Tumor necrosis factor receptor-associated factor 5 protects against intimal hyperplasia by regulation of macrophage polarization via directly targeting PPARγ.

OBJECTIVES: Intimal hyperplasia is a serious clinical problem associated with the failure of therapeutic methods in multiple atherosclerosis-related coronary heart diseases, which are initiated and aggravated by the polarization of infiltrating macrophages. The present study aimed to determine the effect and underlying mechanism by which tumor necrosis factor receptor-associated factor 5 (TRAF5) regulates macrophage polarization during intimal hyperplasia. METHODS: TRAF5 expression was detected in mouse carotid arteries subjected to wire injury. Bone marrow-derived macrophages, mouse peritoneal macrophages and human myeloid leukemia mononuclear cells were also used to test the expression of TRAF5 in vitro. Bone marrow-derived macrophages upon to LPS or IL-4 stimulation were performed to examine the effect of TRAF5 on macrophage polarization. TRAF5-knockout mice were used to evaluate the effect of TRAF5 on intimal hyperplasia. RESULTS: TRAF5 expression gradually decreased during neointima formation in carotid arteries in a time-dependent manner. In addition, the results showed that TRAF5 expression was reduced in classically polarized macrophages (M1) subjected to LPS stimulation but was increased in alternatively polarized macrophages (M2) in response to IL-4 administration, and these changes were demonstrated in three different types of macrophages. An in vitro loss-of-function study with TRAF5 knockdown plasmids or TRAF5-knockout mice revealed high expression of markers associated with M1 macrophages and reduced expression of genes related to M2 macrophages. Subsequently, we incubated vascular smooth muscle cells with conditioned medium of polarized macrophages in which TRAF5 expression had been downregulated or ablated, which promoted the proliferation, migration and dedifferentiation of VSMCs. Mechanistically, TRAF5 knockdown inhibited the activation of anti-inflammatory M2 macrophages by directly inhibiting PPARγ expression. More importantly, TRAF5-deficient mice showed significantly aggressive intimal hyperplasia. CONCLUSIONS: Collectively, this evidence reveals an important role of TRAF5 in the development of intimal hyperplasia through the regulation of macrophage polarization, which provides a promising target for arterial restenosis-related disease management.

Leucine zipper protein 1 attenuates pressure overload-induced cardiac hypertrophy through inhibiting Stat3 signaling.

INTRODUCTION: Cardiac hypertrophy is an important contributor of heart failure, and the mechanisms remain unclear. Leucine zipper protein 1 (LUZP1) is essential for the development and function of cardiovascular system; however, its role in cardiac hypertrophy is elusive. OBJECTIVES: This study aims to investigate the molecular basis of LUZP1 in cardiac hypertrophy and to provide a rational therapeutic approach. METHODS: Cardiac-specific Luzp1 knockout (cKO) and transgenic mice were established, and transverse aortic constriction (TAC) was used to induce pressure overload-induced cardiac hypertrophy. The possible molecular basis of LUZP1 in regulating cardiac hypertrophy was determined by transcriptome analysis. Neonatal rat cardiomyocytes were cultured to elucidate the role and mechanism of LUZP1 in vitro. RESULTS: LUZP1 expression was progressively increased in hypertrophic hearts after TAC surgery. Gain- and loss-of-function methods revealed that cardiac-specific LUZP1 deficiency aggravated, while cardiac-specific LUZP1 overexpression attenuated pressure overload-elicited hypertrophic growth and cardiac dysfunction in vivo and in vitro. Mechanistically, the transcriptome data identified Stat3 pathway as a key downstream target of LUZP1 in regulating pathological cardiac hypertrophy. Cardiac-specific Stat3 deletion abolished the pro-hypertrophic role in LUZP1 cKO mice after TAC surgery. Further findings suggested that LUZP1 elevated the expression of Src homology region 2 domain-containing phosphatase 1 (SHP1) to inactivate Stat3 pathway, and SHP1 silence blocked the anti-hypertrophic effects of LUZP1 in vivo and in vitro. CONCLUSION: We demonstrate that LUZP1 attenuates pressure overload-induced cardiac hypertrophy through inhibiting Stat3 signaling, and targeting LUZP1 may develop novel approaches to treat pathological cardiac hypertrophy.

Sintilimab-Induced Myocarditis in a Patient with Gastric Cancer: A Case Report and Literature Review.

Immune checkpoint inhibitors (ICIs) have emerged as a powerful and efficacious therapeutic approach for many cancer patients. Sintilimab is a fully human IgG4 monoclonal antibody that binds with programmed cell death receptor-1 (PD-1) to block its interaction with ligands, thereby enhancing the antitumor effects of T cells. However, ICIs may induce immune-related adverse events (irAEs) in various systems and organs, with fulminant myocarditis being the most severe one. We report the case of a 45-year-old female with gastric cancer who developed chest pain two weeks after chemotherapy with sintilimab; she was diagnosed with immune-associated fulminant myocarditis and experienced an Adams-Stokes syndrome attack in the hospital. Eventually, she was discharged after being treated with methylprednisolone, immunoglobulin, and an IABP.

Safety and immunogenicity of the COVID-19 mRNA vaccine CS-2034: A randomized, double-blind, dose-exploration, placebo-controlled multicenter Phase I clinical trial in healthy Chinese adults.

BACKGROUND: The novel coronavirus pneumonia (COVID-19) is an infectious disease caused by the infection of a novel coronavirus known as Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), which has resulted in millions of deaths. We aimed to evaluate the safety and immunogenicity of the COVID-19 mRNA vaccine (CS-2034, CanSino, Shanghai, China) in adults without COVID-19 infection from China. METHOD: This is a multicenter Phase I clinical trial with a randomized, double-blinded, dose-exploration, placebo-controlled design. The trial recruited 40 seronegative participants aged 18-59 years who had neither received any COVID-19 vaccine nor been infected before. They were divided into a low-dose group (administered with either the CS-2034 vaccine containing 30 µg of mRNA or a placebo of 0.3 ml type 5 adenovirus vector) and a high-dose group (administered with either the CS-2034 vaccine containing 50 µg of mRNA or a placebo of 0.5 ml type 5 adenovirus vector). Participants were randomly assigned in a 3:1 ratio to receive either the mRNA vaccine or a placebo on days 0 and 21 according to a two-dose immunization schedule. The first six participants in each dosage group were assigned as sentinel subjects. Participants were sequentially enrolled in a dose-escalation manner from low to high dose and from sentinel to non-sentinel subjects. Blood samples were collected from all participants on the day before the first dose (Day 0), the day before the second dose (day 21), 14 days after the second dose (day 35), and 28 days after the second dose (day 49) to evaluate the immunogenicity of the CS-2034 vaccine. Participants were monitored for safety throughout the 28-day follow-up period, including solicited adverse events, unsolicited adverse events, adverse events of special interest (AESI), and medically attended adverse events (MAE). This report focuses solely on the safety and immunogenicity analysis of adult participants aged 18-59 years, while the long-term phase of the study is still ongoing. This study is registered at ClinicalTrials.gov, NCT05373485. FINDINGS: During the period from May 17, 2022, to August 8, 2022, a total of 155 participants aged 18-59 years were screened for this study. Among them, 115 participants failed the screening process, and 40 participants were randomly enrolled (15 in the low-dose group, 15 in the high-dose group, and 10 in the placebo group). Throughout the 28-day follow-up period, the overall incidence of adverse reactions (related to vaccine administration) in the low-dose group, high-dose group, and placebo group was 93.33% (14/15), 100.00% (15/15), and 80.00% (8/10), respectively. There was a statistically significant difference in the incidence of local adverse reactions (soreness, pruritus, swelling at the injection site) among the low-dose group, high-dose group, and placebo group (P = 0.002). All adverse reactions were mainly of severity grade 1 (mild) or 2 (moderate), and no adverse events of severity grade 4 or higher occurred. Based on the analysis of Spike protein Receptor Binding Domain (S-RBD) IgG antibodies against the BA.1 strain, the seroconversion rates of antibodies at day 21 after the first dose were 86.67%, 93.33%, and 0.00% in the low-dose group, high-dose group, and placebo group, respectively. The geometric mean titer (GMT) of antibodies was 61.2(95%CI 35.3-106.2), 55.4(95%CI 36.3-84.4), and 15.0(95%CI 15.0-15.0), and the geometric mean fold increase (GMI) was 4.08(95%CI 2.35-7.08), 3.69(95%CI 2.42-5.63), and 1.00(95%CI 1.00-1.00) for each group. At day 28 after the full vaccination, the seroconversion rates of antibodies were 100.00%, 93.33%, and 0.00%, and the GMT of antibodies was 810.0(95%CI 511.4-1283.0), 832.2(95%CI 368.1-1881.6), and 15.0(95%CI 15.0-15.0), and the GMI was 54.00(95%CI 34.09-85.53), 55.48(95%CI 24.54-125.44), and 1.00(95%CI 1.00-1.00) for each group, respectively. Based on the analysis of CD3+/CD4+ cell cytokine response, the percentages of IL-2+, IL-4+, IFN-γ+, and TNF-α+ cells increased after 14 days and 28 days of full vaccination in both the low-dose group and high-dose group. The increase was most pronounced in the high-dose group. INTERPRETATION: At day 28 after the full vaccination, both the low-dose and the high-dose CS-2034 vaccine were able to induce the production of high titers of S-RBD IgG antibodies against the BA.1 strain. Adverse reactions in the low-dose and high-dose groups were mainly of severity grade 1 or 2, and no trial-limiting safety concerns were identified. These findings support further development of this vaccine.

Lipoprotein(a) and Benefit of PCSK9 Inhibition in Emergency Complex Higher-risk and Indicated Patients.

OBJECTIVE: There is a large population of patients classified as complex higher-risk and indicated patients (CHIPs) in China with a poor prognosis. The treatment of these patients is complex and challenging, especially when acute cardiac events occur, such as acute coronary syndrome (ACS) or heart failure. Pharmacotherapy and some mechanical circulatory support (MCS) therapeutic devices can provide stable hemodynamic support for CHIPs-percutaneous coronary intervention (PCI). LDL-C is an important pathogenic factor in atherosclerosis, and the target of blood lipid control. Recent studies have revealed that lipoprotein(a) [Lp(a)], which is formed when a covalent bond between apolipoprotein(a) and apolipoprotein B-100 is made, produces an LDL-like particle. This particle is an independent risk factor for the development of atherosclerosis, and is closely correlated to stent thrombosis and restenosis. Furthermore, this requires active intervention. PCSK9 inhibitors have been used in lipid-lowering treatment, and preventing atherosclerosis. The present study explores the efficacy of PCSK9 inhibitors in CHIPs-ACS, and the association between the change in Lp(a) and survival after 2 years of follow-up. METHODS: The present real-world, prospective control study enrolled 321 CHIPs-ACS who underwent emergency PCI from August 2019 to November 2020, and these patients were followed up for 2 years. These patients were divided into two groups: PCSK9 group (n=161) given the combined PCSK9 inhibitor (140 mg of evolocumab every 2 weeks) and statins-based therapy, and SOC group (n=160) treated with statin-based lipid-lowering therapy alone. Then, the change in lipid index was measured, and the cardiovascular (CV) event recurrence rate was evaluated after one month and 2 years. Afterwards, the contribution of serum lipid parameters, especially the Lp(a) alteration, in patients with earlier initiation of the PCSK9 inhibitor to the CV outcome was analyzed. RESULTS: The LDL-C level was significantly reduced in both groups: 52.3% in the PCSK9 group and 32.3% (P<0.001) in the SOC group. It is noteworthy that the Lp(a) level decreased by 13.2% in the PCSK9 group, but increased by 30.3% in the SOC group (P<0.001). Furthermore, the number of CV events was not significantly different between the PCSK9 and SOC groups after the 2-year follow-up period. In the PCSK9 group, the Lp(a) reduction was associated with the baseline Lp(a) levels of the patients (r2 =-0.315, P<0.001). Moreover, the decrease in Lp(a) contributed to the decline in CV events in patients who received ACS CHIPs-PCI, and the decrease in Lp(a) level was independent of the LDL-C level reduction. CONCLUSION: The early initiation of PCSK9 inhibitors can significantly reduce the LDL-C and Lp(a) levels in ACS CHIPs-PCI. However, further studies are needed to confirm whether PCSK9 inhibitors can reduce the incidence of CV disease in CHIPs.

Leucine zipper protein 1 prevents doxorubicin-induced cardiotoxicity in mice.

OBJECTIVE: Doxorubicin (DOX) is commonly used for chemotherapy; however, its clinical value is extremely dampened because of the fatal cardiotoxicity. Leucine zipper protein 1 (LUZP1) plays critical roles in cardiovascular development, and this study is designed for determining its function and mechanism in DOX-induced cardiotoxicity. METHODS: Cardiac-specific Luzp1 knockout (cKO) and transgenic (cTG) mice received a single or repeated DOX injections to establish acute and chronic cardiotoxicity. Biomarkers of inflammation, oxidative damage and cell apoptosis were evaluated. Transcriptome and co-immunoprecipitation analysis were used to screen the underlying molecular pathways. Meanwhile, primary cardiomyocytes were applied to confirm the beneficial effects of LUZP1 in depth. RESULTS: LUZP1 was upregulated in DOX-injured hearts and cardiomyocytes. Cardiac-specific LUZP1 deficiency aggravated, while cardiac-specific LUZP1 overexpression attenuated DOX-associated inflammation, oxidative damage, cell apoptosis and acute cardiac injury. Mechanistic studies revealed that LUZP1 ameliorated DOX-induced cardiotoxicity through activating 5'-AMP-activated protein kinase (AMPK) pathway, and AMPK deficiency abolished the cardioprotection of LUZP1. Further findings suggested that LUZP1 interacted with protein phosphatase 1 to activate AMPK pathway. Moreover, we determined that cardiac-specific LUZP1 overexpression could also attenuate DOX-associated chronic cardiac injury in mice. CONCLUSION: LUZP1 attenuates DOX-induced inflammation, oxidative damage, cell apoptosis and ventricular impairment through regulating AMPK pathway, and gene therapy targeting LUZP1 may provide novel therapeutic approached to treat DOX-induced cardiotoxicity.

The diagnostic importance of multiple cytokines in adult hemophagocytic lymphohistiocytosis.

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a category of immunological illnesses that cause out-of-control T cells and macrophages to release life-threatening cytokines. The HLH-2004 diagnostic criteria are the gold standard for HLH diagnosis, but there is a need to investigate the usefulness of various cytokines for HLH diagnosis. METHODS: Patients admitted to Beijing Friendship Hospital of Capital Medical University from January 2016 to December 2020 were included in this retrospective study, with 166 patients with confirmed HLH and 142 febrile patients requiring differential diagnosis completing the sum. Multiplex cytokine assays using multifactor liquid phase microarray technology-based multifactor liquid phase microarray technology were used to detect 33 cytokines. Twenty-eight cytokines detected using the Luminex analytical platform technology were ultimately included in the analysis. RESULTS: Interleukin-1 receptor antagonist (IL-1 RA), IL-18, interferon-γ (IFN-γ), and interferon-induced protein 10 (IP-10) regulated upon activation normal T cell expressed and secreted (RANTES), eotaxin, growth-related oncogene α (GRO-α), and macrophage inflammatory protein-1 α (MIP-1α) were higher in the HLH group than in the non-HLH group, and the differences were statistically significant. Among them, the area under the curve (AUC) for IL-18 for HLH diagnosis was reported for the first time as 82.69%, with a sensitivity of 76.32% and a specificity of 79.61%; the AUC of IL-1 RA was 72.34%, with a sensitivity of 62.71% and a specificity of 75.97%; and the AUC of IP-10 was 71.73%, with a sensitivity of 60.14% and a specificity of 75.15%. Moreover, the AUC of the combined diagnostic tests for IL-1 RA, IL-18, IFN-γ, IP-10, and RANTES was 99.6%, with a sensitivity of 95.8% and a specificity of 98.6%. CONCLUSION: Our study concluded that multiple cytokines are valid biological markers for the diagnosis of HLH. The findings of this study remain to be validated in an external dataset.

High-Coverage Reconstruction of XCO2 Using Multisource Satellite Remote Sensing Data in Beijing-Tianjin-Hebei Region.

The extreme climate caused by global warming has had a great impact on the earth's ecology. As the main greenhouse gas, atmospheric CO2 concentration change and its spatial distribution are among the main uncertain factors in climate change assessment. Remote sensing satellites can obtain changes in CO2 concentration in the global atmosphere. However, some problems (e.g., low time resolution and incomplete coverage) caused by the satellite observation mode and clouds/aerosols still exist. By analyzing sources of atmospheric CO2 and various factors affecting the spatial distribution of CO2, this study used multisource satellite-based data and a random forest model to reconstruct the daily CO2 column concentration (XCO2) with full spatial coverage in the Beijing-Tianjin-Hebei region. Based on a matched data set from 1 January 2015, to 31 December 2019, the performance of the model is demonstrated by the determination coefficient (R2) = 0.96, root mean square error (RMSE) = 1.09 ppm, and mean absolute error (MAE) = 0.56 ppm. Meanwhile, the tenfold cross-validation (10-CV) results based on samples show R2 = 0.91, RMSE = 1.68 ppm, and MAE = 0.88 ppm, and the 10-CV results based on spatial location show R2 = 0.91, RMSE = 1.68 ppm, and MAE = 0.88 ppm. Finally, the spatially seamless mapping of daily XCO2 concentrations from 2015 to 2019 in the Beijing-Tianjin-Hebei region was conducted using the established model. The study of the spatial distribution of XCO2 concentration in the Beijing-Tianjin-Hebei region shows its spatial differentiation and seasonal variation characteristics. Moreover, daily XCO2 map has the potential to monitor regional carbon emissions and evaluate emission reduction.

Host Plant Selection Imprints Structure and Assembly of Fungal Community along the Soil-Root Continuum.

The soil fungal community plays pivotal roles in soil nutrient cycling and plant health and productivity in agricultural ecosystems. However, the differential adaptability of soil fungi to different microenvironments (niches) is a bottleneck limiting their application in agriculture. Hence, the understanding of ecological processes that drive fungal microbiome assembly along the soil-root continuum is fundamental to harnessing the plant-associated microbiome for sustainable agriculture. Here, we investigated the factors that shape fungal community structure and assembly in three compartment niches (the bulk soil, rhizosphere, and rhizoplane) associated with tobacco (Nicotiana tabacum L.), with four soil types tested under controlled greenhouse conditions. Our results demonstrate that fungal community assembly along the soil-root continuum is governed by host plant rather than soil type and that soil chemical properties exert a negligible effect on the fungal community assembly in the rhizoplane. Fungal diversity and network complexity decreased in the order bulk soil > rhizosphere > rhizoplane, with a dramatic decrease in Ascomycota species number and abundance along the soil-root continuum. However, facilitations (positive interactions) were enhanced among fungal taxa in the rhizoplane niche. The rhizoplane supported species specialization with enrichment of some rare species, contributing to assimilative community assembly in the rhizoplane in all soil types. Mortierella and Pyrenochaetopsis were identified as important indicator genera of the soil-root microbiome continuum and good predictors of plant agronomic traits. The findings provide empirical evidence for host plant selection and enrichment/depletion processes of fungal microbiome assembly along the soil-root continuum. IMPORTANCE Fungal community assembly along the soil-root continuum is shaped largely by the host plant rather than the soil type. This finding facilitates the implementations of fungi-associated biocontrol and growth-promoting for specific plants in agriculture practice, regardless of the impacts from variations in geographical environments. Furthermore, the depletion of complex ecological associations in the fungal community along the soil-root continuum and the enhancement of facilitations among rhizoplane-associated fungal taxa provide empirical evidence for the potential of community simplification as an approach to target the plant rhizoplane for specific applications. The identified indicators Mortierella and Pyrenochaetopsis along the soil-root microbiome continuum are good predictors of tobacco plant agronomic traits, which should be given attention when manipulating the root-associated microbiome.

EBV protection- and susceptibility-related HLA alleles and EBV status in the Chinese population: A single-center study.

BACKGROUND: Although most adults are infected by Epstein-Barr virus (EBV), some patients develop highly lethal diseases associated with EBV infection, including EBV-hemophagocytic lymphohistiocytosis (EBV-HLH), chronic active EBV infections (CAEBV), and lymphoma, the pathogeneses of which remain to be investigated. The human leukocyte antigen (HLA) complex may be associated with the viral infection pathway, and, therefore, HLA alleles may be associated with EBV-related diseases and subpopulations of infected cells, studies related to EBV-associated diseases, and subpopulations of infected cells that were conducted in China are scarce. METHODS: In this study, we analyzed the high-resolution HLA genotypes of 269 patients with EBV-associated diseases and 213 EBV-seronegative hematopoietic stem cell donors using PCR-SBT assay and elucidated the associations of HLA-A, -B, -C, -DRB1, and -DQB1 alleles with EBV-associated diseases in the Chinese population, Benjamini-Hochberg correction to adjust for multiple testing. HLA genotypes were also analyzed in patients with EBV-associated diseases showing EBV-infected lymphocyte subpopulations. RESULTS: We found that individuals carrying the following alleles showed the following levels of risks: HLA-DRB1*11 allele, reduced risk of EBV-related disease (OR [odds ratio]: 0.56; 95% confidence interval [95% CI]: 0.32-0.99; p < .05; Adjust p = .71); HLA-DQB1*06:02 allele, reduced risk (OR: 0.5699; 95% CI: 0.3486-0.9317; p < .05; Adjust p = .57); and HLA-B*15:01 allele, increased risk (OR: 1.763; 95% CI: 0.3486-0.9317; p < .05; Adjust p = .57). Patients with EBV-associated diseases showing the B*15:01 genotype had a higher risk of T-cell, NK-cell, and multicell infections than those with other genotype subgroups. CONCLUSIONS: These findings highlight the importance of HLA genotype for assessing EBV infectivity.

Sitagliptin ameliorates hypoxia-induced damages in endometrial stromal cells: an implication in endometriosis.

Hypoxia-induced damage in endometrial stromal cells (ESCs) is an important event in the pathological progression of Endometriosis. It is reported that significant inflammation is induced by hypoxia in ESCs, mediated by serval inflammatory progressions, pathways, or factors. Sitagliptin, an important member of the dipeptidyl peptidase-4 (DPP-4) inhibitors family and has been widely used for the management of type 2 diabetes. It has been recently reported to exert significant anti-inflammatory effects. Here, we aim to assess whether Sitagliptin possesses a protective effect against hypoxia-induced damages in ESCs. Our findings indicate that exposure to hypoxia significantly increased oxidative stress in ESCs by increasing the production of reactive oxygen species (ROS) and decreasing the levels of reduced glutathione (GSH), which was ameliorated by Sitagliptin. Additionally, the excessively produced inflammatory mediators, including tumor necrosis factor (TNF)-α, interleukin (IL)-6, monocyte chemoattractant protein-1 (MCP-1), cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), and high mobility group box (HMGB)-1, in hypoxia-treated HESCs were pronouncedly repressed by Sitagliptin. The activated p38 mitogen-activated protein kinases (MAPK) pathway was observed in hypoxia-stimulated HESCs, then greatly inhibited by the introduction of Sitagliptin. Lastly, hypoxia-induced phosphorylation and degradation of IκBα, as well as the upregulation of nuclear factor kappa-B (NF-κB) p65 and increased transcriptional activity of NF-κB, were dramatically abolished by Sitagliptin. Collectively, Sitagliptin ameliorated hypoxia-induced damages in ESCs by suppressing the inflammation.

Clinical Features and Prognostic Risk Prediction of Non-Hodgkin Lymphoma-Associated Hemophagocytic Syndrome.

BACKGROUND: Malignancies, especially lymphoma, are a common cause of adult secondary HLH and an independent risk factor for the prognosis of HLH patients. METHODS: Patients with lymphoma alone or concurrent lymphoma-associated phagocytic syndrome (LAHS) admitted to Beijing Friendship Hospital from January 2016 to December 2020 were enrolled in this study. FINDINGS: There were 348 lymphoma patients, 104 concurrent with LAHS. The pathological type of lymphoma without LAHS was dominated by B-cell lymphoma, while those with LAHS were T/NK-cell lymphoma predominantly (p < 0.001). Superficial lymph node enlargement was more significant in patients with B-LAHS (p = 0.006), while patients with T/NK-LAHS had lower neutrophil counts (p = 0.005), lower fibrinogen levels (p < 0.001), higher transaminase levels, and more co-infection with EBV (p < 0.001). B-LAHS had significantly higher IL-10 levels than with T/NK-LAHS (p = 0.006), and NK/T-LAHS had significantly higher IP-10 levels than other T-LAHS (p = 0.008). Age, platelet count, IPI, history of NK/T lymphoma, and no remission of HLH were independent risk factors for prognosis in patients with non-Hodgkin lymphoma-associated phagocytic syndrome (NHL-LAHS), and a prognostic risk score model for NHL-LAHS was developed. CONCLUSION: LAHS is a life-threatening disease with a poor prognosis. The prognostic risk score model for NHL-LAHS with a good fit and validation for the test has value for clinical application.

[Exhaustion of CD8+T Lymphocytes Plays a Critical Role in the Pathogenesis of Secondary Hemophagocytic Lymphohistiocytosis].

OBJECTIVE: To investigate the changes in function of CD8+ T cell subsets, and explore its significance in pathogenesis of secondary hemophagocytic lymphohistiocytosis (sHLH). METHODS: Flow cytometry was used to detect the expressions of PD-1, TIM-3, and LAG-3, which were the markers of exhausted CD8+ T cell, as well as the secretion levels of interferon γ (IFN-γ) and expression of ΔCD107a after the stimulation; the numbers of effector-memory CD8+ T cells, regulatory T cells and double negative T cells were also detected. RESULTS: The expressions of inhibitory receptors (PD-1, TIM3 and LAG-3) on CD8+ T cells of sHLH patients were 40.73±22.64, 15.97±14.45 and 0.73 (0-37.41), respectively, which were significantly higher than those of the control group (P<0.001). In contrast, the expression of ΔCD107a (4.49±2.71 vs 6.07±2.14, P=0.035) and secretion level of IFN-γ (37.30±24.46 vs 55.17±22.23, P=0.034) were significantly lower. The number of effector-memory CD8+ T cells in sHLH patients was also lower as compared with that in control group (14.35±10.37 vs 22.92±11.12, P=0.016). But there was no significant difference in the number of regulatory T cell and double negative T cell. In addition, the expressions of PD-1, TIM3 and LAG-3 in active stage of sHLH were 38.09±21.87, 14.35±13.70 and 0.82 (0-13.22), respectively, which were significant higher than those in remission stage [24.27±17.23 (P=0.03), 8.64±5.60 (P=0.014) and 0.13 (0-3.69)]. CONCLUSION: The exhausted CD8+ T lymphocytes may play a critical role in the development of sHLH.

Hodgkin lymphoma-associated hemophagocytic lymphohistiocytosis-a dangerous disease.

This study investigated the clinical characteristics of Hodgkin lymphoma-associated hemophagocytic lymphohistiocytosis (HLH-HL). Clinical data of 8 patients with HLH-HL and 20 non-HLH-HL patients were included. All eight HLH-HL patients tested positive for plasma Epstein-Barr virus (EBV)-DNA and EBV-encoded small RNA (EBER), and six patients were positive for EBV-DNA in the peripheral blood mononuclear cells (PBMCs). Two out of the 20 non-HLH-HL patients were confirmed positive for EBER, and the remaining 18 patients were negative. Among the HLH-HL patients, five patients received ABVD (doxorubicin/bleomycin/vinblastine/dacarbazine) chemotherapy regimens in other hospitals, and their conditions were considered to be worse, for which reason they were transferred to our center, and three patients were treated with DEP (doxorubicin-etoposide-methylprednisolone) regimens to target HLH and were alive as of the writing of this article. Two patients were critically ill upon admission and were not able to undergo chemotherapy. Significant differences in survival time were observed between the HLH-HL and non-HLH-HL patients (P = 0.005). HL patients found positive for EBV (plasma/PBMCs EBV-DNA(+)/EBER(+)) may be more likely to develop HLH-HL. It may be beneficial to target HLH during the acute phase of HLH, followed by treating HL once the HLH condition has stabilized. HLH-HL patients have worse prognosis and higher mortality than non-HLH-HL patients.

Long noncoding RNAs C2dat1 enhances vascular smooth muscle cell proliferation and migration by targeting MiR-34a-5p.

Deregulated proliferation of vascular smooth muscle cells (VSMCs) is one common phenomenon of atherosclerosis progression. Long noncoding RNAs (lncRNAs) are one group of noncoding RNAs that play essential roles in many cell biological processes, including cell development, growth, and migration. However, the role of a novel calcium/calmodulin-dependent protein kinase type II subunit delta (CAMK2D)-associated lncRNA, CAMK2D-associated transcript 1 (C2dat1), in VSMCs is still uncovered. In this study, we showed that the expression level of C2dat1 was higher in coronary artery disease (CAD) tissues than in normal arterial tissues and the C2dat1 expression level was upregulated in the proliferating VSMC after being treated with PDGF-bb or TNF-α. In addition, we indicated that overexpression of C2dat1 promoted VSMC growth and enhanced proliferating cell nuclear antigen (PCNA) expression in VSMC. Moreover, ectopic expression of C2dat1 increased VSMC migration. Furthermore, we showed that elevated expression of C2dat1 suppressed microRNA-34a (miR-34a) expression and promoted sirtuin 1 (SIRT1) expression, which was a direct target gene of miR-34a. We demonstrated that the expression level of miR-34a was lower in CAD tissues than in normal arterial tissues and the expression of miR-34a was negatively correlated with C2dat1 expression. Restored expression of C2dat1 increased VSMC proliferation and migration through promoting SIRT1 expression. These data suggested that lncRNA C2dat1 might be a potential therapeutic target to promote VSMC growth and migration in CAD.