Fluorescence in situ hybridization reveals the evolutionary biology of minor clone of gain/amp(1q) in multiple myeloma.

Growing evidence suggests that gain or amplification [gain/amp(1q)] accumulates during disease progression of multiple myeloma (MM). Previous investigations have indicated that small gain/amp(1q) subclones present at the time of diagnosis may evolve into dominant clones upon MM relapse. However, the influence of a minor clone of gain/amp(1q) on MM survival, as well as the correlation between different clonal sizes of gain/amp(1q) and the chromosomal instability (CIN) of MM, remains poorly understood. In this study, we analyzed fluorescence in situ hybridization (FISH) results of 998 newly diagnosed MM (NDMM) patients. 513 patients were detected with gain/amp(1q) at diagnosis. Among these 513 patients, 55 had a minor clone (≤20%) of gain/amp(1q). Patients with a minor clone of gain/amp(1q) displayed similar survival outcomes compared to those without gain/amp(1q). Further analysis demonstrated patients with a minor clone of gain/amp(1q) exhibited a clonal architecture similar to those without gain/amp(1q). Lastly, our results showed a significant increase in the clonal size of the minor clone of gain/amp(1q), frequently observed in MM. These findings suggested that a minor clone of gain/amp(1q) might represent an earlier stage in the pathogenesis of gain/amp(1q) and propose a "two-step" process in the clonal size changes of gain/amp(1q) in MM.

Epigenetic regulation of CD38/CD48 by KDM6A mediates NK cell response in multiple myeloma.

Anti-CD38 monoclonal antibodies like Daratumumab (Dara) are effective in multiple myeloma (MM); however, drug resistance ultimately occurs and the mechanisms behind this are poorly understood. Here, we identify, via two in vitro genome-wide CRISPR screens probing Daratumumab resistance, KDM6A as an important regulator of sensitivity to Daratumumab-mediated antibody-dependent cellular cytotoxicity (ADCC). Loss of KDM6A leads to increased levels of H3K27me3 on the promoter of CD38, resulting in a marked downregulation in CD38 expression, which may cause resistance to Daratumumab-mediated ADCC. Re-introducing CD38 does not reverse Daratumumab-mediated ADCC fully, which suggests that additional KDM6A targets, including CD48 which is also downregulated upon KDM6A loss, contribute to Daratumumab-mediated ADCC. Inhibition of H3K27me3 with an EZH2 inhibitor resulted in CD38 and CD48 upregulation and restored sensitivity to Daratumumab. These findings suggest KDM6A loss as a mechanism of Daratumumab resistance and lay down the proof of principle for the therapeutic application of EZH2 inhibitors, one of which is already FDA-approved, in improving MM responsiveness to Daratumumab.

Monitoring Minimal Residual Disease in Patients with Multiple Myeloma by Targeted Tracking Serum M-Protein Using Mass Spectrometry (EasyM).

PURPOSE: We investigated both the clinical utilities and the prognostic impacts of the clonotypic peptide mass spectrometry (MS)-EasyM, a blood-based minimal residual disease (MRD) monitoring protocol in multiple myeloma. EXPERIMENTAL DESIGN: A total of 447 sequential serum samples from 56 patients with multiple myeloma were analyzed using EasyM. Patient-specific M-protein peptides were sequenced from diagnostic samples; sequential samples were quantified by EasyM to monitor the M-protein. The performance of EasyM was compared with serum immunofixation electrophoresis (IFE), bone marrow multiparameter flow cytometry (MFC), and next-generation flow cytometry (NGF) detection. The optimal balance of EasyM sensitivity/specificity versus NGF (10-5 sensitivity) was determined and the prognostic impact of MS-MRD status was investigated. RESULTS: Of the 447 serum samples detected and measured by EasyM, 397, 126, and 92 had time-matching results for comparison with serum IFE, MFC-MRD, and NGF-MRD, respectively. Using a dotp >0.9 as the MS-MRD positive, sensitivity was 99.6% versus IFE and 100.0% versus MFC and NGF. Using an MS negative cutoff informed by ROC analysis (<1.86% of that at diagnosis), EasyM sensitivity remained high versus IFE (88.3%), MFC (85.1%), and NGF (93.2%), whereas specificity increased to 90.4%, 55.8%, and 93.2%, respectively. In the multivariate analysis, older diagnostic age was an independent predictor for progression-free survival [PFS; high risk (HR), 3.15; 1.26-7.86], the best MS-MRD status (MS-MRD negative) was independent predictor for both PFS (HR, 0.25; 0.12-0.52) and overall survival (HR, 0.16; 0.06-0.40). CONCLUSIONS: EasyM is a highly sensitive and minimal invasive method of MRD monitoring in multiple myeloma; MS-MRD had significant predictive ability for survival outcomes.

MAF translocation remains a strong prognostic factor despite concurrent chromosomal abnormalities.

Not available.

NMAAP1 regulated macrophage polarizion into M1 type through glycolysis stimulated with BCG.

Bacillus Calmette Guerin (BCG) perfusion is widely used as cancer adjuvant therapy, in which macrophages play an important role. Novel macrophage activated associated protein 1 (NMAAP1), upregulated after BCG's activation, was proved to promote macrophage polarization to the M1 type. We found that BCG could stimulate mice BMDM to the M1 type and kill tumor cells. After the deletion of NMAAP1, the tumor volume of mice became larger, and the number of M1 type macrophages in the tumor decreased significantly. When macrophages were induced into the M1 type, aerobic glycolysis, the Warburg effect manifested in the increased uptake of glucose and the conversion of pyruvate to lactic acid. NMAAP1 could bind with IP3R and regulate macrophage polarization to the M1 type. However, the specific mechanism of how NMAAP1 regulates macrophage polarization towards the M1 type and plays an antitumor role must be clarified. NMAAP1 could promote the release of lactic acid and pyruvate, enhance the glycolysis of macrophages, and affect the expression of HIF-1α. After inhibition of glycolysis by 2-DG and lactic acid generation by FX11, the effects of NMAAP1 promoting macrophage polarization to the antitumor M1 type were weakened. Furthermore, NMAAP1 upregulated the expression of HIF-1α, which is associated with glycolysis. Moreover, the Ca2+/NF-κB pathway regulated HIF-1α expression by NMAAP1 in the macrophages. NMAAP1 promotes the polarization of macrophages towards the M1 type by affecting the Warburg effect stimulated by BCG.

Minor clone of del(17p) provides a reservoir for relapse in multiple myeloma.

The deletion of chromosome 17p (del(17p)) is considered a crucial prognostic factor at the time of diagnosis in patients with multiple myeloma (MM). However, the impact of del(17p) on survival at different clonal sizes at relapse, as well as the patterns of clonal evolution between diagnosis and relapse and their prognostic value, has not been well described. To address these issues, we analyzed the interphase fluorescence in situ hybridization (iFISH) results of 995 newly diagnosed MM (NDMM) patients and 293 patients with MM at their first relapse. Among these patients, 197 had paired iFISH data at diagnosis and first relapse. Our analysis of paired iFISH revealed that a minor clone of del(17p) at relapse but not at diagnosis was associated with poor prognosis in MM (hazard ratio for median overall survival 1.64 vs. 1.44). Fifty-six and 12 patients developed one or more new cytogenetic abnormalities at relapse, mainly del(17p) and gain/amp(1q), respectively. We classified the patients into six groups based on the change patterns in the clonal size of del(17p) between the two time points. Patients who did not have del(17p) during follow-up showed the best outcomes, whereas those who acquired del(17p) during their disease course, experienced compromised survival (median overall survival: 61.3 vs. 49.4 months; hazard ratio =1.64; 95% confidence interval: 1.06-2.56; P<0.05). In conclusion, our data confirmed the adverse impact of a minor clone of del(17p) at relapse and highlighted the importance of designing optimal therapeutic strategies to eliminate high-risk cytogenetic abnormalities (clinicaltrials gov. identifier: NCT04645199).

Immunophenotypic profile defines cytogenetic stability and unveils distinct prognoses in patients with newly-diagnosed multiple myeloma (NDMM).

Prognostic significance of multiple immune antigens in multiple myeloma has been well established. However, a level of uncertainty remains regarding the intrinsic relationship between immunophenotypes and cytogenetic stability and precise risk stratification. To address these unresolved issues, we conducted a study involving 1389 patients enrolled in the National Longitudinal Cohort of Hematological Diseases in China (NCT04645199). Our results revealed that the correlation between antigen expression and cytogenetics is more prominent than cytopenia or organ dysfunction. Most immune antigens, apart from CD38, CD138, and CD81, exhibit significant associations with the incidence of at least one cytogenetic abnormality. In turn, we identified CD138-low/CD27-neg as specific adverse immunophenotypic profile, which remaining independent impact on progression-free survival (HR, 1.49; P = 0.007) and overall survival (HR, 1.77; P < 0.001) even in the context of cytogenetics. Importantly, CD138-low/CD27-neg profile was also associated with inferior survival after first relapse (P < 0.001). Moreover, the antigen expression profiles were not strictly similar when comparing diagnosis and relapse; in particular, the CD138-low/CD27-neg pattern was notably increased after disease progression (19.1 to 29.1%; P = 0.005). Overall, our study demonstrates that diverse immune profiles are strongly associated with cytogenetic stability, and a specific immunophenotype (CD138-low/CD27-neg) could effectively predict prognoses across different disease stages.

Characterization of garlic oil/ß-cyclodextrin inclusion complexes and application.

Garlic oil is a liquid extracted from garlic that has various natural antibacterial and anti-inflammatory properties and is believed to be used to prevent and treat many diseases. However, the main functional components of garlic oil are unstable. Therefore, in this study, encapsulating garlic oil with cyclodextrin using the saturated co-precipitation method can effectively improve its chemical stability and water solubility and reduce its characteristic odor and taste. After preparation, the microcapsules of garlic oil cyclodextrin were characterized, which proved that the encapsulation was successful. Finally, the results showed that the encapsulated garlic oil still had antioxidant ability and slow-release properties. The final addition to plant-based meat gives them a delicious flavor and adds texture and mouthfeel. Provided a new reference for the flavor application of garlic cyclodextrin micro-capsules in plant-based meat patties.

Preparation of Citral Oleogel and Antimicrobial Properties.

The objective of this study was to analyze a natural and safe oleogel with antimicrobial properties that can replace animal fats while lengthening the product's shelf life. The oleogel was created using direct dispersion (MG-SO), and its material characterization exhibited the exceptional performance of the hybrid gelant. Additionally, citral was integrated into the oil gel to prepare the citral oleogel (MG-SO). The antimicrobial nature of the material was examined and the findings revealed that it inhibited the growth of various experimental model bacteria, including Escherichia coli, Staphylococcus aureus, Aspergillus niger, Botrytis cinerea, and Rhizopus stolonifer. In addition, the material had a comparable inhibitory impact on airborne microorganisms. Lastly, MG-SON was utilized in plant-based meat patties and demonstrated an ability to significantly reduce the growth rate of microorganisms.

Exploring the potential of ume-derived proanthocyanidins: novel applications for blueberry preservation.

Proanthocyanidins (PCs) extracted from ume have many well-known functional properties. The aim of this study was to explore a novel natural food preservative using ume plum pulp proanthocyanidins (UPPP). The crude product of PCs from ume plum was obtained by using ethanol as extraction solvent and ultrasonic-assisted extraction, and then the pure product of UPPP was obtained by purification with AB-8 resin. The bacteriostatic ability of UPPP and the freshness preservation effect on blueberry were analyzed. The results showed that UPPP had a high inhibitory effect on Staphylococcus aureus (MIC of 1.563 mg/mL) and Escherichia coli (MIC of 3.125 mg/mL). Findings revealed that, in comparison to 0.02% potassium sorbate, blueberries treated with a high concentration of UPPP in a dipping treatment displayed superior quality maintenance after 7 days of storage at 4°C. Importantly, analysis of the various metrics showed that treatment with UPPP was significantly better compared to blueberries treated with 0.02% potassium sorbate. For example, the decay rate, weight loss, and total number of colonies of blueberries treated with 0.02% potassium sorbate were 55.56, 3.48%, and 4.24 ± 0.07 log CFU/mL, whereas the values of the above indexes for blueberries treated with 25 mg/mL of UPPP were 22.22, 3.09%, and 3.10 ± 0.17 log CFU/mL, respectively. Conversely, blueberries that were not dipped in any preservative displayed signs of deterioration as early as the 3rd day of the storage period, highlighting the potential of UPPP as a valuable method for preserving fruits and vegetables. Therefore, UPPP holds great promise as an innovative natural food preservative, effectively enhancing food safety, quality, and extending shelf-life.

Targeting BCMA in Multiple Myeloma: Advances in Antibody-Drug Conjugate Therapy.

Multiple myeloma (MM) is an incurable cancer of the plasma cells. In the last twenty years, treatment strategies have evolved toward targeting MM cells-from the shotgun chemotherapy approach to the slightly more targeted approach of disrupting important MM molecular pathways to the immunotherapy approach that specifically targets MM cells based on protein expression. Antibody-drug conjugates (ADCs) are introduced as immunotherapeutic drugs which utilize an antibody to deliver cytotoxic agents to cancer cells distinctively. Recent investigations of ADCs for MM treatment focus on targeting B cell maturation antigen (BCMA), which regulates B cell proliferation, survival, maturation, and differentiation into plasma cells (PCs). Given its selective expression in malignant PCs, BCMA is one of the most promising targets in MM immunotherapy. Compared to other BCMA-targeting immunotherapies, ADCs have several benefits, such as lower price, shorter production period, fewer infusions, less dependence on the patient's immune system, and they are less likely to over-activate the immune system. In clinical trials, anti-BCMA ADCs have shown safety and remarkable response rates in patients with relapsed and refractory MM. Here, we review the properties and clinical applications of anti-BCMA ADC therapies and discuss the potential mechanisms of resistance and ways to overcome them.

Development of a food preservative from sea buckthorn together with chitosan: Application in and characterization of fresh-cut lettuce storage.

The purpose was to create a novel composite food preservative for fresh-cut lettuce using flavonoids and chitosan from sea buckthorn leaves (SBL). Sea buckthorn leaves were extracted with ethanol as the extraction solvent and ultrasonic-assisted extraction to obtain flavonoid from sea buckthorn leaf crude (FSL), and then the FSL was secondarily purified with AB-8 resin and polyamide resin to obtain flavonoid from sea buckthorn leaf purified (FSL-1). Different concentrations of FSL-1 and chitosan were made into a composite preservative (FCCP) by magnetic stirring and other methods, containing 1% chitosan preservative (CP) alone, 0.5-2 mg/ml of FSL-1 and 1% chitosan composite preservative (FCCP-1, FCCP-2, FCCP-3, and FCCP-4), and the FSL-1 concentrations were analyzed the effect of FSL-1 concentration on the physicochemical properties of the composite preservatives, including their film-forming ability, antioxidant capacity and ability to prevent bacterial growth, was analyzed. To further investigate the effect of the combined preservatives on fresh-cut lettuce, different FCCPs were applied to the surface was stored at 4°C for 7 days. Then the changes in weight loss, hardness, browning index, total chlorophyll content, SOD and MDA were analyzed. It was used to assess the physicochemical indicators of fresh-cut lettuce throughout storage. According to the results of Fourier transform infrared spectroscopy, FSL-1 and chitosan interacted to form hydrogen bonds, and the contact angle and viscosity of FCCP increased on both horizontal glass and polystyrene plates, indicating the good film-forming properties of the composite preservation solution. With the diameter of the antibacterial zone of Staphylococcus aureus, Escherichia coli, Salmonella typhimurium, and Listeria monocytogenes being (21.39 ± 0.22), (17.43 ± 0.24), (15.30 ± 0.12), and (14.43 ± 0.24) mm, respectively. It was proved that the antibacterial activity of FCCP became stronger with the increase of FSL-1 concentration and had the best antibacterial effect on S. aureus. The complex preservative showed the best scavenging effect on ferric reducing antioxidant capacity, DPPH radicals (96.64%) and 2,2'-Azinobis- (3-ethylbenzthiazoline-6-sulphonate) (ABTS) radicals (99.42%) when FSL-1 was added at 2 mg/ml. When fresh-cut lettuce was coated with FCCP for the same storage time, various indicators of lettuce such as weight loss, hardness, browning index, SOD activity and MDA content were better than the control group showing good potential in fresh-cut vegetables and fruits preservation. FCCP holds great promise for food safety quality and shelf-life extension as a new natural food preservative. The waste utilization of sea buckthorn leaves can greatly improve his utilization and economic benefits.

Evaluating the Safe-Haven Abilities of Bitcoin and Gold for Crude Oil Market: Evidence During the COVID-19 Pandemic.

The COVID-19 pandemic poses a serious threat to investors in the crude oil market. Furthermore, investors have an increasing need to find a safe haven in their investment portfolios when facing unprecedented risks in crude oil markets during the COVID-19 pandemic. According to a review of the literature, there are contradictory findings on which investment is the safer haven for the oil market. Therefore, this paper aims to evaluate whether bitcoin is a safer haven for the crude oil market than the commonly used gold during the COVID-19 pandemic. Three spillover measurements based on the time, and frequency domains, and a network framework are employed to quantify the return spillover effects among bitcoin, gold and three major crude oil futures markets. We divide the sample into two periods, pre-COVID-19 and post-COVID-19. The results show that bitcoin has a weak safe-haven effect on the crude oil market only over a short period, while gold maintains a good safe-haven ability for crude oil futures across various time horizons (frequencies), both before and after the outbreak of the COVID-19 pandemic. The findings of this study have important implications for policy-makers, crude oil producers and global investors. In particularly, investors cannot ignore the importance of bitcoin and gold in selecting more profitable portfolio policies when searching for safe-haven assets.

Preparation of Solid Lipid Nanoparticles of Cinnamaldehyde and Determination of Sustained Release Capacity.

Natural plant essential oils cannot be applied on a large scale due to their high volatility, easy deactivation, etc. This study provides a new method to prepare a long-lasting, slow-release essential oil product by taking advantage of solid lipid nanoparticles, which will provide a scientific guideline for the future essential oil industry. In this article, solid lipid cinnamaldehyde nanoparticles were prepared using an ultrahigh-pressure homogenization method. SLN-CA with a particle size of 74 ± 5 nm, PDI of 0.153 ± 0.032, and zeta potential of -44.36 ± 2.2 mV was screened using an additional amount of cinnamaldehyde, the ratio of oil phase components, and the homogenization pressure and number of times as factors. Differential thermal analysis and spectroscopy demonstrated that cinnamaldehyde was successfully encapsulated inside the nanoparticles. The change in particle size of nanoparticles under different conditions and times was used as an indicator of stability. The stability of the finished nanoparticles was evaluated. The retention and slow-release ability of cinnamaldehyde were investigated using the concentration of cinnamaldehyde in nanoparticles as an indicator. The results showed that after 15 days, SLN-CA retained 52.36% of the concentration from 15 days prior. The bacterial inhibition test shows that SLN-CA can inhibit bacteria.

Preparation and characterization of geraniol nanoemulsions and its antibacterial activity.

Geraniol nanoemulsions (G-NE) based on Tween 80 and medium chain triglyceride (MCT) as surfactant and co-surfactant, respectively, has been prepared by the spontaneous emulsification method. Its physical and chemical properties such as mean particle size, zeta potential, PDI, pH, viscosity, contact angle, appearance morphology, and stability (storage stability, thermal stability, centrifugal properties, acid-base stability, and freeze-thaw properties) of the droplet were analyzed. The results showed that the mean particle size of G-NE was 90.33 ± 5.23 nm, the PDI was 0.058 ± 0.0007, the zeta potential was -17.95 ± 5.85 mV and the encapsulation efficiency was >90%. The produced G-NE has been demonstrated to be fairly stable in long-term storage at 4°C, pH = 5 and high-speed centrifuges. Moreover, G-NE had a significant inhibition effect on Staphylococcus aureus, Escherichia coli, Salmonella typhimurium and Listeria monocytogenes (p < 0.05). The bacterial inhibition rates of G-NE at a concentration of 1 MIC were 48, 99, 71.73, and 99% after 12 h of action against these four foodborne pathogenic bacteria, respectively. Therefore, the results obtained indicated that nanoemulsification enhanced the stability and antibacterial activity of geraniol to some extent, which will promote the utilization of geraniol in food preservation.

Protective Effect of Flavonoids from Mulberry Leaf on AAPH-Induced Oxidative Damage in Sheep Erythrocytes.

To evaluate the antioxidant activity of flavonoids extracted from Chinese herb mulberry leaves (ML), flavonoids from mulberry leaves (FML) were extracted and purified by using ultrasonic-assisted enzymatic extraction and D101 macroporous resin. Using LC-MS/MS-Liquid Chromatography with tandem mass spectrometry analysis, hesperidin, rutoside, hyperoside, cyanidin-3-o-glucoside, myricitrin, cyanidin, and quercetin were identified, and NMR and UV were consistent with the verification of IR flavonoid characteristics. The antioxidant activity of FML has also been evaluated as well as the protective effect on 2,2 0-azobis (2-amidinopropane) dihydrochloride (AAPH)-induced oxidative stress. The results showed that FML exhibited powerful antioxidant activity. Moreover, FML showed dose-dependent protection against AAPH-induced sheep erythrocytes' oxidative hemolysis. In the enzymatic antioxidant system, pretreatment with high FML maintained the balance of SOD, CAT, and GSH-Px; in the non-enzymatic antioxidant system, the content of MDA can be effectively reduced after FML treatment. This study provides a research basis for the development of natural products from mulberry leaves.

Neuroprotection of Gastrodia elata polyphenols against H2O2-induced PC12 cell cytotoxicity by reducing oxidative stress.

It has been suggested that oxidative stress (OS) has a role in the development of aging and neurodegenerative disorders. Biological molecules are easily damaged by reactive oxygen species, which can ultimately result in necrotic or apoptotic cell death. Foods containing phytochemicals, such as phenolic compounds, may have potential preventive effects against several diseases, including alzheimer's disease (AD), according to epidemiological and in vitro research. Gastrodia elata is a well-known homology of medicine and food plant that has been used for centuries in China and other East Asian countries to treat central nervous system disorders. In this study, we focused on the potential of the extract, Gastrodia elata polyphenols (GPP), for the prevention and treatment of AD. H2O2 induced PC12 cell damage was used to simulate the oxidative stress of AD. The effects of GPP on the injury model were evaluated by cell survival rate, lactate dehydrogenase (LDH), lipid peroxidation (MDA), production of intracellular antioxidant enzymes, reactive oxygen species (ROS), mitochondrial membrane potential (MMP), cellular inflammation level and apoptosis level. The results showed that GPP pretreatment had a protective effect by increasing cell viability, reducing lactate dehydrogenase infiltration, decreasing MDA and increasing intracellular antioxidant enzymes, diminishing reactive oxygen species production and decreasing mitochondrial membrane potential, reducing cell inflammation and decreasing apoptosis. Accordingly, it is suggested that GPP possessed promising neuroprotective benefits which enabled the prevention or therapeutic implementation of AD along with serving as a reference towards the exploitation of functional foods or drugs derived from Gastrodia elata.

Litter-derived nitrogen reduces methane uptake in tropical rainforest soils.

Litter comprises a major nutrient source when decomposed via soil microbes and functions as subtract that limits gas exchange between soil and atmosphere, thereby restricting methane (CH4) uptake in soils. However, the impact and inherent mechanism of litter and its decomposition on CH4 uptake in soils remains unknown in forest. Therefore, to declare the mechanisms of litter input and decomposition effect on the soil CH4 flux in forest, this study performed a litter-removal experiment in a tropical rainforest, and investigated the effects of litter input and decomposition on the CH4 flux among forest ecosystems through a literature review. Cumulative annual CH4 flux was -3.30 kg CH4-C ha-1 y-1. The litter layer decreased annual accumulated CH4 uptake by 8% which greater in the rainy season than the dry season in the tropical rainforest. Litter decomposition and the input of carbon and nitrogen in litter biomass reduced CH4 uptake significantly and the difference in CH4 flux between treatment with litter and without litter was negatively associated with N derived from litter input. Based on the literature review about litter effect on soil CH4 around world forests, the effect of litter dynamics on CH4 uptake was regulated by litter-derived nitrogen input and the amount soil inorganic nitrogen content. Our results suggest that nitrogen input via litter decomposition, which increased with temperature, caused a decline in CH4 uptake by forest soils, which could weaken the contribution of the forest in mitigating global warming.

International stock market risk contagion during the COVID-19 pandemic.

This paper examines the risk contagion among international stock markets during the COVID-19 pandemic by using the realized volatility information from sixteen major stock markets in the world. The empirical evidence based on the connectedness methods of Diebold and Yilmaz (2012) and Baruník and Krehlík (2018) shows that the COVID-19 epidemic significantly increases the risk contagion effects in international stock markets. Besides, the risk spillovers from stock markets in European and American regions increase rapidly but those in Asian markets decrease obviously after the outbreak of COVID-19 pandemic. Finally, the risk contagion among international stock markets caused by the pandemic can last for about 6 to 8 months. These results provide important implications regarding to financial risk management and macroprudential design.