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1.
Transplant Cell Ther ; 2022 Nov 16.
Article in English | MEDLINE | ID: covidwho-2246470

ABSTRACT

Between 2020 and 2021, 31,525 hematopoietic stem cell transplantations (HSCTs) were reported to the Chinese Blood and Marrow Transplantation Registry Group (CBMTRG) throughout mainland China. In this report, we describe the activity and current trends for HSCT in China during the SARS-CoV-2 pandemic. In 2020, a total of 13,415 cases of HSCT were reported from 166 transplant teams, and 75% (10,042 cases) were allogeneic HSCTs. In 2021, a total of 18,110 cases of HSCT were reported from 174 transplant teams, and 70% (12,744 cases) were allogeneic HSCTs. Haploidentical donor (HID) transplantation accounted for 63% (7977 cases) of allogeneic HSCTs in 2021. The most common indications for allogeneic HSCT for malignant disease were acute myeloid leukemia (AML) (37%) and acute lymphoblastic leukemia (ALL) (23%), and the largest proportion of nonmalignant disease comprised aplastic anemia (AA) (13%). The PB stem cell source accounted for 41% of HIDs and 75% of MSDs. The BuCy-based regimen (57%) was the most popular conditioning regimen for allogeneic HSCT, followed by the BuFlu-based regimen (28%) and TBI-based regimen (11%). This survey provides comprehensive information about the current activities and might benefit clinical physicians' decision planning for HSCT.

2.
Lancet Haematol ; 10(2): e107-e116, 2023 Feb.
Article in English | MEDLINE | ID: covidwho-2237504

ABSTRACT

BACKGROUND: Chimeric antigen receptor (CAR) T-cell therapy targeting B-cell maturation antigen (BCMA) has shown activity in treating relapsed or refractory multiple myeloma; however, relapse is still common, and new targets are needed. We aimed to assess the activity and safety profile of G protein-coupled receptor class C group 5 member D (GPRC5D)-targeted CAR T cells (OriCAR-017) in patients with relapsed or refractory multiple myeloma. METHODS: POLARIS was a first-in-human, single-centre, single-arm, phase 1 trial of GPRC5D-targeted CAR T cells (OriCAR-017) done at the First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China. Eligible patients were adults aged 18-75 years with a diagnosis of relapsed or refractory multiple myeloma and an ECOG performance status of 0-2, had GPRC5D expression in bone marrow plasma cells greater than 20% or were positive for GPRC5D by immunohistochemistry, and had received at least three previous lines of treatment including proteasome inhibitors, immunomodulatory drugs, and chemotherapy. Patients were consecutively assigned to receive a single dose of intravenous OriCAR-017 at 1 × 106 CAR T cells per kg, 3 × 106 CAR T cells per kg, or 6 × 106 CAR T cells per kg in the dose-escalation phase. In the expansion phase, patients received the recommended phase 2 dose. Recruitment to the expansion phase terminated early due to the COVID-19 pandemic on May 1, 2022. The primary endpoints were safety, the maximum tolerated dose and the recommended phase 2 dose. Safety and activity analyses included all patients who received OriCAR-017. This trial is registered with ClinicalTrials.gov, NCT05016778. This trial has been completed and is entering long-term follow-up. FINDINGS: Between June 9, 2021, and Feb 28, 2022, we recruited 13 patients for inclusion into the study. One patient was excluded because of GPRC5D negativity and two patients discontinued after apheresis because of rapid progression. Nine patients were assigned to the dose escalation phase (three received 1 × 106 CAR T cells per kg, three received 3 × 106 CAR T cells per kg, and three received 6 × 106 CAR T cells per kg). The maximum tolerated dose was not identified, because no dose-limiting toxic effects were observed. On the basis of safety and preliminary activity, the recommended phase 2 dose was set at 3 × 106 CAR T cells per kg, which was received by one additional patient in the dose expansion phase. Five patients (50%) were female, five (50%) were male, and all were Chinese. Five patients (50%) were previously treated with BCMA-targeted CAR T-cell therapy. Median follow-up was 238 days (IQR 182-307). There were no serious adverse events and no treatment-related deaths. The most common grade 3 or worse adverse events were haematological, including neutropenia (ten [100%] of ten patients), thrombocytopenia (nine [90%]), leukopenia (nine [90%]), and anaemia (seven [70%]). All patients had cytokine release syndrome (nine [90%] grade 1 and one [10%] grade 2). No neurological toxic effects were reported. Ten (100%) of ten patients had an overall response, of whom six (60%) had a stringent complete response and four (40%) had very good partial response. Two patients discontinued due to disease progression (one GPRC5D-positive patient in the middle-dose group and one GPRC5D-negative patient in the low-dose group). INTERPRETATION: The results of this study suggest that GPRC5D is an active target for immunotherapy in multiple myeloma. GPRC5D-targeted CAR T-cell therapy is a promising treatment modality for patients with relapsed or refractory multiple myeloma and deserves further testing. FUNDING: OriCell Therapeutics.


Subject(s)
Anemia , COVID-19 , Multiple Myeloma , Thrombocytopenia , Adult , Humans , Male , Female , Multiple Myeloma/drug therapy , B-Cell Maturation Antigen , Pandemics , Neoplasm Recurrence, Local , T-Lymphocytes , Receptors, G-Protein-Coupled/therapeutic use
3.
Front Microbiol ; 13: 1071394, 2022.
Article in English | MEDLINE | ID: covidwho-2199024

ABSTRACT

Porcine epidemic diarrhea virus (PEDV) in the Coronavirus family is a highly contagious enteric pathogen in the swine industry, which has evolved mechanisms to evade host innate immune responses. The PEDV-mediated inhibition of interferons (IFNs) has been linked to the nuclear factor-kappa B (NF-κB) pathway. MicroRNAs (miRNAs) are involved in virus-host interactions and IFN-I regulation. However, the mechanism by which the PEDV regulates IFN during PEDV infection has not yet been investigated in its natural target cells. We here report a novel mechanism of viral immune escape involving miR-615, which was screened from a high-throughput sequencing library of porcine intestinal epithelial cells (IECs) infected with PEDV. PEDV infection altered the profiles of miRNAs and the activities of several pathways involved in innate immunity. Overexpression of miR-615 increased PEDV replication, inhibited IFN expression, downregulated the NF-κB pathway, and blocked p65 nuclear translocation. In contrast, knockdown of miR-615 enhanced IFN expression, suppressed PEDV replication, and activated the NF-κB pathway. We further determined that IRAK1 is the target gene of miR-615 in IECs. Our findings show that miR-615 suppresses activation of the NF-κB pathway by suppressing the IRAK1 protein and reducing the generation of IFN-IIIs, which in turn facilitates PEDV infection in IECs. Moreover, miR-615 inhibited PEDV replication and NF-κB pathway activation in both IECs and MARC-145 cells. These findings support an important role for miR-615 in the innate immune regulation of PEDV infections and provide a novel perspective for developing new treatments.

4.
Tob Induc Dis ; 20: 97, 2022.
Article in English | MEDLINE | ID: covidwho-2113051

ABSTRACT

INTRODUCTION: Smoking cessation is an efficient approach to reducing disease burden. Traditional Chinese Medicine (TCM) therapies such as acupuncture, acupressure, and herbal drugs are often used to help quit smoking. However, there is a lack of overarching bibliometric analysis of the clinical research on smoking cessation focusing on TCM. The aim of our study is to explore the current patterns and trends of TCM therapy for smoking cessation through bibliometric methods with visual presentation. METHODS: This study is an assessment of academic publications retrieved from the Scopus database on smoking cessation using TCM therapy published in the period 2005-2021. Sankey diagram, word-cloud, network analysis, thematic maps, tree-maps, and the collaborative work of authors, institutions and countries, were used to identify research trends on TCM therapy for smoking cessation. The total cited index and H-index (for journals, authors, countries, organizations) were used to identify the trends of worldwide development by R Package and Excel 2016. RESULTS: There was an upward trend, with some fluctuations, of 1908 articles from 2005 to 2021. The most productive country was China. The top institution in this field was Beijing University. The dominant author that contributed to TCM therapy for smoking cessation was Wang Y, who has the highest H-Index. The most productive cited journals were Evidence-Based Complementary and Alternative Medicines and the Chinese Journal of Clinical Rehabilitation. Liu L, (2011, STROKE) had the highest centrality. The keywords 'acupuncture', 'traditional Chinese medicine', 'colitis', 'hypertension', 'chronic obstructive pulmonary disease', 'risk factors' and 'alternative medicine' ranked highest in frequency. The diseases of healthy people concerned mainly cardiovascular, cancer, diabetes, hypertension and pregnancy. The diseases of the patients concerned mainly cancer, diabetes, hematopathy, stroke, cardiovascular, diabetes, lung disease, and hypertension. Treatment methods were mainly traditional Chinese medicine and acupuncture. The research methods mainly included randomized controlled trials that were multi-center and double-blind. CONCLUSIONS: A substantial number of articles on TCM therapy for smoking cessation, mainly focusing on TCM and acupuncture were identified. It is worth noting that research that focused on TCM therapy for smoking cessation also was related to COVID-19.

5.
J Genet Eng Biotechnol ; 20(1): 149, 2022 Nov 01.
Article in English | MEDLINE | ID: covidwho-2098596

ABSTRACT

BACKGROUND: COVID-19 is a disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Rigorous detection and treatment strategies against SARS-CoV-2 have become very challenging due to continuous evolutions to the viral genome. Therefore, careful genomic analysis is sorely needed to understand transmission, the cellular mechanism of pathogenicity, and the development of vaccines or drugs. OBJECTIVE: In this study, we intended to identify SARS-CoV-2 genome variants that may help understand the cellular and molecular foundation of coronavirus infections required to develop effective intervention strategies. METHODS: SARS-CoV-2 genome sequences were downloaded from an open-source public database, processed, and analyzed for variants in target detection sites and genes. RESULTS: We have identified six unique variants, G---AAC, T---AAC---T, AAC---T, AAC--------T, C----------T, and C--------C, at the nucleocapsid region and eleven major hotspot mutant genes: nsp3, surface glycoprotein, nucleocapsid phosphoprotein, ORF8, nsp6, nsp2, nsp4, helicase, membrane glycoprotein, 3'-5' exonuclease, and 2'-O-ribose methyltransferases. In addition, we have identified eleven major mutant genes that may have a crucial role in SARS-CoV-2 pathogenesis. CONCLUSION: Studying haplotype variants and 11 major mutant genes to understand the mechanism of action of fatal pathogenicity and inter-individual variations in immune responses is inevitable for managing target patient groups with identified variants and developing effective anti-viral drugs and vaccines.

6.
ACS Appl Mater Interfaces ; 14(45): 50534-50542, 2022 Nov 16.
Article in English | MEDLINE | ID: covidwho-2087120

ABSTRACT

The CRISPR-Cas system was developed into a molecular diagnostic tool with high sensitivity, low cost, and high specificity in recent years. Colorimetric assays based on nanozymes offer an attractive point-of-care testing method for their low cost of use and user-friendly operation. Here, a MnO2 nanozyme-mediated CRISPR-Cas12a system was instituted to detect SARS-CoV-2. MnO2 nanorods linked to magnetic beads via a single-stranded DNA (ssDNA) linker used as an oxidase-like nanozyme inducing the color change of 3,3',5,5'-tetramethylbenzidine, which can be distinguished by the naked eye. The detection buffer color will change when the Cas12a is activated by SARS-CoV-2 and indiscriminately cleave the linker ssDNA. The detection limit was 10 copies per microliter and showed no cross-reaction with other coronaviruses. The nanozyme-mediated CRISPR-Cas12a system shows high selectivity and facile operation, with great potential for molecular diagnosis in point-of-care testing applications.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , SARS-CoV-2/genetics , CRISPR-Cas Systems/genetics , Manganese Compounds , COVID-19/diagnosis , Nucleic Acid Amplification Techniques/methods , Oxides , DNA, Single-Stranded
8.
Journal of combinatorial optimization ; : 1-14, 2022.
Article in English | EuropePMC | ID: covidwho-2057938

ABSTRACT

The coronavirus disease (COVID-19) pandemic has caused significant changes in the external environment of enterprises, resulting in tremendous negative impacts. Accordingly, the irregular fluctuation of business data poses a critical challenge to traditional approaches. Therefore, to combat the effects of the COVID-19 pandemic, an effective model is required to proactively predict an enterprise’s performance and simultaneously generate scientific performance optimization solutions. Consequently, at the intersection of artificial intelligence algorithms, operations research, and management science, an intelligent DEA-SVM model, which has a theoretical contribution, is developed in this study. The capabilities of this model are verified through sufficient numerical experiments. On the one hand, this model outperforms traditional algorithms in prediction accuracy. On the other hand, effective performance optimization solutions for low-performance enterprises are obtained from the input–output perspective. Moreover, the application value of this model is reflected in its successful implementation in the healthcare industry. Thus, it is a user-friendly tool for realizing the stable operation of enterprises in the context of the COVID-19 pandemic.

9.
Trials ; 23(1): 797, 2022 Sep 21.
Article in English | MEDLINE | ID: covidwho-2038855

ABSTRACT

BACKGROUND: Depression and anxiety are common among pregnant women. Internet-delivered psychological therapies such as cognitive behavioral therapy (iCBT) have been developed to increase accessibility and address common help-seeking barriers, especially during pandemic period. The objective of this trial is to evaluate the short-term and long-term effects of iCBT on reducing depressive symptoms among pregnant women during the COVID-19 pandemic with the overall goal of preventing depression recurrence in the first 12 months postpartum. METHODS: A multi-site randomized controlled trial will be conducted where 300 pregnant women early in their third trimester will be screened for depression symptoms using the Edinburgh Postnatal Depression Scale (EPDS) during a routine obstetrical visit. Eligible and consenting women with a score greater than 9 will be randomly allocated (1:1) to either intervention group or control group. ICBT involving the completion of 7 weekly online modules will be delivered via a well-designed perinatal mental healthcare app. The primary objective is to evaluate the effect of iCBT on reducing depression symptoms among pregnant Chinese women starting from their third trimester. The secondary objectives are to examine the effect of iCBT on anxiety, sleep quality, social support, parenting stress, co-parenting relationship, and infant development. DISCUSSION: This multi-center randomized controlled trial has been planned in accordance with best practices in behavioral trial design. The internet-based intervention addressed the needs of pregnant women during a major pandemic where face-to-face therapy is not preferable. The trial has a relatively large sample size with sufficient power to evaluate the efficacy of iCBT intervention for the primary and secondary outcomes. One year follow-up evaluation in the study is designed to determine the longer-term effect of the intervention on both maternal and infant outcomes. Although a limitation is the assessment of depression and anxiety using self-report measures, these easily incorporated and maternal-preferred assessments allow for real-life scalability if the intervention is proven to be effective. ETHICS AND DISSEMINATION: Ethics was approved by the institutional review board of International Peace Maternity and Child Health Hospital (GKLW2020-25). Dissemination of results will be published in peer-reviewed academic journals and presented at scientific conferences. TRIAL STATUS: The first patient was enrolled on 19 August 2020. To date, 203 participants have met eligibility requirements and been randomized to either the intervention group or control group. Data collection aims to be complete in September 2022. Date and version identifier: 2020715-version1.0. TRIAL REGISTRATION: ChiCTR2000033433. Registered 31 May 2020, http://www.chictr.org.cn/showproj.aspx?proj=54482 .


Subject(s)
COVID-19 , Cognitive Behavioral Therapy , Child , Cognitive Behavioral Therapy/methods , Depression/diagnosis , Depression/therapy , Female , Humans , Internet , Multicenter Studies as Topic , Pandemics , Pregnancy , Randomized Controlled Trials as Topic , Treatment Outcome
10.
J Med Chem ; 65(17): 11840-11853, 2022 09 08.
Article in English | MEDLINE | ID: covidwho-2016520

ABSTRACT

Site-selective lysine modification of peptides and proteins in aqueous solutions or in living cells is still a big challenge today. Here, we report a novel strategy to selectively quinolylate lysine residues of peptides and proteins under native conditions without any catalysts using our newly developed water-soluble zoliniums. The zoliniums could site-selectively quinolylate K350 of bovine serum albumin and inactivate SARS-CoV-2 3CLpro via covalently modifying two highly conserved lysine residues (K5 and K61). In living HepG2 cells, it was demonstrated that the simple zoliniums (5b and 5B) could quinolylate protein lysine residues mainly in the nucleus, cytosol, and cytoplasm, while the zolinium-fluorophore hybrid (8) showed specific lysosome-imaging ability. The specific chemoselectivity of the zoliniums for lysine was validated by a mixture of eight different amino acids, different peptides bearing potential reactive residues, and quantum chemistry calculations. This study offers a new way to design and develop lysine-targeted covalent ligands for specific application.


Subject(s)
Lysine , Peptides , Coronavirus 3C Proteases/chemistry , Lysine/chemistry , Peptides/chemistry , SARS-CoV-2/enzymology , Serum Albumin, Bovine/chemistry , Water/chemistry
11.
China CDC Wkly ; 4(30): 655-659, 2022 Jul 29.
Article in English | MEDLINE | ID: covidwho-1965175

ABSTRACT

What is already known about this topic?: Many regions in China have recently reported outbreaks of the coronavirus disease 2019 (COVID-19) caused by the Omicron variant. What is added by this report?: Wuchuan County, Guizhou Province reacted quickly and implemented accurate intervention measures to effectively control the outbreak. The susceptible-exposed-infectious-asymptomatic-removed (SEIAR) model was applied to evaluate the effectiveness of intervention measures. What are the implications for public health practice?: Fast response measures should be taken to prevent the spread of outbreaks caused by the Omicron variant.

12.
Front Immunol ; 13: 946731, 2022.
Article in English | MEDLINE | ID: covidwho-1952336

ABSTRACT

Mitochondria get caught in the crossfire of coronavirus disease 2019 (COVID-19) and antiviral immunity. The mitochondria-mediated antiviral immunity represents the host's first line of defense against viral infection, and the mitochondria are important targets of COVID-19. However, the specific manifestations of mitochondrial damage in patients with COVID-19 have not been systematically clarified. This study comprehensively analyzed one single-cell RNA-sequencing dataset of lung tissue and two bulk RNA-sequencing datasets of blood from COVID-19 patients. We found significant changes in mitochondrion-related gene expression, mitochondrial functions, and related metabolic pathways in patients with COVID-19. SARS-CoV-2 first infected the host alveolar epithelial cells, which may have induced excessive mitochondrial fission, inhibited mitochondrial degradation, and destroyed the mitochondrial calcium uniporter (MCU). The type II alveolar epithelial cell count decreased and the transformation from type II to type I alveolar epithelial cells was blocked, which exacerbated viral immune escape and replication in COVID-19 patients. Subsequently, alveolar macrophages phagocytized the infected alveolar epithelial cells, which decreased mitochondrial respiratory capacity and activated the ROS-HIF1A pathway in macrophages, thereby aggravating the pro-inflammatory reaction in the lungs. Infected macrophages released large amounts of interferon into the blood, activating mitochondrial IFI27 expression and destroying energy metabolism in immune cells. The plasma differentiation of B cells and lung-blood interaction of regulatory T cells (Tregs) was exacerbated, resulting in a cytokine storm and excessive inflammation. Thus, our findings systematically explain immune escape and excessive inflammation seen during COVID-19 from the perspective of mitochondrial quality imbalance.


Subject(s)
COVID-19 , SARS-CoV-2 , Antiviral Agents/therapeutic use , Humans , Inflammation , Lung , Mitochondria , RNA
13.
Anal Chim Acta ; 1221: 340120, 2022 Aug 15.
Article in English | MEDLINE | ID: covidwho-1914086

ABSTRACT

Early and accurate diagnosis of SARS-CoV-2 was crucial for COVID-19 control and urgently required ultra-sensitive and rapid detection methods. CRISPR-based detection systems have great potential for rapid SARS-CoV-2 detection, but detecting ultra-low viral loads remains technically challenging. Here, we report an ultrasensitive CRISPR/Cas12a-based electrochemical detection system with an electrochemical biosensor, dubbed CRISPR-SPCE, in which the CRISPR ssDNA reporter was immobilized onto a screen-printed carbon electrode. Electrochemical signals are detected due to CRISPR cleavage, giving enhanced detection sensitivity. CRISPR-SPCE enables ultrasensitive SARS-CoV-2 detection, reaching as few as 0.27 copies µL-1. Moreover, CRISPR-SPCE is also highly specific and inexpensive, providing a fast and simple SARS-CoV-2 assay.


Subject(s)
Biosensing Techniques , COVID-19 , Biosensing Techniques/methods , COVID-19/diagnosis , COVID-19 Testing , Carbon , Electrodes , Humans , SARS-CoV-2/genetics , Sensitivity and Specificity
14.
Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences ; 49(2):147-157, 2020.
Article in Chinese | EuropePMC | ID: covidwho-1772475

ABSTRACT

当前2019冠状病毒病(COVID-19)疫情仍处于胶着状态。浙江大学医学院附属第一医院是国家感染性疾病临床医学中心,浙江省COVID-19患者救治中心。疫情一线的专家集智攻关,以国家卫生健康委员会和国家中医药管理局发布的COVID-19诊治指南为依据,以抗病毒、抗休克、抗低氧血症、抗继发感染、维持水电解质和酸碱平衡、维持微生态平衡的“四抗二平衡”救治策略为核心,总结完善诊治方案,聚焦临床实践的一些具体问题,为COVID-19患者临床诊治提供借鉴。推荐以多学科协作诊治个性化治疗提高COVID-19患者救治质量。建议病原学检测、炎症指标监测和肺部影像学动态观察指导临床诊治。痰液的病毒核酸检测阳性率最高,约10%的急性期患者血液中检测到病毒核酸,50%的患者粪便中检测到病毒核酸,粪便中可分离出活病毒,须警惕粪便是否具有传染性;开展细胞因子等炎症指标监测有助于发现是否出现细胞因子风暴,判断是否需要人工肝血液净化治疗。通过以“四抗二平衡”为核心的综合治疗提高治愈率、降低病死率;早期抗病毒治疗能减少重症、危重症发生,前期使用阿比多尔联合洛匹那韦/利托那韦抗病毒显示出一定效果。休克和低氧血症多为细胞因子风暴所致,人工肝血液净化治疗能迅速清除炎症介质,阻断细胞因子风暴,对维持水电解质酸碱平衡也有很好的作用,可以提高危重型患者的疗效。重型病例疾病早期可适量、短程应用糖皮质激素。氧疗过程中,患者氧合指数小于200 mmHg时应及时转入重症医学科治疗;采用保守氧疗策略,不推荐常规进行无创通气;机械通气患者应严格执行集束化呼吸机相关性肺炎预防管理策略;氧合指数大于150 mmHg时,及早减、停镇静剂并撤机拔管。不推荐预防性使用抗菌药物,对于病程长,体温反复升高和血降钙素原水平升高的患者可酌情使用抗菌药物;要关注COVID-19患者继发真菌感染的诊治。COVID-19患者有肠道微生态紊乱,肠道乳酸杆菌、双歧杆菌等有益菌减少,推荐对所有患者进行营养和胃肠道功能评估,以营养支持和补充大剂量肠道微生态调节剂,纠正肠道微生态失衡,减少细菌移位和继发感染。COVID-19患者普遍存在焦虑和恐惧心理,应建立动态心理危机干预和处理。提倡中西医结合辨证施治;优化重型患者护理促进康复。严重急性呼吸综合征冠状病毒2(SARS-CoV-2)感染后病毒清除规律仍不明了,出院后仍须居家隔离2周,并定期随访。以上经验和建议在本中心实行,取得较好效果,但COVID-19是一种新的疾病,其诊治方案及策略仍有待进一步探索与完善。

15.
Frontiers in immunology ; 13, 2022.
Article in English | EuropePMC | ID: covidwho-1762251

ABSTRACT

In contrast to dexamethasone, the clinical efficacy of methylprednisolone (MP) remains controversial, and a systems biology study on its mechanism is lacking. In this study, a total of 38 severe COVID-19 patients were included. The demographics, clinical characteristics, and severity biomarkers including C-reactive protein (CRP), d-dimer, albumin, and Krebs von den Lungen 6 of patients receiving MP (n=26, 40 mg or 80 mg daily for 3-5 days) and supportive therapy (n=12) were compared. Longitudinal measurements of 92 cytokines in MP group from admission to over six months after discharge were performed by multiplex Proximity Extension Assay. The results showed that demographics, baseline clinical characteristics were similar in MP and non-MP groups. No death occurred and the hospital stays between the two groups were similar. Kinetics studies showed that MP was not better than supportive therapy at improving the four severity biomarkers. Cytokines in MP group were characterized by five clusters according to their baseline levels and responses to MP. The immunological feature of severe COVID-19 could be defined by the “core signature” cytokines in cluster 2: MCP-3, IL-6, IFN-γ, and CXCL10, which strongly correlated with each other and CRP, and are involved in cytokine release storm. The “core signature” cytokines were significantly upregulated at baseline and remained markedly elevated after MP treatment. Our work showed a short course of MP therapy could not rapidly improve the immune disorders among severe COVID-19 patients or clinical outcomes, also confirmed “core signature” cytokines, as severity biomarkers similar to CRP, could be applied to evaluate clinical treatment effect.

16.
Sci Signal ; 15(715): eabh0068, 2022 01 04.
Article in English | MEDLINE | ID: covidwho-1741564

ABSTRACT

The transcription regulator ID2 plays an essential role in the development and differentiation of immune cells. Here, we report that ID2 also negatively regulates antiviral innate immune responses. During viral infection of human epithelial cells, ID2 bound to TANK-binding kinase 1 (TBK1) and to inhibitor of nuclear factor κB kinase ε (IKKε). These interactions inhibited the recruitment and activation of interferon (IFN) regulatory factor 3 (IRF3) by TBK1 or IKKε, leading to a reduction in the expression of IFN-ß1 (IFNB1). IFN-ß induced the nuclear export of ID2 to form a negative feedback loop. Knocking out ID2 in human cells enhanced innate immune responses and suppressed infection by different viruses, including SARS-CoV-2. Mice with a myeloid-specific deficiency of ID2 produced more IFN-α in response to viral infection and were more resistant to viral infection than wild-type mice. Our findings not only establish ID2 as a modulator of IRF3 activation induced by TBK1 and/or IKKε but also introduce a mechanism for cross-talk between innate immunity and cell development and differentiation.


Subject(s)
COVID-19 , I-kappa B Kinase , Animals , Antiviral Agents , Humans , I-kappa B Kinase/genetics , I-kappa B Kinase/metabolism , Immunity, Innate , Inhibitor of Differentiation Protein 2 , Interferon Regulatory Factor-3/genetics , Interferon Regulatory Factor-3/metabolism , Mice , Phosphorylation , Protein Serine-Threonine Kinases/genetics , SARS-CoV-2
17.
Front Immunol ; 12: 838082, 2021.
Article in English | MEDLINE | ID: covidwho-1674340

ABSTRACT

Recombinant antibodies such as nanobodies are progressively demonstrating to be a valid alternative to conventional monoclonal antibodies also for clinical applications. Furthermore, they do not solely represent a substitute for monoclonal antibodies but their unique features allow expanding the applications of biotherapeutics and changes the pattern of disease treatment. Nanobodies possess the double advantage of being small and simple to engineer. This combination has promoted extremely diversified approaches to design nanobody-based constructs suitable for particular applications. Both the format geometry possibilities and the functionalization strategies have been widely explored to provide macromolecules with better efficacy with respect to single nanobodies or their combination. Nanobody multimers and nanobody-derived reagents were developed to image and contrast several cancer diseases and have shown their effectiveness in animal models. Their capacity to block more independent signaling pathways simultaneously is considered a critical advantage to avoid tumor resistance, whereas the mass of these multimeric compounds still remains significantly smaller than that of an IgG, enabling deeper penetration in solid tumors. When applied to CAR-T cell therapy, nanobodies can effectively improve the specificity by targeting multiple epitopes and consequently reduce the side effects. This represents a great potential in treating malignant lymphomas, acute myeloid leukemia, acute lymphoblastic leukemia, multiple myeloma and solid tumors. Apart from cancer treatment, multispecific drugs and imaging reagents built with nanobody blocks have demonstrated their value also for detecting and tackling neurodegenerative, autoimmune, metabolic, and infectious diseases and as antidotes for toxins. In particular, multi-paratopic nanobody-based constructs have been developed recently as drugs for passive immunization against SARS-CoV-2 with the goal of impairing variant survival due to resistance to antibodies targeting single epitopes. Given the enormous research activity in the field, it can be expected that more and more multimeric nanobody molecules will undergo late clinical trials in the next future. Systematic Review Registration.


Subject(s)
Single-Domain Antibodies/chemistry , Single-Domain Antibodies/therapeutic use , Animals , Autoimmune Diseases/immunology , Autoimmune Diseases/therapy , Communicable Diseases/immunology , Communicable Diseases/therapy , Humans , Immunomodulation , Molecular Imaging , Molecular Targeted Therapy , Neoplasms/diagnostic imaging , Neoplasms/immunology , Neoplasms/therapy , Recombinant Proteins/chemistry , Recombinant Proteins/immunology , Recombinant Proteins/therapeutic use , Single-Domain Antibodies/immunology
18.
J Diabetes Res ; 2021: 4632745, 2021.
Article in English | MEDLINE | ID: covidwho-1556856

ABSTRACT

Gestational diabetes mellitus (GDM) is a common pregnancy complication which is normally diagnosed in the second trimester of gestation. With an increasing incidence, GDM poses a significant threat to maternal and offspring health. Therefore, we need a deeper understanding of GDM pathophysiology and novel investigation on the diagnosis and treatment for GDM. MicroRNAs (miRNAs), a class of endogenic small noncoding RNAs with a length of approximately 19-24 nucleotides, have been reported to exert their function in gene expression by binding to proteins or being enclosed in membranous vesicles, such as exosomes. Studies have investigated the roles of miRNAs in the pathophysiological mechanism of GDM and their potential as noninvasive biological candidates for the management of GDM, including diagnosis and treatment. This review is aimed at summarizing the pathophysiological significance of miRNAs in GDM development and their potential function in GDM clinical diagnosis and therapeutic approach. In this review, we summarized an integrated expressional profile and the pathophysiological significance of placental exosomes and associated miRNAs, as well as other plasma miRNAs such as exo-AT. Furthermore, we also discussed the practical application of exosomes in GDM postpartum outcomes and the potential function of several miRNAs as therapeutic target in the GDM pathological pathway, thus providing a novel clinical insight of these biological signatures into GDM therapeutic approach.


Subject(s)
Diabetes, Gestational/drug therapy , MicroRNAs/pharmacology , Adult , Diabetes, Gestational/genetics , Exosomes/metabolism , Female , Gene Expression/genetics , Gene Expression/physiology , Humans , MicroRNAs/metabolism , MicroRNAs/therapeutic use , Pregnancy
20.
Signal Transduct Target Ther ; 6(1): 367, 2021 10 20.
Article in English | MEDLINE | ID: covidwho-1475287

ABSTRACT

Cytokine release syndrome (CRS) embodies a mixture of clinical manifestations, including elevated circulating cytokine levels, acute systemic inflammatory symptoms and secondary organ dysfunction, which was first described in the context of acute graft-versus-host disease after allogeneic hematopoietic stem-cell transplantation and was later observed in pandemics of influenza, SARS-CoV and COVID-19, immunotherapy of tumor, after chimeric antigen receptor T (CAR-T) therapy, and in monogenic disorders and autoimmune diseases. Particularly, severe CRS is a very significant and life-threatening complication, which is clinically characterized by persistent high fever, hyperinflammation, and severe organ dysfunction. However, CRS is a double-edged sword, which may be both helpful in controlling tumors/viruses/infections and harmful to the host. Although a high incidence and high levels of cytokines are features of CRS, the detailed kinetics and specific mechanisms of CRS in human diseases and intervention therapy remain unclear. In the present review, we have summarized the most recent advances related to the clinical features and management of CRS as well as cutting-edge technologies to elucidate the mechanisms of CRS. Considering that CRS is the major adverse event in human diseases and intervention therapy, our review delineates the characteristics, kinetics, signaling pathways, and potential mechanisms of CRS, which shows its clinical relevance for achieving both favorable efficacy and low toxicity.


Subject(s)
Cytokine Release Syndrome , Signal Transduction/immunology , Acute Disease , Autoimmune Diseases/complications , Autoimmune Diseases/immunology , Autoimmune Diseases/therapy , COVID-19/complications , COVID-19/immunology , COVID-19/therapy , Cytokine Release Syndrome/etiology , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/therapy , Graft vs Host Disease/complications , Graft vs Host Disease/immunology , Graft vs Host Disease/therapy , Hematopoietic Stem Cell Transplantation , Humans , Immunotherapy, Adoptive/adverse effects , Influenza, Human/complications , Influenza, Human/immunology , Neoplasms/complications , Neoplasms/immunology , Neoplasms/therapy , SARS-CoV-2/immunology , Severe Acute Respiratory Syndrome/complications , Severe Acute Respiratory Syndrome/immunology , Severe Acute Respiratory Syndrome/therapy
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