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Frontiers of Medicine

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    2020, Vol.14  No.6

    Durability of humoral immunity against SARS-CoV-2 infection. The ongoing pandemic of coronavirus disease 19 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused arguably the most challenging pandemic disease to date. How long the adaptive immunity triggered by SARS-CoV-2 can last is of critical clinical relevance in assessing the probability of second infection and efficacy of vaccination. Here, we report the persi [Detail] ...

    Table of Contents

, Volume 14 Issue 6

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REVIEW
Precision medicine in acute lymphoblastic leukemia
Ching-Hon Pui
Front. Med.. 2020, 14 (6): 689-700.  https://doi.org/10.1007/s11684-020-0759-8
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The cure rate of childhood acute lymphoblastic leukemia (ALL) has exceeded 90% in some contemporary clinical trials. However, the dose intensity of conventional chemotherapy has been pushed to its limit. Further improvement in outcome will need to rely more heavily on molecular therapeutic as well as immuno- and cellular-therapy approaches together with precise risk stratification. Children with ETV6-RUNX1 or hyperdiploid>50 ALL who achieve negative minimal residual disease during early remission induction are suitable candidates for reduction in treatment. Patients with Philadelphia chromosome (Ph)-positive or Ph-like ALL with ABL-class fusion should be treated with dasatinib. BH3 profiling and other preclinical methods have identified several high-risk subtypes, such as hypodiplod, early T-cell precursor, immature T-cell, KMT2A-rearranged, Ph-positive and TCF-HLF-positive ALL, that may respond to BCL-2 inhibitor venetoclax. There are other fusions or mutations that may serve as putative targets, but effective targeted therapy has yet to be established. For other high-risk patients or poor early treatment responders who do not have targetable genetic lesions, current approaches that offer hope include blinatumomab, inotuzumab and CAR-T cell therapy for B-ALL, and daratumumab and nelarabine for T-ALL. With the expanding therapeutic armamentarium, we should start focus on rational combinations of targeted therapy with non-overlapping toxicities.

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Chimeric antigen receptor T cell therapies for acute myeloid leukemia
Bin Gu, Jianhong Chu, Depei Wu
Front. Med.. 2020, 14 (6): 701-710.  https://doi.org/10.1007/s11684-020-0763-z
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Chimeric antigen receptor T cell (CAR T) therapies have achieved unprecedented efficacy in B-cell tumors, prompting scientists and doctors to exploit this strategy to treat other tumor types. Acute myeloid leukemia (AML) is a group of heterogeneous myeloid malignancies. Relapse remains the main cause of treatment failure, especially for patients with intermediate or high risk stratification. Allogeneic hematopoietic stem cell transplantation could be an effective therapy because of the graft-versus-leukemia effect, which unfortunately puts the patient at risk of serious complications, such as graft-versus-host disease. Although the identification of an ideal target antigen for AML is challenging, CAR T therapy remains a highly promising strategy for AML patients, particularly for those who are ineligible to receive a transplantation or have positive minimal residual disease. In this review, we focus on the most recent and promising advances in CAR T therapies for AML.

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A giant step forward: chimeric antigen receptor T-cell therapy for lymphoma
Houli Zhao, Yiyun Wang, Elaine Tan Su Yin, Kui Zhao, Yongxian Hu, He Huang
Front. Med.. 2020, 14 (6): 711-725.  https://doi.org/10.1007/s11684-020-0808-3
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The combination of the immunotherapy (i.e., the use of monoclonal antibodies) and the conventional chemotherapy increases the long-term survival of patients with lymphoma. However, for patients with relapsed or treatment-resistant lymphoma, a novel treatment approach is urgently needed. Chimeric antigen receptor T (CAR-T) cells were introduced as a treatment for these patients. Based on recent clinical data, approximately 50% of patients with relapsed or refractory B-cell lymphoma achieved complete remission after receiving the CD19 CAR-T cell therapy. Moreover, clinical data revealed that some patients remained in remission for more than two years after the CAR-T cell therapy. Other than the CD19-targeted CAR-T, the novel target antigens, such as CD20, CD22, CD30, and CD37, which were greatly expressed on lymphoma cells, were studied under preclinical and clinical evaluations for use in the treatment of lymphoma. Nonetheless, the CAR-T therapy was usually associated with potentially lethal adverse effects, such as the cytokine release syndrome and the neurotoxicity. Therefore, optimizing the structure of CAR, creating new drugs, and combining CAR-T cell therapy with stem cell transplantation are potential solutions to increase the effectiveness of treatment and reduce the toxicity in patients with lymphoma after the CAR-T cell therapy.

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Programming CAR T cells to enhance anti-tumor efficacy through remodeling of the immune system
Xiaohui Wang, Zhiqiang Wu, Wei Qiu, Ping Chen, Xiang Xu, Weidong Han
Front. Med.. 2020, 14 (6): 726-745.  https://doi.org/10.1007/s11684-020-0746-0
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Chimeric antigen receptor (CAR) T cells have been indicated effective in treating B cell acute lymphoblastic leukemia and non-Hodgkin lymphoma and have shown encouraging results in preclinical and clinical studies. However, CAR T cells have achieved minimal success against solid malignancies because of the additional obstacles of their insufficient migration into tumors and poor amplification and persistence, in addition to antigen-negative relapse and an immunosuppressive microenvironment. Various preclinical studies are exploring strategies to overcome the above challenges. Mobilization of endogenous immune cells is also necessary for CAR T cells to obtain their optimal therapeutic effect given the importance of the innate immune responses in the elimination of malignant tumors. In this review, we focus on the recent advances in the engineering of CAR T cell therapies to restore the immune response in solid malignancies, especially with CAR T cells acting as cellular carriers to deliver immunomodulators to tumors to mobilize the endogenous immune response. We also explored the sensitizing effects of conventional treatment approaches, such as chemotherapy and radiotherapy, on CAR T cell therapy. Finally, we discuss the combination of CAR T cells with biomaterials or oncolytic viruses to enhance the anti-tumor outcomes of CAR T cell therapies in solid tumors.

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RESEARCH ARTICLE
Durability of neutralizing antibodies and T-cell response post SARS-CoV-2 infection
Yun Tan, Feng Liu, Xiaoguang Xu, Yun Ling, Weijin Huang, Zhaoqin Zhu, Mingquan Guo, Yixiao Lin, Ziyu Fu, Dongguo Liang, Tengfei Zhang, Jian Fan, Miao Xu, Hongzhou Lu, Saijuan Chen
Front. Med.. 2020, 14 (6): 746-751.  https://doi.org/10.1007/s11684-020-0822-5
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The ongoing pandemic of coronavirus disease 19 (COVID-19) is caused by a newly discovered β coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). How long the adaptive immunity triggered by SARS-CoV-2 can last is of critical clinical relevance in assessing the probability of second infection and efficacy of vaccination. Here we examined, using ELISA, the IgG antibodies in serum specimens collected from 17 COVID-19 patients at 6–7 months after diagnosis and the results were compared to those from cases investigated 2 weeks to 2 months post-infection. All samples were positive for IgGs against the S- and N-proteins of SARS-CoV-2. Notably, 14 samples available at 6–7 months post-infection all showed significant neutralizing activities in a pseudovirus assay, with no difference in blocking the cell-entry of the 614D and 614G variants of SARS-CoV-2. Furthermore, in 10 blood samples from cases at 6–7 months post-infection used for memory T-cell tests, we found that interferon γ-producing CD4+ and CD8+ cells were increased upon SARS-CoV-2 antigen stimulation. Together, these results indicate that durable anti-SARS-CoV-2 immunity is common in convalescent population, and vaccines developed from 614D variant may offer protection from the currently predominant 614D variant of SARS-CoV-2.

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Chinese herbal medicine reduces mortality in patients with severe and critical coronavirus disease 2019: a retrospective cohort study
Guohua Chen, Wen Su, Jiayao Yang, Dan Luo, Ping Xia, Wen Jia, Xiuyang Li, Chuan Wang, Suping Lang, Qingbin Meng, Ying Zhang, Yuhe Ke, An Fan, Shuo Yang, Yujiao Zheng, Xuepeng Fan, Jie Qiao, Fengmei Lian, Li Wei, Xiaolin Tong
Front. Med.. 2020, 14 (6): 752-759.  https://doi.org/10.1007/s11684-020-0813-6
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This study aimed to evaluate the efficacy of Chinese herbal medicine (CHM) in patients with severe/critical coronavirus disease 2019 (COVID-19). In this retrospective study, data were collected from 662 patients with severe/critical COVID-19 who were admitted to a designated hospital to treat patients with severe COVID-19 in Wuhan before March 20, 2020. All patients were divided into an exposed group (CHM users) and a control group (non-users). After propensity score matching in a 1:1 ratio, 156 CHM users were matched by propensity score to 156 non-users. No significant differences in seven baseline clinical variables were found between the two groups of patients. All-cause mortality was reported in 13 CHM users who died and 36 non-users who died. After multivariate adjustment, the mortality risk of CHM users was reduced by 82.2% (odds ratio 0.178, 95% CI 0.076–0.418; P<0.001) compared with the non-users. Secondly, age (odds ratio 1.053, 95% CI 1.023–1.084; P<0.001) and the proportion of severe/critical patients (odds ratio 0.063, 95% CI 0.028–0.143; P<0.001) were the risk factors of mortality. These results show that the use of CHM may reduce the mortality of patients with severe/critical COVID-19.

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Clinical features and the traditional Chinese medicine therapeutic characteristics of 293 COVID-19 inpatient cases
Zixin Shu, Yana Zhou, Kai Chang, Jifen Liu, Xiaojun Min, Qing Zhang, Jing Sun, Yajuan Xiong, Qunsheng Zou, Qiguang Zheng, Jinghui Ji, Josiah Poon, Baoyan Liu, Xuezhong Zhou, Xiaodong Li
Front. Med.. 2020, 14 (6): 760-775.  https://doi.org/10.1007/s11684-020-0803-8
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Coronavirus disease 2019 (COVID-19) is now pandemic worldwide and has heavily overloaded hospitals in Wuhan City, China during the time between late January and February. We reported the clinical features and therapeutic characteristics of moderate COVID-19 cases in Wuhan that were treated via the integration of traditional Chinese medicine (TCM) and Western medicine. We collected electronic medical record (EMR) data, which included the full clinical profiles of patients, from a designated TCM hospital in Wuhan. The structured data of symptoms and drugs from admission notes were obtained through an information extraction process. Other key clinical entities were also confirmed and normalized to obtain information on the diagnosis, clinical treatments, laboratory tests, and outcomes of the patients. A total of 293 COVID-19 inpatient cases, including 207 moderate and 86 (29.3%) severe cases, were included in our research. Among these cases, 238 were discharged, 31 were transferred, and 24 (all severe cases) died in the hospital. Our COVID-19 cases involved elderly patients with advanced ages (57 years on average) and high comorbidity rates (61%). Our results reconfirmed several well-recognized risk factors, such as age, gender (male), and comorbidities, as well as provided novel laboratory indications (e.g., cholesterol) and TCM-specific phenotype markers (e.g., dull tongue) that were relevant to COVID-19 infections and prognosis. In addition to antiviral/antibiotics and standard supportive therapies, TCM herbal prescriptions incorporating 290 distinct herbs were used in 273 (93%) cases. The cases that received TCM treatment had lower death rates than those that did not receive TCM treatment (17/273= 6.2% vs. 7/20= 35%, P = 0.0004 for all cases; 17/77= 22% vs. 7/9= 77.7%, P = 0.002 for severe cases). The TCM herbal prescriptions used for the treatment of COVID-19 infections mainly consisted of Pericarpium Citri Reticulatae, Radix Scutellariae, Rhizoma Pinellia, and their combinations, which reflected the practical TCM principles (e.g., clearing heat and dampening phlegm). Lastly, 59% of the patients received treatment, including antiviral, antibiotics, and Chinese patent medicine, before admission. This situation might have some effects on symptoms, such as fever and dry cough. By using EMR data, we described the clinical features and therapeutic characteristics of 293 COVID-19 cases treated via the integration of TCM herbal prescriptions and Western medicine. Clinical manifestations and treatments before admission and in the hospital were investigated. Our results preliminarily showed the potential effectiveness of TCM herbal prescriptions and their regularities in COVID-19 treatment.

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Clinical manifestations and pathogen characteristics in children admitted for suspected COVID-19
Xiaofang Cai, Hanlan Jiang, Simin Zhang, Shengying Xia, Wenhui Du, Yaoling Ma, Tao Yu, Wenbin Li
Front. Med.. 2020, 14 (6): 776-785.  https://doi.org/10.1007/s11684-020-0820-7
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Coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has spread around the world. However, approaches to distinguish COVID-19 from pneumonia caused by other pathogens have not yet been reported. We retrospectively analyzed the clinical data of 97 children with probable COVID-19. A total of 13 (13.4%) patients were confirmed positive for SARS-CoV-2 infection by nucleic acid RT-PCR testing, and 41 (42.3%) patients were found to be infected with other pathogens. Notably, no pathogen was detected in 43 (44.3%) patients. Among all patients, 25 (25.8%) had familial cluster exposure history, and 52 (53.6%) had one or more coexisting conditions. Fifteen (15.5%) patients were admitted or transferred to the PICU. In the 11 confirmed COVID-19 cases, 5 (45.5%) and 7 (63.6%) were positive for IgM and IgG against SARS-CoV-2, respectively. In 22 patients with suspected COVID-19, 1 (4.5%) was positive for IgG but negative for IgM. The most frequently detected pathogen was Mycoplasma pneumonia (29, 29.9%). One patient with confirmed COVID-19 died. Our results strongly indicated that the detection of asymptomatic COVID-19 or coexisting conditions must be strengthened in pediatric patients. These cases may be difficult to diagnose as COVID-19 unless etiologic analysis is conducted. A serologic test can be a useful adjunctive diagnostic tool in cases where SARS-CoV-2 infection is highly suspected but the nucleic acid test is negative.

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Different sites of extranodal involvement may affect the survival of patients with relapsed or refractory non-Hodgkin lymphoma after chimeric antigen receptor T cell therapy
Lili Zhou, Ping Li, Shiguang Ye, Xiaochen Tang, Junbang Wang, Jie Liu, Aibin Liang
Front. Med.. 2020, 14 (6): 786-791.  https://doi.org/10.1007/s11684-020-0751-3
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Factors associated with complete and durable remissions after anti-CD19 chimeric antigen receptor T (CAR-T) cell immunotherapy for relapsed or refractory non-Hodgkin lymphoma (r/r NHL) have not been well characterized. In this study, we found that the different sites of extranodal involvement may affect response, overall survival (OS), and progression-free survival (PFS) in patients with r/r NHL treated with anti-CD19 CAR-T cells. In a cohort of 32 treated patients, 12 (37.5%) and 8 (25%) patients exhibited soft tissue lymphoma and bone marrow (BM) infiltrations, respectively, and 13 (41%) patients exhibited infiltration at other sites. The factors that may affect prognosis were identified through multivariable analysis. As an independent risk factor, soft tissue infiltration was the only factor significantly correlated with adverse prognosis (P<0.05), whereas other factors did not reach statistical significance. Furthermore, the site of extranodal tumor infiltration significantly and negatively affected OS and PFS in patients with r/r NHL treated with anti-CD19 CAR-T cell therapy. PFS and OS in patients with BM involvement were not significantly different from those of patients with lymph node involvement alone. Thus, anti-CD19 CAR-T cell therapy may improve the prognosis of patients with BM infiltration.

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Cerebral regional and network characteristics in asthma patients: a resting-state fMRI study
Siyi Li, Peilin Lv, Min He, Wenjing Zhang, Jieke Liu, Yao Gong, Ting Wang, Qiyong Gong, Yulin Ji, Su Lui
Front. Med.. 2020, 14 (6): 792-801.  https://doi.org/10.1007/s11684-020-0745-1
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Asthma is a serious health problem that involves not only the respiratory system but also the central nervous system. Previous studies identified either regional or network alterations in patients with asthma, but inconsistent results were obtained. A key question remains unclear: are the regional and neural network deficits related or are they two independent characteristics in asthma? Answering this question is the aim of this study. By collecting resting-state functional magnetic resonance imaging from 39 patients with asthma and 40 matched health controls, brain functional measures including regional activity (amplitude of low-frequency fluctuations) and neural network function (degree centrality (DC) and functional connectivity) were calculated to systematically characterize the functional alterations. Patients exhibited regional abnormities in the left angular gyrus, right precuneus, and inferior temporal gyrus within the default mode network. Network abnormalities involved both the sensorimotor network and visual network with key regions including the superior frontal gyrus and occipital lobes. Altered DC in the lingual gyrus was correlated with the degree of airway obstruction. This study elucidated different patterns of regional and network changes, thereby suggesting that the two parameters reflect different brain characteristics of asthma. These findings provide evidence for further understanding the potential cerebral alterations in the pathophysiology of asthma.

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Serum uric acid and risk of incident diabetes in middle-aged and elderly Chinese adults: prospective cohort study
Di Cheng, Chunyan Hu, Rui Du, Hongyan Qi, Lin Lin, Xueyan Wu, Lina Ma, Kui Peng, Mian Li, Min Xu, Yu Xu, Yufang Bi, Weiqing Wang, Yuhong Chen, Jieli Lu
Front. Med.. 2020, 14 (6): 802-810.  https://doi.org/10.1007/s11684-019-0723-7
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The association between serum uric acid and the risk of incident diabetes in Chinese adults remains unknown. This study aimed to investigate this association in a community-dwelling population aged≥40 years in Shanghai, China. Oral glucose tole3rance test was conducted during baseline and follow-up visits. Relative risk regression was utilized to examine the associations between baseline gender-specific serum uric acid levels and incident diabetes risk. A total of 613 (10.3%) incident diabetes cases were identified during the follow-up visit after 4.5 years. Fasting plasma glucose, postload glucose, and glycated hemoglobin A1c during the follow-up visit progressively increased across the sex-specific quartiles of serum uric acid (all Ps<0.05). The incidence rate of diabetes increased across the quartiles of serum uric acid (7.43%, 8.77%, 11.47%, and 13.43%). Multivariate adjusted regression analysis revealed that individuals in the highest quartile had 1.36-fold increased risk of diabetes compared with those in the lowest quartile of serum uric acid (odds ratio (95% confidence interval) = 1.36 (1.06−1.73)). Stratified analysis indicated that the association was only observed in women. Accordingly, serum uric acid was associated with the increased risk of incident diabetes among middle-aged and elderly Chinese women.

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COMMENTARY
Chimeric antigen receptor T-cell therapy: a promising treatment modality for relapsed/refractory mantle cell lymphoma
Ping Li, Ningxin Dong, Yu Zeng, Jie Liu, Xiaochen Tang, Junbang Wang, Wenjun Zhang, Shiguang Ye, Lili Zhou, Alex Hongsheng Chang, Aibin Liang
Front. Med.. 2020, 14 (6): 811-815.  https://doi.org/10.1007/s11684-020-0740-6
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Mantle cell lymphoma (MCL) is a distinct histological type of B-cell lymphoma with a poor prognosis. Several agents, such as proteasome inhibitors, immunomodulatory drugs, and inhibitors of B cell lymphoma-2 and Bruton’s tyrosine kinase have shown efficacy for relapsed or refractory (r/r) MCL but often have short-term responses. Chimeric antigen receptor (CAR) T-cell therapy has emerged as a novel treatment modality for r/r non-Hodgkin’s lymphoma. However, long-term safety and tolerability associated with CAR T-cell therapy are not defined well, especially in MCL. In this report, we described a 70-year-old patient with r/r MCL with 48-month duration of follow-up who achieved long-term remission after CAR T-cell therapy. CAR T-cell-related toxicities were also mild and tolerated well even in this elderly patient. This report suggested that CAR T-cell therapy is a promising treatment modality for patients with MCL, who are generally elderly and have comorbid conditions.

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PERSPECTIVE
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