【⽂献阅读3】
Evaluation of the safety and efficacy of using human menstrual blood-derived menchymal stromal cells in treating vere and critically ill COVID-19 patients: An exploratory clinical trial
评估使⽤间充质基质⼲细胞治疗重症和危重症新冠患者的安全性和有效性：⼀项探索性临床试验
Abstract
The coronavirus dia 2019 (COVID-19), caud by vere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified in December 2019 and has subquently spread worldwide. Currently, there is no effective method to cure COVID-19.
Menchymal stromal cells (MSCs) may be able to effectively treat COVID-19, especially for vere and critical patients. Menstrual blood-derived MSCs have recently received much attention due to their superior proliferation ability and their lack
of ethical problems. Forty-four patients were enrolled from January to April 2020 in a multicenter,
open/label,nonrandomized,parallelcontrolled exploratory trial. Twenty-six patients received allogeneic,
menstrual blood-derivedMSC therapy,and concomitant medications (experimental group),and 18 patients received only concomitant
medications (control group). The experimental group was treated with three infusions totaling 9 × 107 MSCs,one infusion every other day. Primary and condary endpoints related to safety and efficacy were assd at various time points during the 1-month period following MSC infusion. Safety was measured using the frequency of treatmentrelated adver events (AEs). Patients in the MSC group showed significantly lower mortality (7.69% died in the experimental group vs 33.33% in the control group; P = .048). There was a significant improvement in dyspnea while undergoing MSC infusion on days 1, 3, and 5. Additionally, SpO2 was significantly improved following MSC infusion, and chest imaging results were improved in the experimental group in the first month after MSC infusion. The incidence of most AEs did not differ between the groups. MSC-bad therapy may rve as a promising alternative method for treating vere and critical COVID-19.
由严重急性呼吸综合症新冠2 (SARS-CoV-2)引起的，2019的新冠病毒，在2019年12⽉被确诊并且在世界各地⼴泛传播。近期，对于治疗COVID-19没有有效的⽅法。MSCs治疗COVID-19可能有效，特别是重症和危重症患者。MSCs由于超强繁殖能⼒和缺乏伦理问题近期受到⼤量关注。在⼀项多中⼼、开放、不随机、⽆平⾏对照的探索性试验中从2020年1⽉到4⽉⼊组44例患者。26例患者接受异
体经⾎MCS治疗和伴随⽤药（试验组），18例患者只接受伴随⽤药（对照组）。试验组接受三次输液合计9 × 107 MSCs，每隔⼀天输⼀次。根据MSC注射后⼀个⽉内的重要时间节点评估与安全性和有效性有关的主要及次要指标。安全性评估使⽤与药物相关的不良事件。在MSC组患者显⽰显著的低死亡率(试验组7.69%。对照组33.33%，P=0.048)。在第1、3、5天接受MSC注射呼吸困难有显著改善。另外，SpO2在MSC注射后有显著改善，并且在试验组注射MSC后的第⼀个⽉胸部成像结果得到改善。⼤部分AEs发⽣率在组间没有差异，基于MSC疗法可能作为⼀项治疗重症和危重症新冠患者有前景的替代疗法。
Mortality=death rate
Incidence：
Therapy=treat
Serve as =considered
Promising=hopeful
Alternative=alter+native=改变+原来的，当地⼈=替代
结束的英文
翻译难点，
may rve as的翻译，直译为作为⼀项⽅法为患者服务，三个信息点，它是基于MSC的⼀项疗法，它可能作为⼀项最有前景的替代疗法，它是为重症和危重症新冠患者服务的。
（2）every other day，新知识，每隔⼀天。河南大学四六级报名
2021年6⽉8⽇星期⼆（第1天翻译250个词）
1.introduction
The coronavirus dia 2019 (COVID-19), caud by vere~acute respiratory syndrome coronavirus 2 (SARSCoV2), was initially identified in December 2019 as causing a cluster of respiratory infections.1,2 COVID19 quickly attracted global concern and panic since it is highly contagious.3–5 Due to a lack of adequate awareness in the first few weeks of the outbreak, the number of infected patients incread swiftly, rapidly spreading to more and more countries.6,7 As of January 7, 2021, there have been over 85 929 000 confirmed cas of COVID-19 worldwide,leading to 1 876 100 deaths. Currently, the number of infected patients is still increasing worldwide.
blown
这个新冠疾病2019（COVID-19），由严重急性呼吸综合冠状病毒2(SARS-CoV-2)引起的，在2019年12⽉被明确定义为引起⼀系列呼吸道感染。COVID-19由于⾼度传染性快速引起全球⼴泛关注和恐慌。
由于在爆发开始的⼏周缺乏⾜够的意识。感染患者⼈数极速增加，传播到越来越多的国家。在2021年7⽉，在全球已经超过了85929000 COVID-19确诊病例，导致1876100⼈死亡。进来，感染患者的⼈数仍然在全球持续增加。
COVID19 has an incubation period which can range from 1 to 14 days but usually ranges from 3 to 7 days.8 The main symptoms are fever, headache, dry cough, and chest tightness.911 Many patients also experience a sore throat, diarrhea, nasal congestion, and rhinorrhea.12,13
Severe patients often develop expiratory hyperextension and dyspnea 1 week after the ont of the dia. In the most vere cas, patients can quickly develop acute respiratory distress syndrome (ARDS), vere acute lung injury, ptic shock, metabolic acidosis, and coagulopathy,as reported in a biopsy and autopsy study.14 COVID-19 can easily cau expiratory dyspnea and ARDS. Of the COVID-19 patients, 13.8% of the cas were vere, 6.1% cas were critical, and about 2.3% cas had fatal outcomes.Since no effective or authorized vaccines are available for preventing COVID19 infections, a breakthrough in the therapeutic strategy is vital for the treatment of COVID19 and especially for vere or critically ill patients who may develop ARDS and/or expiratory dyspnea.17–21 Currently,a few drugs (such as remdesivir and dexamethasone)have shown positive preliminary results in randomized,controlled, open.label, clinical trials.22,23 Even more excitingly, C
OVID19 vaccines
with acceptable safety, tolerability,and immunogenicity have been reported by Zhuet al and Folegatti et al as being effective in initial human clinical trials. Apart from the, many other groups are also developing available vaccines such as the
BNT162mRNA vaccine26 sponsored by Pfizer Inc. and BioNTech SE; the chimpanzee adenovirus vectored vaccine ChAdOx1 nCoV-19 (AZD1222) sponsored by AstraZeneca;the mRNA-1273 vaccine29 codeveloped by the Cambridge,Massachutts-bad biotechnology company Moderna,
Inc., and the National Institute of Allergy and Infectious Dias (NIAID); the adenovirus rotype 26 (Ad26) vaccine30 developed by Jansn Vaccines & Prevention B.V.; the BBIBP-CorV vaccine31 developed by the Beijing Institute of Biological Products; the CoronaVac vaccine developed by Sinovac Life Sciences; and the NVX-CoV2373
Vaccine sponsored by Novavax, Inc. However, no specific drugs have been reported to be absolutely effective in treating COVID-19. Moreover, SARS-CoV-2-induced condary infections have been reported to induce multiple organ dysfunction syndrome in vere or critically ill patients, and this issue remains a rious problem worldwide.
COVID-19的孵化周期是1-14天，但⼀般范围是3-7天。最重要的症状是发烧、头痛、⼲咳、胸闷。⼀些患者也会经历咽喉疼痛、腹泻、⿐塞、流⿐涕。重症患者通常在发病⼀周后出现呼吸性伸展和呼吸困难（ont进攻）。根据活检和⼫检研究报告，在最严重的情况下，患者很快发展成急性呼吸窘迫综合症（ARDS），急性重症肺部损伤，感染性休克、代谢酸中毒、凝⾎病。COVID-19很容易引起呼⽓型呼吸困难和ARDS。COVID-19患者中，13.8%病例是重症，6.1%病例是危重症，并且⼤约2.3%病例有致命结果。由于没有有效和权威的疫苗能够阻⽌COVID-19感染，COVID-19治疗尤其改善ARDS和呼⽓型呼吸困难的重症和危重症患者的治疗策略的突破⼗分关键。近期，在⼀项随机、对照、开发标签的临床试验⼀些药物显⽰了初步的阳性结果。甚⾄更加激动⼈⼼的是，具有可接受的安全性、耐受性和免疫原性的COVID-19疫苗被zhu等⼈和Folegatti等⼈报道了。除了这些，其他研究⼩组也发展了可接受疫苗，
例如：（1）Pfizer（辉瑞）和BioNTech SE赞助的BNT162 mRNA苗；
frax
（2）AstraZeneca（阿斯利康）赞助的⿊猩猩腺病毒载体疫苗ChAdOx1 nCoV-19 (AZD1222)；
（3）由位于马萨诸塞州剑桥市的⽣物技术公司 Moderna, Inc. 和美国国家过敏和传染病研究所 (NIAID) 共同开发的 mRNA-1273 疫苗；
（4）由Jansn Vaccines & Prevention B.V.研发的腺病毒⾎清型 26 (Ad26)疫苗
（5）北京⽣物制品研究所研制的BBIBP-CorV疫苗
（6）Sinovac⽣命科学研发的CoronaVac疫苗
（7）Novavax, Inc赞助NVX-CoV2373疫苗
然⽽没有特别的药物被报道对治疗COVID-19明显有效。⽽且， SARS-CoV-2 引起的继发感染被报道可促使重症和危重症患者多组织功能障碍综合症，这个问题仍然是全球范围内的⼀个严重问题（induce重点谓语翻译错误，诱导、促使；remain翻译错误，本意是仍然）。
Menchymal stem cells have been ud for almost three decades, and have made great progress.34 According to the recommendations of the International Society for Cell & Gene Therapy (ISCT) in 2019, menchymal stem cells should be named menchymal stromal cells (MSCs).35 MSC-bad cellular therapy has been the subject of an increasing number of studies due to the cells’ lf-renewing capacity, multipotent potential, low immunogenicity, anti-inflammatory activity, and ability to home to damaged tissue.More importantly, MSCs have unique immunomodulatory functions of both innate and adaptive immune respons, making them an attractive cell therapy tool.38,39 MSCs regulate adaptive immune responsmainly through targeting T lymphocytes, B lymphocytes,antigen-prenting cells (APCs), dendritic cells (DCs),
natural killer (NK) cells, and regulatory T cells (Tregs).38 MSCs also regulate innate immune respons mainly through
targeting DCs, NK cells, innate TH17 cells, neutrophils, monocytes, macrophages, and mast cells.39 Further,MSC-bad therapies have shown promising
results in veral clinical studies across a variety of dias.40,41 With the development of stem cell rearch,rearchers have found that after injecting MSCs, the human body activates the host’s innate immune cascade system, such as complement and blood coagulation,which is defined as the instant blood-mediated inflammatory espon (IBMIR).42 IBMIR is
of key importance onsidering the highly procoagulant state of many critically nd verely ill patients in need of MSC
therapy.43 SCs can be obtained from various sources, including one marrow (BM), adipo (AD), umbilical cord (UC),placenta, menstrual blood, muscle, dental pulp, Wharton’s elly (WJ), fetal liver, amniotic membrane, amniotic luid, urine etc.44–48 Furthermore, MSC-bad treatment has demonstrated promising results in studies on inflammatory lung dia, showing an ability to inhibit alveolar collap, cell apoptosis, and collagen accumulation in lung tissues.49 The angiotensin-conv
erting enzyme 2 (ACE2) is identified as a receptor of SARS-CoV-2 entering into target cells.50,51 In addition, rearchers have demonstrated
thatMSCs do not express ACE2, andMSCs are resistant to SARS-CoV-2 infection as well as when expod to SARSCoV-2-infected cells.52,53 Additionally, following infusion of allogeneic MSCs into nine patients with ARDS, Wilsonet al54 obrved no prespecified side effects including cardiac arrhythmia, hypoxemia, and ventricular tachycardia.Further, our team reported that MSC transplantation significantly lowers the mortality of epidemic Influenza A (H7N9)-induced ARDS patients.55 BM-MSCs have been shown to improve repair after ventilator-induced lung injury, to facilitate the resolution of inflammation, and to restore lung function and structure in ARDS patients.56 With regard to the COVID-19 epidemic, MSCs from different sources (especially UC-MSCs) have been ud in clinical trials.53,57 A good proliferation rate plays an important role in clinical application, becau stem cell-bad treatment is do-dependent, and usually human clinical rearch requires millions of
stem cells. The doubling time for menstrual blood-derived MSCs is about 20 h, and the doubling time for BM-MSCs is about
40-45 h. Thus, MSCs from menstrual blood can obtain a better yield within a shorter time at early passages.58,59 More importantly, menstrual blood-derived MSCs offer an alternative that is both painless and free of the ethical issues that may ari from BM-MSCs donations.60 Thus, menstrual bloodderivedMSC-
bad therapy may be a promising treatment for COVID-19, particularly to combat the inflammatory cytokine storms
obrved in vere and critical patients.
间充质⼲细胞被使⽤已经有30年了，并且有很⼤的进步。在2019年根据科学家的解释推荐细胞联合基因治疗，间充质⼲细胞被命名为间充质基质细胞(MSCs)。基于MSC的细胞疗法，由于⾃我新⽣能⼒，多种潜在能⼒，低免疫原性，抗炎活性，修复受损组织能⼒等成为了研究数量逐增的课题。更重要的是，MSCs在先天性和适应性免疫反应，有独特的免疫调节，让他们成为有吸引⼒的细胞治疗⼯具。MSCs调节适应性免疫反应主要
通过靶向T淋巴细胞、B淋巴细胞、抗原呈递细胞、树突状细胞、⾃然杀伤细胞和调节性T细胞。MSCs也可以调节先天性免疫反应主要通过靶向DCs、NK细胞、先天TH17细胞、中性粒细胞、单核细胞、巨噬细胞、肥⼤细胞。更进⼀步来说，基于MSC治疗显⽰良好的结果在通过各种疾病的多项临床
研究中。随着⼲细胞的研究发展，研究者发现接种MSCs之后。⼈体激活宿主。IBMIR要⾄关重要的考虑到需要MSC治疗的许多重症和危重症患者的⾼度凝⾎状态。MSCs可以从不同的来源获取，包括包括⾻髓（BM）、脂肪（AD）、脐带（UC）、胎盘、经⾎、肌⾁、⽛髓、沃顿⽒胶（WJ）、胎肝、⽺膜、⽺⽔、尿液等。此外，基于MSC治疗在炎症性肺部疾病研究中表明有⾮常可观的结果，显⽰了抑制肺泡塌陷、细胞凋亡和肺组织中胶原蛋⽩积累的能⼒。ACE2被鉴定为SARS-CoV-2进⼊靶细胞的受体。另外，研究者表明MSCs没有表达ACE2，MSC 对SARS-CoV-2 感染以及暴露于 SARS-CoV-2 感染的细胞具有抵抗⼒。
另外，同种异体MSCs注射进⼊9个ARDS患者, Wilson等⼈没有观察到提前制定的副作⽤，包括⼼律失常、低氧⾎症和室性⼼动过速。
另外，我们的团队报告MSCs细胞移植显著降低流⾏性甲型流感（H7N9）诱发的ARDS患者的死亡率。BM-MSCs也显⽰可以提⾼呼吸机所致肺损伤后修复，促进炎症的“再解决”消退，并恢复 ARDS 患者的肺功能和结构。随着COVID-19的流⾏，不同来源的MSCs已经使⽤在临床试验中。在临床试验中⼀个良好繁殖率起着⾮常重要的作⽤，因为基于⼲细胞治疗具有剂量依赖性，并且通常⼈类临床研究者要求数百万的⼲细胞。经⾎MSCs的倍增时间约是20h，BM-MSCs的倍增时间约是40-45h。因此，在早期的短时间内来⾃经⾎的MSCs可以获得更好的量。更重要的是，来⾃经⾎的MSCs提供⼀种可替代⽅案，既⽆痛和也没有来⾃BM-MSCs捐献者产⽣的伦理问题（alternative名词，替代⽅案）。
因此，基于经⾎来源的MSCs可能是最有前景的治疗⽅法，对于COVID-19，特别是对抗在重症和危重症患者观察到的炎症细胞因⼦风暴。
This study is an exploratory trial to asss the ability of menstrual blood-derived MSCs to treat vere and critically ill COVID-19 patients. To this end, we assd the safety, therapeutic efficacy, and tolerability of transplanted MSCs with a 1 month follow-up after SARS-CoV-2 infection. In particular, we assd any improvements in pulmonary
function. Our results not only shed light on the ability ofMSCs to treat COVID-19 patients, but also suggest that MSCs are a promising tool to treat acute or chronic pneumonia in future clinical applications.
这个研究是评估经⾎MSCs治疗COVID-19重症和危重症患者能⼒的⼀项探索性是试验。在最后，我们评估了SARS-CoV-2感染后MSCs移植⼀个⽉随访的安全性，治疗有效性，以及耐受性。特别是我们评估了肺功能的⼀些改善。我们的结果不仅揭⽰患者MSCS治疗COVID-19患者的能⼒，也表明在未来临床应⽤中，MSCs对于治疗急性或慢性肺炎是⾮常有前景的⼯具。
造价师网(2021年7⽉6⽇星期⼆翻译完)
2 MATERIALS AND METHODS
2.1 Study design and participants
This was a multicenter, open-label, nonrandomized, and parallel controlled pha I clinical trial performed at two major academic centers in China: the Renmin Hospital of Wuhan University, Wuhan and the First Affiliated Hospital,College of Medicine Zhejiang University, Hangzhou.
The Shulan (Hangzhou) Hospital, affiliated to Zhejiang Shuren University, Shulan International Medical College,Hangzhou also participated in related studies. Eligible patients were 18-75 years old and confirmed to be positive for the SARS-CoV-2 RNA virus by polymera chain reaction (PCR) analysis performed within biological safety protection level 3 laboratories at Wuhan University and Zhejiang University. Before the initiation of this study, the rearch protocol, ca report form (eCRF), and informed connt form were each obtained and approved by the Ethics Committees of Renmin Hospital of Wuhan University (WDRY2020-K011) and the First Affiliated Hospital,College of Medicine, Zhejiang University in accordance with the Declaration of Helsinki and the criteria of Good Clinical Practice.61 This clinical trial was also registered in the Chine Clinical Trial Registry (ChiCTR2000029606).
The investigators fully educated each patient’s legal reprentative
regarding the informed connt form, the detailed therapeutic procedure, aswell as the possible risks and benefits. The patients had the right to withdraw from this clinical study at any time during the clinical trial. Considering the urgency of the COVID-19 epidemic and the operability of the enrollment process, a randomized table was not ud for randomization in the rearch process at Renmin Hospital of Wuhan University, and cas (including vere and critically ill patients) were matched bad on similar verity levels and similar timing of enrollment/in the study. This clinical trial was an open study and did not involve blinding or emergency unblinding.
2 材料与⽅法
2.1 研究设计和参与者
这是⼀个在中国两个重要的学术中⼼开展的多中⼼、开放、不随机、平⾏对照⼀期临床试验。武汉⼤学⼈民医院和浙江⼤学医学院附属第⼀医院也参与了相关研究。符合资格的病⼈是18-75岁并且在武汉⼤学和浙江⼤学在3级⽣物安全性保护中被RCT分析确认SARS-CoV-2 RNA阳性的。研究开始之前，这研究的安慰剂、eCRF和标准⽂档格式被（武汉⼤学⼈民医院和浙江⼤学医学院附属第⼀医院的）伦理委员会按照赫尔⾟基宣⾔和GCP标准获取和同意。该临床试验也在中国临床试验注册中⼼进⾏注册。研究者要充分通知每⼀个患者法律代表，包括标准⽂档格式、详细的治疗过程和可能的风险
受益。在临床试验进⾏的任何时间患者都可以从临床研究中退出。考虑到COVID-19疫情的紧急性和⼊组过程的可操作性，随机表不适⽤在武汉⼤学⼈民医院的研究过程，案例匹配基于研究中相似的严重程度和相近的⼊组时间。这个临床试验是开放性研究，不涉及设盲或紧急破盲。
2021年6⽉16⽇星期三（第2天翻译282个词）
All patients met the diagnostic criteria for COVID-19 according to the National Health Commission of China (Trial Version 5). Following established clinical guidelines for the diagnosis and treatment of COVID-19, patients can be classified as mild, common, vere, or critical.53,62,63 Only vere and critically ill COVID-19 patients were included in the prent study. Severe patients were defined as tho with respiratory distress, respiratory rate ≥30 breaths/min; resting oxygen saturation ≤93%; or arterial blood partial pressure of oxygen (PaO2)/fraction of inspiration O2 (FiO2) ≤300 mmHg (1 mmHg = 0.133 kPa). Critical COVID-19 patients were defined as tho with respiratory failure who required mechanical ventilation, tho who had experienced shock, or tho for whom a combination of organ failures necessitatedmonitoring and treatment in the intensive care unit (ICU). Exclusion criteria for this trial were as follows:
fengyu(1) vere liver dia;
(2)long-term hemodialysis and vere renal impairment or continuous renal replacement therapy;
(3) comorbidities that might affect the ability of rearchers to determine
drug efficacy (mainly malignant tumors, active tuberculosis,interstitial pneumonia, and pulmonary heart dia);
(4) treatment with glucocorticoid medications or other immunosuppressive drugs for longer than 2 weeks;
俄语翻译培训(5) history of major surgery within 30 days of screening or prence of an unhealed surgical wound;
诧异什么意思(6) allergy to any active/inactive ingredients in the study drug;
(7) pregnant or breastfeeding;
(8) previous history of prothrombotic events (venous thromboembolism/stroke);
(9) other circumstances judged by an investigator to preclude participation.
boastfulThe “other circumstances” leading to exclusion from the study included rious AEs for which the i
nvestigator judged
that the risk of continuing to participate in the trial was too great, as well as the u of other treatments,without authorization and against medical advice, that could have affected the evaluation. The exclusion criteria followed the National Health Commission of China (Trial Version 5). If a patient met all the inclusion or exclusion criteria, he or she was then enrolled in the experimental group (MSC infusion + concomitant medications) or the control group (concomitant medications).
根据中国国家健康委员会（试⽤版5）所有患者均要符合新冠诊断标准。根据新冠诊断和治疗的建⽴的临床指导，患者被分为轻度、普通、重症、危重。只有严重和危重新冠患者被包含在这个研究中。重症患者被定义根据这些呼吸困难，呼吸频率⼤于30次/分钟，休息时氧⽓饱和度⼩于等于93%，或者什么的氧⽓⾎液部分压⼒动脉⾎氧分压(PaO2)/吸⼊氧分数(FiO2) ⼩于等于300 mmHg (1 mmHg = 0.133 kPa)。危重新冠患者被定义为需要借助仪器通⽓呼吸失败衰竭者，经历过休克，在ICU中需要监测和治疗器官衰竭组合患者。
试验排除标准如下：永垂不朽是什么意思
