Susceptibility of TSPAN5 polymorphisms to Kawasaki disease and immunoglobulin therapy resistance in southern Chinese children.

Kawasaki disease (KD) is a condition characterized by acute multi-system vasculitis and high fever in infants and children. Intravenous immunoglobulin (IVIG) is the established therapeutic approach of KD,foralleviating inflammation and mitigate the risk of arterial wall dilation and the development of coronary artery aneurysms (CAA). But almost 20% of the patients developed resistance to IVIG and displayed persistent fever after standard primary treatment. TSPAN5, belonging to the Tetraspanin family, has been demonstrated to modulate innate immunity in a range of human diseases. It accomplishes this by engaging with integrins and actively participating in the process of infection recognition. However, its relevance to susceptibility and IVIG therapy response of KD was unexposed. In the present study, our Integrative analysis of KD transcriptomic data and GTEx data revealed that the eQTL rs12504972 might modify the downregulation of TSPAN5 in KD patients. Moreover, our findings suggest a potential association between TSPAN5/rs12504972 and an elevated susceptibility as well as IVIG resistance among patients with Kawasaki disease in southern China. The results provided a new insight that TSPAN5 triggered KD susceptibility and resistance of IVIG therapy on the genomic level.

Cell membrane-camouflaged DOX-loaded ß-glucan nanoparticles for highly efficient cancer immunochemotherapy.

Biomimetics plays an important role in cancer treatment since it can prolong the circulation of nanoparticles, enhance their delivery and retention in target tissues, and reduce the systemic toxicity of drugs and their carriers. In this study, we developed a biomimetic nanosystem consisting of chemotherapeutic and immunotherapeutic agents wrapped in cell membranes. Specifically, the anti-tumor drug doxorubicin (DOX) was loaded into a bacterial-derived immunomodulatory agent (low molecular weight curdlan, lCUR), and the lCUR-DOX was further wrapped in the red blood cell membrane for camouflage and prolonged circulation. The successful preparation of the lCUR-DOX@RBC nanosystem was supported by various optical and morphological characterizations. In vitro studies indicated that the nanosystem can escape uptake by macrophages, inhibit the invasion of tumor cells, and reprogram M2 macrophages with an immunosuppressive phenotype into M1 macrophages with an immunopromoting phenotype via the MAPK signaling pathway while promoting the phagocytosis of macrophages. In vivo studies showed that the nanosystem effectively inhibits tumor growth in the A-375 tumor-bearing mouse model. Taken together, the above results support further development of the lCUR-DOX@RBC platform for cancer immunochemotherapy in clinical applications.

EZH1/2 as targets for cancer therapy.

The enhancer of zeste homolog 2 (EZH2) and its highly related homolog EZH1 are considered to be epigenetic silencing factors, and they play key roles in the growth and differentiation of cells as the core components of polycomb repressive complex 2 (PRC2). EZH1 and EZH2 are known to have a role in human malignancies, and alterations in these two genes have been implicated in transformation of human malignancies. Inhibition of EZH1/2 has been shown to result in tumor regression in humans and has been studied and evaluated in the preclinical setting and in multiple clinical trials at various levels. Our work thus contributes to the understanding of the relationship between regulatory molecules associated with EZH1/2 proteins and tumor progression, and may provide new insights for mechanism-based EZH1/2-targeted therapy in tumors.

Association between Rab31/rs9965664 polymorphism and immunoglobulin therapy resistance in patients with Kawasaki disease.

Background: Kawasaki disease (KD) is an acute febrile systemic vasculitis affecting infants and young children. A high dose of intravenous immunoglobulin (IVIG) is the first-line strategy for patients with KD to reduce persistent inflammation and the risk of coronary artery aneurysm (CAA) formation. Unfortunately, 10-20% of the patients showed no response to the treatment and were defined as resistant to IVIG. Rab31 has been reported to regulate innate immunity in several human diseases. However, whether single nucleotide polymorphism (SNP) in Rab31 gene could predispose to IVIG therapy response in KD was uncovered. Methods: Rab31/rs9965664 polymorphism was genotyped in 1,024 Chinese patients with KD through TaqMan assay. The odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to assess the strength of association between Rab31/rs9965664 polymorphism and IVIG therapeutic effects. Results: Our results showed that Rab31/rs9965664 AA/GA genotype was significantly associated with an increased risk of IVIG resistance compared to GG genotype (GA vs. GG: p = 0.0249; AA vs. GG: p = 0.0016; AA/GA vs. GG: p = 0.0039; and AA vs. GG/GA: p = 0.0072). Moreover, the KD individuals carrying the rs9965664 A allele displayed lower Rab31 protein levels, and the expression level of Rab31 in the IVIG-resistant group was decreased significantly when compared to that observed in the response group. A mechanical study demonstrated that Rab31 modulated IVIG response through NLRP3 and p38 pathways. Conclusion: These results suggested that Rab31/rs9965664 polymorphism might be associated with an increased risk of IVIG resistance in southern Chinese patients with KD. The possible mechanism is that Rab31 regulates the NLRP3 pathway negatively to inhibit IVIG response.

LNC-ZNF33B-2:1 gene rs579501 polymorphism is associated with organ dysfunction and death risk in pediatric sepsis.

Background: Sepsis is a severe systemic reaction disease induced by bacteria and virus invading the bloodstream and subsequently causing multiple systemic organ dysfunctions. For example, the kidney may stop producing urine, or the lungs may stop taking in oxygen. Recent studies have shown that long non-coding RNAs (lncRNAs) are related to the dysfunction of organs in sepsis. This study aims to screen and validate the sepsis-associated lncRNAs and their functional single nucleotide polymorphisms (SNPs). Result: Unconditional multiple logistic regression based on the recessive model (adjusted odds ratio = 2.026, 95% CI = 1.156-3.551, p = 0.0136) showed that patients with the CC genotype of rs579501 had increased risk of sepsis. Stratification analysis by age and gender indicated that patients with the rs579501 CC genotype had higher risk of sepsis among children aged <12 months (adjusted odds ratio = 2.638, 95% CI = 1.167-5.960, p = 0.0197) and in male patients (adjusted odds ratio = 2.232, 95% CI = 1.127-4.421, p = 0.0213). We also found a significant relationship between rs579501 and severe sepsis risk (CC versus AA/AC: adjusted odds ratio = 2.466, 95% CI = 1.346-4.517, p = 0.0035). Stratification analysis for prognosis and number of organ dysfunctions demonstrated that the rs579501 CC genotype increased non-survivors' risk (adjusted odds ratio = 2.827, 95% CI = 1.159-6.898, p = 0.0224) and one to two organs with dysfunction risk (adjusted odds ratio = 2.253, 95% CI = 1.011-5.926, p = 0.0472). Conclusion: Our findings showed that the lnc-ZNF33B-2:1 rs579501 CC genotype increases the susceptibility to sepsis. From the medical perspective, the lnc-ZNF33B-2:1 rs579501 CC genotype could be serving as a biochemical marker for sepsis.

The Associated of the Risk of IVIG Resistance in Kawasaki Disease with ZNF112 Gene and ZNF180 Gene in a Southern Chinese Population.

Background: Kawasaki disease (KD) was one of the most common primary vasculitis. IVIG resistance was associated with an increased risk of coronary artery aneurysm. Accumulating evidences demonstrated that inflammatory gene polymorphisms might play important roles in IVIG resistance, and zinc finger proteins were closely related to immune inflammation regulation, but the effect of ZNF112/rs8113807 and ZNF180/rs2571051 on IVIG resistance in KD patients has not been reported. Methods: A total of 996 KD patients were recruited, and the assay of TaqMan-real-time polymerase chain reaction was used for ZNF112/rs8113807 and ZNF180/rs2571051 genotyping. Odds ratio (OR) and 95% confidence interval (CI) were calculated for estimating the relationship between the polymorphisms of the both SNPs (ZNF112/rs8113807 and ZNF180/rs2571051) and the risk of IVIG resistance. Results: Both of the ZNF112/rs8113807 CC/TC genotype and the ZNF180/rs2571051 TT/CT genotype increased the risk of IVIG resistance in KD (rs8113807: CC vs TT: adjusted OR = 1.83, 95% CI = 1.06-3.16, p = 0.0293; CC/TC vs TT adjusted: OR = 1.49, 95% CI = 1.10-2.02, p = 0.0094. rs2571051: TT vs CC adjusted: OR = 2.64, 95% CI = 1.62-4.29, p < 0.0001; TT/CT vs CC adjusted: OR = 2.14, 95% CI = 1.37-3.37, p = 0.0009; TT vs CC/CT adjusted: OR = 1.66, 95% CI = 1.22-2.27, p = 0.0014). Furthermore, the combinative analysis of risk genotypes in ZNF112/rs8113807 and ZNF180/rs2571051 showed that patients with two unfavorable genotypes were more likely to increase risk of IVIG resistance than those who carried with zero or one unfavorable genotypes (adjusted: OR = 1.68, 95% CI = 1.24-2.27, p = 0.0008). Conclusion: Our findings enriched the genetic background of IVIG resistance risk in the KD development and suggested that the ZNF112/rs8113807 C-carrier and the ZNF180/rs2571051 T-carrier were associated with increased risk of IVIG resistance in KD patients in Chinese southern population.

The rs7404339 AA Genotype in CDH5 Contributes to Increased Risks of Kawasaki Disease and Coronary Artery Lesions in a Southern Chinese Child Population.

Background: Kawasaki disease (KD) is an acute, self-limited febrile illness of unknown cause. And it predominantly affects children <5 years and the main complication is coronary artery lesion (CAL). Studies demonstrated that vascular endothelial cells (VECs) played a very important role in the CAL of KD. VE-cad encoded by CDH5 may exert a relevant role in endothelial cell biology through controlling the cohesion of the intercellular junctions. The pathogenesis of KD remains unclear and genetic factors may increase susceptibility of KD. However, the relationship between CDH5 polymorphisms and KD susceptibility has not been reported before. The present study is aimed at investigating whether the rs7404339 polymorphism in CDH5 is associated with KD susceptibility and CAL in a southern Chinese child population. Methods and Results: We recruited 1,335 patients with KD and 1,669 healthy children. Each participant had supplied 2 mL of fresh blood in the clinical biologic bank at our hospital for other studies. Multiplex PCR is used to assess the genotypes of rs7404339 polymorphism in CDH5. According to the results, we found significant correlated relationship between rs7404339 polymorphism in CDH5 and KD susceptibility [AA vs. GG: adjusted odds ratio (OR) = 1.43, 95% confidence interval (CI) = 1.00-2.05; p = 0.0493; recessive model: adjusted OR = 1.44, 95% CI = 1.01-2.06, P = 0.0431]. In further stratified analysis, we found that children younger than 60 months (adjusted OR = 1.46, 95% CI = 1.01-2.10; p = 0.0424) and male (adjusted OR = 1.70, 95% CI = 1.09-2.65; p = 0.0203) with the rs7404339 AA genotype in CDH5 had a higher risk of KD than carriers of the GA/GG genotype. Furthermore, stratification analysis revealed that patients with the rs7404339 AA genotype exhibited the significantly higher onset risk for CAL than carriers of the GA/GG genotype (adjusted age and gender odds ratio = 1.56, 95% CI = 1.01-2.41; P = 0.0433). Conclusion: Our results showed that rs7404339 AA genotype in CDH5 is significant associated with KD susceptibility. And children younger than 60 months and male with the rs7404339 AA genotype had a higher risk of KD than carriers with the GA/GG genotype. Furthermore, patients with the rs7404339 AA genotype exhibited a significantly higher risk of CAL complication than carriers of the GA/GG genotype.

Resilience to crises of Thai MICE stakeholders: A longitudinal study of the destination image of Thailand as a MICE destination.

The COVID-19 outbreak has changed rapidly the business operation and travel behavior of global communities and calls for research on resilience. This study aims to identify the changing destination image of Thailand as a MICE destination during crises and examine the resilience of Thai MICE stakeholders. A mixed method of qualitative and quantitative design was employed using interviews, observations and questionnaire surveys. A longitudinal study of Thai MICE stakeholders during 14 years revealed that the Buddhist concepts of resilience and Thainess contribute to psychological resilience. Buddhism and Thainess cultivate the concept of crisis concierge. Surveys showed unchanged image of exhibition facilities during the political instability. Thailand's incentive travel benefits from the availability of bleisure (a combination of business and leisure) attractions. Good value for money, Thai hospitality, bleisure attractions, and international standard venues are key resilient factors.