in the TRPM8 ion channel was constructed, which provides reliable structural information for exploring the mechanism of ion selectivity.

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Genetic study of a family of neuronal ceroid lipofuscinosis caused by a heterozygous mutation of CLN6 gene
LOU Tie,HUANG Yingzhi,DONG Minyue
J Zhejiang Univ (Med Sci)    2019, 48 (4): 373-377.   DOI: 10.3785/j.issn.1008-9292.2019.08.04
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Objective: To analyze the genetic cause of a family with autosomal recessive neuronal ceroid lipofuscinoses (NCL). Methods: The proband was screened for mutations within the coding region of the candidate genes through high-throughput targeted sequencing. Potential causative mutations were verified by PCR and Sanger sequencing in the proband and his parents. RT-PCR and TA clone sequencing were performed to investigate whether the mRNAs were abnormally spliced. Results: The sequencing results revealed compound heterozygous mutations of CLN6:c.486+2T>C and c.486+4A>T, which were respectively inherited from his parents. RT-PCR and TA cloning sequencing suggested that the mRNAs were abnormally spliced in two forms due to both mutations. Conclusions: The compound heterozygous mutations of CLN6:c.486+2T>C and c.486+4A>T are possibly the genetic causes of the NCL family. Detection of the novel mutation has extended mutation spectrum of CLN6.

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Genetic analysis of a family of Van der Woude syndrome
XU Yuqing,QIAN Yeqing,YAO Weimiao,DONG Minyue
J Zhejiang Univ (Med Sci)    2019, 48 (4): 378-383.   DOI: 10.3785/j.issn.1008-9292.2019.08.05
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Objective: To analyze clinical and genetic features of a family affected with Van der Woude syndrome. Methods: The umbilical cord blood of the proband and the peripheral blood of the parents were used for the whole exon sequencing to find the candidate gene.Peripheral blood of 9 members of the family were collected for Sanger sequencing verification, bioinformatics analysis and genotype-phenotype correlation analysis. Results: The proband was diagnosed with cleft lip and palate by ultrasound. His father and grandmother had hollow lower lip and all other family members did not have the similar phenotype. A missense c.263A>G (p.N88S) mutation was found in exon 4 of IRF6 gene in the proband, his father and his grandmother.The mutation was not found in other family members. Conclusion: A missense c.263A>G (p.N88S) mutation in IRF6 gene probably underlies the pathogenesis of Van der Woude syndrome in the family and the mutation has been firstly discovered in China.

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