1.Transcription factor activator protein 2C contribute to molar development in mice
Liwei LIU ; Xue HAN ; Zhewen ZHU ; Zuolin WANG
Chinese Journal of Stomatology 2024;59(7):706-714
Objective:Explore the expression pattern of transcription factor activator protein 2C (TFAP2C) and identify the roles of Tfap2c during tooth development.Methods:Real-time fluorescence quantitative PCR (RT-qPCR) was used to analyze the relative expression level of Tfap2c in various organs of embryonic day(E)14.5 mouse embryos and mouse molar germs at E12.5-E18.5 and postnatal day (P)0-P7. The expression position of Tfap2c in mouse molar germs was demonstrated by frozen section immunofluorescence staining. Cultured mandibular molar germs were transfected with control small interfering RNA (siRNA) or Tfap2c siRNA to evaluate the effect of Tfap2c on tooth molar germs development, and RT-qPCR was used to detect the relative expression level of genes related to odontoblast expression. Dental mesenchymal cells were isolated from E14.5 molar germs and transfected with control siRNA or Tfap2c siRNA, cell counting kit 8 (CCK-8) and scratch healing test were applied to detect dental mesenchymal cell viability and migration.Results:Tfap2c was highly expressed in the early development period of mouse molar germs. Tfap2c was expressed in the epithelial and mesenchymal tissues of E13.5 mouse molar germs and there was no significant difference of relative expression of Tfap2c between them ( t=1.06, P=0.472). Tfap2c was expressed in mesenchymal tissues of E14.5 mouse molar germs and the relative expression of Tfap2c in mesenchymal tissues was significantly higher than epithelial tissues ( t=37.29, P<0.0001). For molar germs transfected with Tfap2c siRNA, the relative height of cusps (0.708±0.171) and the ratio of cusp height and crown height (0.321±0.068) was significantly lower than control group (1.000±0.287 and 0.483±0.166) ( t=2.79, P=0.012; t=2.85, P=0.015). But there was no significant difference in relative height (1.078±0.206, 0.993±0.254, t=0.83, P=0.419)and relative width (1.000±0.116, 0.999±0.122, t=0.01, P=0.992) of crowns between two groups. The relative expression level of genes related to odontoblast expression was decreased (Dspp: t=15.33, P<0.001; Dmp1: t=13.81, P<0.001). Tfap2c siRNA hinders cell migration in dental mesenchymal cells ( t=29.86, P=0.001), but there was no significant difference in CCK-8 absorbance value between two groups. The relative expression level of genes related to odontoblast expression was also decreased in dental mesenchymal cells transfected with Tfap2c siRNA (Dspp: t=3.86, P=0.031; Dmp1; t=4.36, P=0.022). Conclusions:Tfap2c highly expressed in the early morphogenesis period of mouse molar germs, mainly in mesenchymal tissues. Tfap2c affected the cusps formation of mouse molar germs and migration of dental mesenchymal cells.
2.Correlation of the duration of preoperative biliary drainage and postoperative complications after pancreaticoduodenectomy
Huajun LIN ; Zhewen FENG ; Chengjian GUAN ; Xiaodong ZHANG ; Chenglin XIN ; Xiaozhe GU ; Yiyang MIN ; Dong WANG ; Wei GUO
Cancer Research and Clinic 2023;35(5):321-327
Objective:To investigate the effect of the duration of preoperative biliary drainage on postoperative complications after pancreaticoduodenectomy.Methods:The clinical data of 102 patients with benign and malignant hepatopancreatic ductal periampullary tumors who underwent pancreaticoduodenectomy and preoperative biliary drainage in Beijing Friendship Hospital, Capital Medical University from January 2016 to July 2020 were retrospectively analyzed. According to the median duration of preoperative biliary drainage, the patients were divided into short-term drainage group (≤ the median duration of biliary drainage) and long-term drainage group (> the median duration of biliary drainage). The general data, the effect of biliary drainage, inflammation-related indicators and postoperative complications were compared between the two groups. Multivariate logistic regression was used to screen the risk factors related to the postoperative severe complications.Results:Of the 102 patients, 68 (66.7%) were males and 34 (33.3%) were females, with a median age of 63 years (43-80 years). The median duration of preoperative biliary drainage was 14 d. There were 68 patients in short-term drainage group and 34 patients in long-term drainage group. There were no statistically significant differences in age, gender, body mass index (BMI), hypertension, diabetes mellitus, surgery history of upper abdominal, American Society of Anesthesiologists (ASA) grade, carcinoembryonic antigen, carbohydrate antigen 125, alpha-fetoprotein, prothrombin time, pancreaticojejunostomy method, operation time, and pathological type between the two groups (all P > 0.05). However, patients in long-term drainage group had higher conversion rate, more blood loss and longer hospital stay compared with those in short-term drainage group (all P < 0.05). Before biliary drainage, alanine aminotransferase (ALT) level in short-term drainage group was higher than that in long-term drainage group ( Z = -2.59, P = 0.009), and there were no statistically significant differences in aspartate aminotransferase (AST), albumin (ALB), total bilirubin (TB) and direct bilirubin (DB) levels between the two groups before biliary drainage (all P > 0.05). After biliary drainage, DB in short-term drainage group was higher than that in long-term drainage group ( Z = -3.34, P = 0.001), and there was no statistically significant difference in ALT, AST, ALB, TB levels between the two groups (all P > 0.05). There were no statistically significant differences in the levels of white blood cells, neutrophils, lymphocytes and the ratio of neutrophils to lymphocytes between the two groups on the 1st and 3rd day after the operation (all P > 0.05). The total incidence of postoperative related complications in short-term drainage group and long-term drainage group was 63.2% (43/68), 70.6% (24/34), respectively, and the difference was statistically significant ( χ2 = 0.54, P = 0.461); the incidences of bile leakage, abdominal or gastrointestinal bleeding, intra-abdominal infection, delayed gastric emptying, all grades of pancreatic leakage, grade B and C pancreatic leakage were not statistically different between the two groups (all P > 0.05); the incidence of severe postoperative related complications in short-term drainage group was higher than that in long-term drainage group [27.9% (19/68) vs. 8.8% (3/34), χ2 = 4.90, P = 0.027]. Multivariate logistic regression analysis showed that the long-term preoperative biliary drainage was an independent protective factor for postoperative severe complications (long-term drainage vs. short-term drainage: OR = 0.253, 95% CI 0.066-0.975, P = 0.046), while BMI ( OR = 1.174, 95% CI 0.986-1.398, P = 0.071) and pathological type (benign or borderline vs. malignant tumor: OR = 0.247, 95% CI 0.043-1.419, P = 0.117) were not independent influencing factors for postoperative severe complications. Conclusions:Short-term biliary drainage (≤14 d) is a risk factor for postoperative severe complications in patients with hepatopancreatic ductal periampullary tumor undergoing preoperative biliary drainage. Preoperative biliary drainage time is not associated with postoperative total complications, pancreatic leakage, bile leakage, abdominal or gastrointestinal bleeding, intra-abdominal infection, delayed gastric emptying.
3.Influencing of preoperative biliary drainage on surgery-related complications after pancreatico-duodenectomy
Huajun LIN ; Zhewen FENG ; Chenglin XIN ; Chengjian GUAN ; Xiaodong ZHANG ; Yiyang MIN ; Xiaozhe GU ; Wei GUO ; Dong WANG
Chinese Journal of Digestive Surgery 2023;22(7):909-915
Objective:To investigate the influencing of preoperative biliary drainage on surgery-related complications after pancreaticoduodenectomy.Methods:The retrospective case-control study was conducted. The clinical data of 267 patients with periampullary space-occupying lesion who were admitted to Beijing Friendship Hospital of Capital Medical University from January 2016 to July 2020 were collected. There were 166 males and 101 females, aged 61 (range, 54?84)years. Observation indicators: (1) comparison of preoperative situations in patients with and without preoperative biliary drainage; (2) comparison of intraoperative and postoperative situations in patients with and without preoperative biliary drainage; (3) methods and efficacy of preoperative biliary drainage; (4) factors influencing surgery-related complications after pancreaticoduodenec-tomy. Measurement data with normal distribution were represented as Mean± SD, and comparison between groups was conducted using the t test. Measurement data with skewed distribution were represented as M(rang) or M( Q1, Q3), and comparison between groups was conducted using the Mann-Whitney U test. Count data were described as absolute numbers or percentages, and comparison between groups was conducted using the chi-square test. Univariate analysis was conducted using the corresponding statistical methods based on data type. Multivariate analysis was conducted using the Logistic stepwise regression model. Results:(1) Comparison of preoperative situations in patients with and without preoperative biliary drainage. Of the 267 patients, there were 104 cases with preoperative biliary drainage and 163 cases without preoperative biliary drainage. Cases with malignant tumor, cases with borderline tumor, cases with chronic pancreatitis were 89, 13, 2 in patients with preoperative biliary drainage, versus 111, 41, 11 in patients without preoperative biliary drainage, showing significant differences in pathology type between them ( χ2=10.652, P<0.05). (2) Comparison of intraoperative and postoperative situations in patients with and without preoperative biliary drainage. There was no significant difference in operation time, volume of intra-operative blood loss, postoperative complications, grade B pancreatic fistula, grade C pancreatic fistula, biliary leakage, abdominal or gastrointestinal bleeding, incidence of abdominal infection, white blood cell count at postoperative day 1, white blood cell count at postoperative day 3, neutrophil-to-lymphocyte ratio at postoperative day 1, neutrophil-to-lymphocyte ratio at postoperative day 3, C-reactive protein-albumin ratio at postoperative day 1, C-reactive protein-albumin ratio at post-operative day 3, duration of hospital stay between the 104 patients with preoperative biliary drainage and the 163 patients without preoperative biliary drainage ( P>0.05). (3) Methods and efficacy of preoperative biliary drainage. Of the 104 patients with preoperative biliary drainage, there were 40 cases receiving endoscopic nasobiliary drainage with drainage time as (12±2)days, there were 38 cases receiving percutaneous transhepatic cholangial drainage with drainage time as (7±1)days, and there were 26 cases receiving endoscopic retrograde biliary drainage with drainage time as (19±2)days. The total bilirubin, direct bilirubin, aspartate transaminase, alanine aminotrans-ferase in 104 patients were (223±18)μmol/L, (134±11)μmol/L, (112±10)U/L, (160±16)U/L before biliary drainage and (144±13)μmol/L, (84±8)μmol/L, (79±8)U/L, (109±12)U/L after biliary drainage, showing significant differences in the above indicators ( t=3.544, 3.608, 2.523, 2.509, P<0.05). (4) Factors influencing surgery-related complications after pancreatocoduodenectomy. Results of multi-variate analysis showed that operation time was an independent factor influencing surgery-related complications after pancreaticoduodenectomy ( odds ratio=1.005, 95% confidence interval as 1.002?1.008, P<0.05). Conclusions:Preoperative biliary drainage does not increase the incidence of complications related to pancreaticoduodenectomy in patients with periampullary space-occupying lesion. Operation time is an independent factor influencing postoperative surgery-related complications.
4.Efficacy of robot-assisted minimally-invasive sacroiliac screw fixation combined with LC-II external fixation in treatment of pelvic fractures
Nan ZUO ; Guang YANG ; Baochang QI ; Tianhao ZHAO ; Zhewen LIU ; Zihang WANG ; Dahui SUN
Chinese Journal of Orthopaedics 2023;43(19):1269-1276
Objective:To investigate the clinical efficacy of robot-assisted minimally invasive sacroiliac screw fixation combined with LC-II external fixation in the treatment of pelvic fracture.Methods:A retrospective analysis was conducted on 28 cases with pelvic fractures treated with robot-assisted minimally invasive sacroiliac screw fixation combined with LC-II external fixation from May 2018 to November 2022. There were 19 males and 9 females, with an average age of 43.4±16.9 years (range, 14-74 years). There was 1 case of B1 type, 1 case of B2 type, 4 cases of B3 type, 10 cases of C1 type, 9 cases of C2 type and 3 cases of C3 type by Tile classification. All the cases were treated with closed reduction, LC-II external fixation for the anterior lesions and robot-assisted minimally invasive sacroiliac screw fixation for the posterior lesions. The operation time, fluoroscopy time and excellent rate of screw placement were recorded. The quality of fracture reduction was evaluated by Matta's criteria, and the clinical effect was evaluated by Majeed score.Results:All the 28 cases successfully underwent the surgery. In 11 cases the fractures were reduced by the pelvic unlocking closed reduction device while in the other 17 cases manual reduction was applied. In this cohort, 43 screws were implanted. All the screw positions reached level I by Gras grading. The average fluoroscopy time was 16.3±5.2 s (range, 9-31 s) per screw. The average operation time was 154.9±54.7 min (range, 55-226 min). According to the Matta's criteria, the reduction was rated as excellent in 19 cases, good in 7 cases, fair in 2 cases, yielding an excellent or good rate of 93% (26/28). No iatrogenic neurovascular injury was found in all the 28 patients. The average follow-up was 18.3±7.3 months (range, 4-31 months). The fractures healed at 3.6±1.1 months (range, 2-6 months) after the surgeries. At the final follow-up, the results of the Majeed scores were rated as excellent in 13 cases, good in 11 cases, fair in 3 cases and poor in 1 case, with an excellent or good rate of 86% (24/28).Conclusion:The technique of robot-assisted minimally invasive sacroiliac screw fixation combined with LC-II external fixation used in the treatment of pelvic fracture showed good clinical results.
5.The image characteristics of spectral-domain optical coherence tomography on retinal tuft
Haidong LI ; Lifeng CHEN ; Jun WANG ; Hengli LIAN ; Zhewen ZHANG
Chinese Journal of Ocular Fundus Diseases 2022;38(11):891-894
Objective:To describe the spectral-domain optical coherence tomography (SD-OCT) features of retinal tuft.Methods:A retrospective clinical study. From May 2019 to April 2020, 22 patients (22 eyes) diagnosed as retinal tuft by clinical fundus examination in Eye Hospital of Wenzhou Medical University at Hangzhou were included in the study. There were 9 eyes in 9 males and 13 eyes in 13 females. All patients underwent ultra-widefield laser scanning fundus photography and SD-OCT examination. SD-OCT was performed with a 55° wide-angle lens to observe the morphology, color, size and location of the lesions.Results:Twenty-six retinal tuft lesions were found in 22 eyes, all of which were solitary, gray, thylakoid and protrusion. SD-OCT images showed that all the lesions of retinal tuft showed a local protuberant appearance with moderate and hyperreflectivity, which was higher than the surrounding retina plane. In 22 lesions (84.62%, 22/26), there were one or more irregular hyporeflective cavities between the retinal neuroepithelial layers, and the other 4 lesions (15.38%,4/26) contained no hyporeflective cavities. In addition, 23 cases (88.46%, 23/26) with hyperreflective condensed cortical vitreous attached to the retina at the top of lesions, 8 cases (30.77%, 8/26) with retinal tear, and 6 cases (23.08%, 6/26) with shallow retinal detachment.Conclusions:In SD-OCT, the retinal tufts show moderate and strong local protrusion, which are higher than the surrounding retinal plane. In most of the lesions, there are multiple or single irregular weak reflex cavities, and there are hyperreflective condensed cortical vitreous attached to the retina at the top of lesions. Local retinal tears or shallow retinal detachment are present in some lesions.
6.Continuous transversus abdominis plane block versus patient-controlled intravenous analgesia after abdominal surgery: A systematic review and Meta-analysis
Dongming LI ; Yun YANG ; Yufan WANG ; Hao WANG ; Zhewen FENG ; Yingchi YANG ; Lan JIN ; Zhongtao ZHANG
International Journal of Surgery 2021;48(4):226-232,F3
Objective:To compare the safety and efficacy of continuous transversus abdominis plane (CTAP) block and patient-controlled intravenous analgesia (PCIA) in abdominal surgery postoperatively.Methods:PubMed, Embase, Web of Science, CNKI and other English and Chinese databases were searched since their establishment to February 2021 with "continuous/modified, transversus/transverse abdominis plane block, TAP block, patient controlled analgesia, patient-controlled analgesia, patient controlled intravenous analgesia, patient-controlled intravenous analgesia, PCA/PCIA/IV-PCA" as the search keywords. According to the analgesia treatment methods, patients were divided into continuous transversus abdominis plane block group (CTAP group) and patient-controlled intravenous analgesia group (PCIA group). Review Manager 5.4 software was used to conduct a Meta-analysis on outcome indicators such as postoperative nausea and (or) vomiting (PONV), dizziness, pain score and recovery status after abdominal surgery. Risk ratio ( RR) was calculated for counting data, Mean ± SD was calculated for measurement data. Heterogeneity was measured by I2, and related data were analyzed by using either a fixed effects model or a random effects model. Results:(1) The results of literature search: A total of 6 randomized controlled trials, including 2 published in English and 4 published in Chinese were analyzed, involving 479 patients. The results of the Meta-analysis: Compared with PCIA, CTAP block had lower incidence of PONV ( RR=0.22, 95% CI: 0.08-0.62, P<0.01), lower incidence of dizziness ( RR=0.27, 95% CI: 0.09-0.79, P=0.02), lower pain scores on movement at 24 h ( MD=-0.75, 95% CI: -1.42--0.08, P=0.03) and 48 h ( MD=-0.68, 95% CI: -1.05--0.31, P<0.001) postoperatively, and earlier time of first mobilization ( MD=-0.49, 95% CI: -0.69--0.30, P<0.001) and first exhaust ( MD=-10.47, 95% CI: -13.53--7.41, P<0.001), with statistically significant differences. However, there were no statistically significant differences in pain scores at rest at 24 h ( MD=-0.25, 95% CI: -0.57-0.08, P=0.14) and 48 h ( MD=-0.15, 95% CI: -0.39-0.09, P=0.22) postoperatively and postoperative length of hospital stay ( MD=-1.01, 95% CI: -2.28-0.26, P=0.12). Conclusion:CTAP block is a relatively safe and effective analgesic method, and it′s more consistent with the concept of enhanced recovery after surgery (ERAS) and can be recommended as an alternative method of PCIA.
7.The Genome Sequence Archive Family:Toward Explosive Data Growth and Diverse Data Types
Chen TINGTING ; Chen XU ; Zhang SISI ; Zhu JUNWEI ; Tang BIXIA ; Wang ANKE ; Dong LILI ; Zhang ZHEWEN ; Yu CAIXIA ; Sun YANLING ; Chi LIANJIANG ; Chen HUANXIN ; Zhai SHUANG ; Sun YUBIN ; Lan LI ; Zhang XIN ; Xiao JINGFA ; Bao YIMING ; Wang YANQING ; Zhang ZHANG ; Zhao WENMING
Genomics, Proteomics & Bioinformatics 2021;19(4):578-583
The Genome Sequence Archive (GSA) is a data repository for archiving raw sequence data, which provides data storage and sharing services for worldwide scientific communities. Considering explosive data growth with diverse data types, here we present the GSA family by expanding into a set of resources for raw data archive with different purposes, namely, GSA (https://ngdc.cncb.ac.cn/gsa/), GSA for Human (GSA-Human, https://ngdc.cncb.ac.cn/gsa-human/), and Open Archive for Miscellaneous Data (OMIX, https://ngdc.cncb.ac.cn/omix/). Compared with the 2017 version, GSA has been significantly updated in data model, online functionalities, and web interfaces. GSA-Human, as a new partner of GSA, is a data repository specialized in human genetics-related data with controlled access and security. OMIX, as a critical complement to the two resources mentioned above, is an open archive for miscellaneous data. Together, all these resources form a family of resources dedicated to archiving explosive data with diverse types, accepting data submissions from all over the world, and providing free open access to all publicly available data in support of worldwide research activities.
8.Whole Genome Analyses of Chinese Population and De Novo Assembly of A Northern Han Genome.
Zhenglin DU ; Liang MA ; Hongzhu QU ; Wei CHEN ; Bing ZHANG ; Xi LU ; Weibo ZHAI ; Xin SHENG ; Yongqiao SUN ; Wenjie LI ; Meng LEI ; Qiuhui QI ; Na YUAN ; Shuo SHI ; Jingyao ZENG ; Jinyue WANG ; Yadong YANG ; Qi LIU ; Yaqiang HONG ; Lili DONG ; Zhewen ZHANG ; Dong ZOU ; Yanqing WANG ; Shuhui SONG ; Fan LIU ; Xiangdong FANG ; Hua CHEN ; Xin LIU ; Jingfa XIAO ; Changqing ZENG
Genomics, Proteomics & Bioinformatics 2019;17(3):229-247
To unravel the genetic mechanisms of disease and physiological traits, it requires comprehensive sequencing analysis of large sample size in Chinese populations. Here, we report the primary results of the Chinese Academy of Sciences Precision Medicine Initiative (CASPMI) project launched by the Chinese Academy of Sciences, including the de novo assembly of a northern Han reference genome (NH1.0) and whole genome analyses of 597 healthy people coming from most areas in China. Given the two existing reference genomes for Han Chinese (YH and HX1) were both from the south, we constructed NH1.0, a new reference genome from a northern individual, by combining the sequencing strategies of PacBio, 10× Genomics, and Bionano mapping. Using this integrated approach, we obtained an N50 scaffold size of 46.63 Mb for the NH1.0 genome and performed a comparative genome analysis of NH1.0 with YH and HX1. In order to generate a genomic variation map of Chinese populations, we performed the whole-genome sequencing of 597 participants and identified 24.85 million (M) single nucleotide variants (SNVs), 3.85 M small indels, and 106,382 structural variations. In the association analysis with collected phenotypes, we found that the T allele of rs1549293 in KAT8 significantly correlated with the waist circumference in northern Han males. Moreover, significant genetic diversity in MTHFR, TCN2, FADS1, and FADS2, which associate with circulating folate, vitamin B12, or lipid metabolism, was observed between northerners and southerners. Especially, for the homocysteine-increasing allele of rs1801133 (MTHFR 677T), we hypothesize that there exists a "comfort" zone for a high frequency of 677T between latitudes of 35-45 degree North. Taken together, our results provide a high-quality northern Han reference genome and novel population-specific data sets of genetic variants for use in the personalized and precision medicine.
9.Effect of adenylate cyclase antagonists andagonist in acute lung injury induced by lipopolysaccharide
Xuefeng WANG ; Feng CHEN ; Shunde SONG ; Zhewen ZHANG ; Huifang TANG
Chinese Pharmacological Bulletin 2017;33(10):1410-1414
Aim To explore the effect of adenylate cyclase(AC) antagonists SQ22536 and agonist forskolin on acute lung injury induced by lipopolysaccharide.Methods ICR mice were randomly divided into normal saline control group(N group), model group(group L), dexamethasone group(group D),AC antagonists s(group SQ) and AC agonist group(group F).The ALI mouse model was induced by instilling intratracheally with LPS(2 mg·kg-1), and 6 h later, the lung tissue and alveolar lavage fluid(BALF) were harvested, pathological changes in lung were observed, white blood cell and neutrophil, albumin content in BALF and myeloperoxidase(MPO) activity of lung tissue homogenate were determined, and tumor necrosis factor α(TNF-α), interleukin-1β(IL-1β), interleukin 6(IL-6) and cAMP content in lung homogenates were detected by ELISA.Results Compared with normal saline group, a large number of neutrophils infiltrated around the pulmonary vessel and airway 6 h after LPS intratracheal instillation in model group.White blood cells and neutrophils and protein content increased in BALF;MPO activity and cAMP levels increased in lung tissues.In the lung tissue TNF-α and IL-6, IL-1β content increased, compared with model group.Forskolin could improve the pathological changes of lung tissue, reduce the total number of leukocytes, number of neutrophils and protein content in BALF, and reduce MPO activity and TNF-α content in lung tissue, at the same time it increased the cAMP content;SQ22536 had no significant effect when compared with model group.Conclusion AC agonists have protective effects on LPS-induced acute lung injury in mice, and the mechanism may be related to elevating cAMP levels, inhibiting neutrophil adhesion and chemotaxis and reducing inflammatory factor levels.
10.Advances of the effects of antibody heterogeneity on the function and metabolism of monoclonal antibody drugs
Chen WANG ; Zhewen ZHANG ; Yingchun LI ; Xiquan ZHANG ; Wei ZHAO
Journal of China Pharmaceutical University 2017;48(5):614-621
Antibody drugs often show "heterogeneity",including the related isomers differing from one another in glycosylation,charge or molecular size.Most of these isomers come from post-translational modifications,such as aggregation,degradation,glycosylation,oxidation,deamidation or disulfide misfolding,of the recombinant protein in the "cell factories".These modifications not only influence the quality,safety and efficacy of the antibodies,but also serve as an important indication of product quality throughout the whole process of antibody production.This paper reviews the relationship between glycoslation,charge and size heterogeneities of monoclonal antibodies and drug efficacy,safety,pharmacokinetics as well as immunogenicity,contributing to a better understanding of the relationship between antibody structure and function.It will provide some support and guidance for the research and development of antibody drugs,especially biosimilars.

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