Systemic HIV and SIV latency reversal via non-canonical NF-κB signalling in vivo.

Long-lasting, latently infected resting CD4+ T cells are the greatest obstacle to obtaining a cure for HIV infection, as these cells can persist despite decades of treatment with antiretroviral therapy (ART). Estimates indicate that more than 70 years of continuous, fully suppressive ART are needed to eliminate the HIV reservoir1. Alternatively, induction of HIV from its latent state could accelerate the decrease in the reservoir, thus reducing the time to eradication. Previous attempts to reactivate latent HIV in preclinical animal models and in clinical trials have measured HIV induction in the peripheral blood with minimal focus on tissue reservoirs and have had limited effect2-9. Here we show that activation of the non-canonical NF-κB signalling pathway by AZD5582 results in the induction of HIV and SIV RNA expression in the blood and tissues of ART-suppressed bone-marrow-liver-thymus (BLT) humanized mice and rhesus macaques infected with HIV and SIV, respectively. Analysis of resting CD4+ T cells from tissues after AZD5582 treatment revealed increased SIV RNA expression in the lymph nodes of macaques and robust induction of HIV in almost all tissues analysed in humanized mice, including the lymph nodes, thymus, bone marrow, liver and lung. This promising approach to latency reversal-in combination with appropriate tools for systemic clearance of persistent HIV infection-greatly increases opportunities for HIV eradication.

An NLR family member X1 mutation (p.Arg707Cys) suppresses hepatitis B virus infection in hepatocytes and favors the interaction of retinoic acid-inducible gene 1 with mitochondrial antiviral signaling protein.

NLR family member X1 (NLRX1) is an important member of the NOD-like receptor (NLR) family and plays unique roles in immune system regulation. Patients with hepatitis B virus (HBV) infection are more likely to have the NLRX1 mutation p.Arg707Cys than healthy individuals. It has been reported that NLRX1 increases the infection rate of HBV in HepG2 cells expressing sodium taurocholate cotransporting polypeptide (NTCP). However, the role of NLRX1 mutation (p.Arg707Cys) in hepatitis remains unclear. We constructed Huh7 cells that stably overexpressed NTCP, using LV003 lentivirus. First, wild-type (WT) and mutant (MT) NLRX1 overexpression plasmids were constructed. The MT plasmid contained a point mutation at position 707 of the WT overexpression plasmid. Then, Huh7-NTCP cells were transfected with the WT or MT NLRX1 overexpression plasmid, and subsequent NLRX1 expression was analyzed using real-time quantitative polymerase chain reaction (RT-qPCR) and western blot. HBV RNA levels were determined using RT-qPCR. HBsAg and HBcAg levels were confirmed immunohistochemically. Interferon alpha (IFN-α), interleukin 6 (IL-6), and type I interferon beta (IFN-ß) levels were determined using enzyme-linked immunosorbent assay kits. p-p65, p-interferon regulatory factor (IRF) 3, and p-IRF7 expression levels were examined using western blot. The interaction of NLRX1 and retinoic acid-inducible gene (RIG)-1/mitochondrial antiviral signaling (MAVS) protein was confirmed by coimmunoprecipitation. The interaction of NLRX1 with IFN-α, IL-6, or IFN-ß was analyzed by dual luciferase reporter gene assay. The levels of HBV RNA, HBsAg, and HBcAg in infected cells transfected with the WT NLRX1 or MT NLRX1 expression plasmid were higher than those in the untransfected control group; and these levels were lower in the cells transfected with MT NLRX1 than in those transfected with WT NLRX1. The levels of IFN-α, IFN-ß, IL-6, p-p65, p-IRF3, and p-IRF7 were lower in cells transfected with WT NLRX1 or MT NLRX1 than in control cells. The levels of IFN-ß, p-p65, p-IRF3, and p-IRF7 were higher in cells transfected with MT NLRX1 than in those transfected with WT NLRX1. Moreover, NLRX1 competitively inhibited RIG1 binding to MAVS, but the mutation in MT NLRX1 reduced this inhibitory effect. In addition, NLRX1 decreased the promoter activity of IFN-α, IFN-ß, and IL-6. Our findings revealed that NLRX1 is a regulatory factor that inhibits the anti-HBV ability of hepatocytes and that the mutation p.Arg707Cys in NLRX1 suppresses HBV infection and activates the IFN/nuclear factor κB pathway.

Construction and validation of prognostic scoring models to risk stratify patients with acquired immune deficiency syndrome-related diffuse large B cell lymphoma.

Acquired immune deficiency syndrome (AIDS)-related diffuse large B cell lymphoma (AR-DLBCL) is a rare disease with a high risk of mortality. There is no specific prognostic model for patients with AR-DLBCL. A total of 100 patients diagnosed with AR-DLBCL were enrolled in our study. Clinical features and prognostic factors for overall survival (OS) and progression-free survival (PFS) were evaluated by univariate and multivariate analyses. Central nervous system (CNS) involvement, opportunistic infection (OI) at lymphoma diagnosis, and elevated lactate dehydrogenase (LDH) were selected to construct the OS model; CNS involvement, OI at lymphoma diagnosis, elevated LDH, and over four chemotherapy cycles were selected to construct the PFS model. The area under the curve and C-index of GZMU OS and PFS models were 0.786/0.712; 0.829/0.733, respectively. The models we constructed showed better risk stratification than International Prognostic Index (IPI), age-adjusted IPI, and National Comprehensive Cancer Network-IPI. Furthermore, in combined cohort, the Hosmer-Lemeshow test showed that the models were good fits (OS: p = 0.8244; PFS: p = 0.9968) and the decision curve analysis demonstrated a significantly better net benefit. The prognostic efficacy of the proposed models was validated independently and outperformed the currently available prognostic tools. These novel prognostic models will help to tackle a clinically relevant unmet need.

Roseomonas acroporae sp. nov., isolated from coral Acropora digitifera.

A non-motile, rod-shaped, pink-pigmented bacterium NAR14T was isolated from coral Acropora digitifera from Daya Bay, Shenzhen, PR China. Cells were Gram-stain-negative, aerobic, catalase-positive and oxidase-negative. NAR14T grew with 0-6 % (w/v) NaCl (optimum, 2-4 %), at 10-41 °C (optimum, 28 °C) and at pH 4.0-9.5 (optimum, 5.0). The major respiratory quinone was Q-10. The predominant fatty acids (more than 10%) were summed feature 8 (65.6 %) and C16 : 0 (17.6%). The DNA G+C content of NAR14T was 73.6 %. The polar lipids of NAR14T comprised one diphosphatidylglycerol, one phosphatidylethanolamine, one phosphatidylglycerol, one phosphatidylcholine, one aminolipid and three unknown polar lipids. The results of phylogenetic analysis based on 16S rRNA gene sequences indicated that NAR14T formed a lineage within the genus Roseomonas of the family Acetobacteraceae, and it was distinct from the most closely related species Roseomonas wooponensis JCM 19527T and Roseomonas riguiloci JCM 17520T with the 16S rRNA gene sequence similarities of 94.61 and 93.98 %, respectively. Phenotypic characteristics (physiological, biochemical and chemotaxonomic) also supported the taxonomic novelty of this isolate. Thus, NAR14T is considered to represent a novel species within the genus Roseomonas, for which the name Roseomonas acroporae sp. nov. is proposed. The type strain is NAR14T (=KCTC 92174T = MCCC 1K07275T).

Neorhizobium turbinariae sp. nov., a coral-beneficial bacterium isolated from Turbinaria peltata.

Coral reef ecosystems are facing decline due to climate change, overfishing, habitat destruction and pollution. Bacteria play an essential role in maintaining the stability of coral reef ecosystems, influencing the well-being and fitness of coral hosts. The exploitation of coral probiotics has become an urgent issue. A short-rod shaped aerobic bacterium, designated NTR19T, was isolated in a healthy coral Turbinaria peltata from Daya Bay, Shenzhen, PR China. Its cells were Gram-negative, motile with a polar flagellum. The activities of catalase and oxidase were positive. Strain NTR19T grew at 10-41 °C (optimum, 28 °C), with NaCl concentrations of 0-4 % (w/v; optimum, 0.5 %) and at pH 5.0-9.5 (optimum, pH 7.0-7.5). The predominant fatty acids (>10 %) were summed feature 8 (57.6 %), C19 : 0 cyclo ω8c (12.6 %) and C16 : 0 (12.0 %). The polar lipids were diphosphatidylglycerol, phosphatidylglycerol, phospholipid and phosphatidylcholine. The major respiratory quinone was Q-10. The draft genome was 4.68 Mbp with 61.2 mol% DNA G+C content. In total, 4477 coding sequences were annotated and there were 64 RNA genes. The average nucleotide identity (ANI) and average amino acid identity (AAI) values between strain NTR19T and the related Neorhizobium species were 78.23-79.70% and 80.26-80.50 %, respectively. This strain encoded many proteins for the activities of catalase and oxidase in the genome. Strain NTR19T was clearly distinct from its closest neighbours Rhizobium oryzicola ACCC 05753T and Neorhizobium petrolearium ACCC 11238T with the 16S rRNA gene sequence similarity values of 96.86 and 96.36 %, respectively. The results of phylogenetic analysis, as well as ANI and AAI values, revealed that strain NTR19T belongs to Neorhizobium and was distinct from other species of this genus. The physiological, biochemical and chemotaxonomic characteristics also supported the species novelty of strain NTR19T. Thus, strain NTR19T is considered to be classified as a novel species in the genus Neorhizobium, for which the name Neorhizobium turbinariae sp. nov. is proposed. The type strain is NTR19T (=JCM 35342T=MCCC 1K07226T).

Algiphilus acroporae sp. nov. and Coraliihabitans acroporae gen. nov. sp. nov., isolated from scleractinian coral Acropora digitifera.

Two Gram-staining-negative, aerobic, rod-shaped bacteria NNCM1T and NNCM2T were isolated from the scleractinian coral Acropora digitifera. NNCM1T grew with 0.5-12 % (w/v) NaCl (optimum, 3-6 %), at 18-37 °C (optimum, 28 °C) and at pH 6.0-10.0 (optimum, 7.0-8.0). NNCM2T grew with 0.5-10 % (w/v) NaCl (optimum, 2 %), at 18-37 °C (optimum, 28 °C) and at pH 6.5-9.0 (optimum, 7.0). The results of phylogenetic analysis based on 16S rRNA gene sequences indicated that NNCM1T formed a lineage within the genus Algiphilus of the family Algiphilaceae, and it was distinct from the most closely related species Algiphilus aromaticivorans DG1253T, with a 16S rRNA gene sequences similarity of 97.05 %. NNCM2T formed a lineage within the family Rhodobacteraceae, and it was distinct from the closely related genera Limibaculum halophilum CAU 1123T, Paroceanicella profunda D4M1T and Pseudoruegeria aestuarii MME-001T with 93.41, 92.78 and 91.09% identities, respectively. The major respiratory quinone was Q-8 and Q-10 for NNCM1T and NNCM2T, respectively. The predominant fatty acids (more than 10 %) were summed feature 8 (39.4 %) and C16 : 0 (19.4 %) for NNCM1T and summed feature 8 (62.8 %) and C16 : 0 (12.4 %) for NNCM2T. The DNA G+C contents of NNCM1T and NNCM2T were 63.3 and 63.4 mol% respectively. The polar lipids of NNCM1T comprised one diphosphatidylglycerol, one phosphatidylethanolamine, one phosphatidylglycerol and one unknown polar lipid, while those of NNCM2T comprised one phosphatidylethanolamine, one phosphatidylglycerol, one aminolipid and four unknown polar lipids. Phenotypic characteristics (physiological, biochemical and chemotaxonomic) also supported the taxonomic novelty of the two isolates. Thus, NNCM1T is considered to represent a novel species within genus Algiphilus, for which the name Algiphilus acroporae sp. nov. is proposed. The type strain is NNCM1T (=KCTC 82966T=MCCC 1K06445T). NNCM2T represents a novel genus and species within the family Rhodobacteraceae, for which the name Coraliihabitans acroporae gen. nov. sp. nov. is proposed. The type strain is NNCM2T (=KCTC 82967T=MCCC 1K06408T).

Flavobacterium coralii sp. nov., a marine bacterium isolated from coral culture seawater.

A Gram-stain-negative, non-motile, strictly aerobic, rod-shaped bacterium, with one polar flagellum and named D11R37T, was isolated from coral culture seawater of Acropora digitifera. Strain D11R37T grew with 0-6 % (w/v) NaCl (optimum, 0.5%), at 10-41 °C (optimum, 28 °C) and at pH 6.0-7.0 (optimum, 7.0). Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain D11R37T formed a lineage within the genus Flavobacterium, and it was distinct from the most closely related species Flavobacterium suzhouense XIN-1T and Flavobacterium suaedae G16-7T with 16S rRNA gene sequences similarities of 95.97% and 95.48 %. The major respiratory quinone was menaquinone-6. The polar lipids comprised one phosphatidylethanolamine, two aminolipids and one unknown polar lipid. The predominant fatty acids (more than 10 % of total fatty acids) were iso-C15 : 0 (18.0%), iso-C17 : 0 3-OH (11.9 %) and summed feature 3 (10.9 %). The DNA G+C content was 41.3 mol%. Based on polyphasic taxonomic data, strain D11R37T is considered to represent a novel species within the genus Flavobacterium, for which the name Flavobacterium coralii sp. nov. is proposed. The type strain is D11R37T (=KCTC 82968T=MCCC 1K06440T).

Aquimarina acroporae sp. nov., isolated from seawater surrounding scleractinian coral Acropora digitifera.

A Gram-stain-negative, aerobic, rod-shaped bacterium (D1M17T) was isolated from the seawater surrounding scleractinian coral Acropora digitifera in Daya Bay, Shenzhen, PR China. Strain D1M17T grew with 0-10 % (w/v) NaCl (optimum, 3-4 %), at 15-37 °C (optimum, 28 °C) and at pH 4.5-8.5 (optimum, pH 7.0-7.5). Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain D1M17T formed a lineage within the genus Aquimarina, family Flavobacteriaceae, and it was distinct from the most closely related species Aquimarina salinaria LMG 25375T, Aquimarina gracilis JCM 17453T and Aquimarina spongiae KCTC 22663T with 16S rRNA gene sequence similarities of 97.2, 97.2 and 97.1 %, respectively. The major respiratory quinone was MK-6. The predominant fatty acids (more than 10 %) were iso-C15 : 0 (28.8 %), iso-C17 : 0 3-OH (21.5 %) and iso-C15 : 1 G (13.1 %). The DNA G+C content of D1M17T was 34.4 mol%. The polar lipids in D1M17T comprised one phospholipid and five unknown polar lipids. Phenotypic characteristics (physiological, biochemical and chemotaxonomic) also supported the taxonomic novelty of this isolate. Thus, strain D1M17T is considered to represent a novel species within the genus Aquimarina, for which the name Aquimarina acroporae sp. nov. is proposed. The type strain is D1M17T (=KCTC 92172T= MCCC 1K07224T).

Longitudinal clinical and radiographic evaluation reveals interleukin-6 as an indicator of persistent pulmonary injury in COVID-19.

Rationale: Previous studies of coronavirus disease 2019 (COVID-19) were mainly focused on cross-sectional analysis. In this study, we sought to evaluate the dynamic changes of immunological and radiographic features, and the association with the outcome of pulmonary lesions in COVID-19 patients. Methods: Peripheral blood samples and radiographic data were collected longitudinally for up to 8 weeks from 158 laboratory-confirmed COVID-19 patients. The chest computed tomography (CT) scans were scored based on a semi-quantification assessment according to the extent of pulmonary abnormalities; the temporal change of the immunological and radiographic features was analyzed. Results: Compared with mild and moderate patients, severe patients had significantly decreased counts of lymphocytes, CD4+ T cells, CD8+ T cells, and CD19+ B cells but dramatically elevated counts of neutrophils and levels of interleukin (IL)-6. Sequential monitoring showed a sustained increase in lymphocytes counts and significantly decreased levels of IL-6 in severe patients during the disease course. Notably, patients with persistent pulmonary lesions (CT score ≥ 5 in week 8) showed high levels of IL-6 during the follow-up period, compared with those with recovery lesions (CT score < 5 in week 8). More importantly, the peak expression of IL-6 prior to the aggravated lung injury was mainly found in patients with persistent lesions, and multivariate analysis showed that IL-6 level upon admission was an independent factor associated with the persistent pulmonary injury. Conclusion: Prolonged elevation of IL-6 is associated with persistent pulmonary lesions in COVID-19 patients. Sequential monitoring and timely intervention of IL-6 may favor the clinical management of COVID-19.

Naturally occurring antiviral drug resistance in HIV patients who are mono-infected or co-infected with HBV or HCV in China.

Drug resistance mutations (DRMs) may reduce the efficacy of antiviral therapy. However, the studies focused on naturally occurring, pre-existing DRMs among co-infected patients in China are limited. To investigate DRMs prevalence in treatment-naïve human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV) mono- and co-infected patients in China, a total of 570 patients were recruited for this study. DRMs sequences were amplified and successfully sequenced in 481 of these patients, who were grouped into three cohorts: (i) The HBV cohort included 100 HIV/HBV co-infected and 110 HBV mono-infected patients who were sequenced for HBV; (ii) The HCV cohort included 91 patients who were HIV/HCV co-infected and 72 who were HCV mono-infected for HCV sequencing; and (iii) The HIV cohort included 39 HIV mono-infected, 22 HIV/HCV, and 47 HIV/HBV co-infected patients for HIV sequencing. Next-generation sequencing and Sanger sequencing were used in this study. The results showed that in the HCV cohort, HCV genotypes 6a (P < 0.001) and 3b (P = 0.004) were more prevalent in HIV/HCV co-infected patients, however, the prevalence of HBV and HIV genotypes were similar within the HBV and HIV cohorts. HBV DRMs prevalence was significantly higher in HIV/HBV co-infected than HBV mono-infected patients (8.0% vs 0.9%, P = 0.015), whereas HCV and HIV DRMs did not differ within the HCV and HIV cohort (P > 0.05). This study revealed that HBV DRMs were more prevalent in HIV/HBV co-infected patients in China, while DRMs in HCV and HIV patients did not differ. Further dynamic surveillance of DRMs may be needed.

Nucleos(T)ide Analogue Treatment Has a More Pronounced Impact on Immune Repertoires of CHB Patients Compared to HCC Patients.

Background: Nucleos(t)ide analogues (NAs) as the first-line treatment for chronic hepatitis B (CHB) have been shown to partially restore the antiviral immunity of the patients. However, hepatitis B virus (HBV) related hepatocellular carcinoma (HCC) patients have a relatively longer duration of HBV infection and lower level of HBV DNA. Whether NAs treatments have a different effect on their immune repertoires between CHB and HCC patients remains to be determined. Patients and Methods: In this study, 126 CHB patients and 85 HBV-related HCC patients who received or did not receive NAs treatment, as well as 361 healthy individuals were enrolled to analyze the effect of NAs treatment on T cell receptor ß chain (TCRß) and B cell receptor heavy chain (BCRh) repertoires in peripheral blood of the patients. Results: We found that after NAs therapy, the richness and evenness of TCRß and BCRh repertoires in CHB patients were significantly lower than those in untreated patients and healthy controls, while the diversity of TCRß and BCRh repertoires was stable in HCC patients. The alanine aminotransferase and HBV DNA levels were not correlated with the TCR or BCR diversity in CHB and HCC patients. Conclusion: The results suggest that NAs therapy could influence the overall T cell and B cell repertoires diversity in CHB patients but has minimal impact on HCC patients, indicating a significant difference in the potential to restore antiviral immunity between CHB and HCC patients by NAs treatment.

RSV infection of humanized lung-only mice induces pathological changes resembling severe bronchiolitis and bronchopneumonia.

Respiratory syncytial virus (RSV) is a substantial cause of severe lower respiratory tract infections in infants, young children, older adults, and immunocompromised individuals. There is a vital need for effective therapeutics to prevent and/or treat severe RSV infection in these high-risk individuals. The development and pre-clinical testing of candidate RSV therapeutics could be accelerated by their evaluation in animals models that recapitulate bronchiolitis and bronchopneumonia; both hallmark features of severe RSV infection of humans. Previously, we demonstrated that implanted human lung tissue in humanized lung-only mice (LoM) can be infected with RSV resulting in a sustained virus replication. Here, we analyzed RSV-associated human lung pathology in the human lung implants of RSV-infected LoM. RSV infected epithelial cells lining the airway and alveolar regions of human lung implants resulting in hallmark histological features of RSV bronchiolitis and bronchopneumonia including distal airway and alveolar lumens clogged with 1) sloughed and necrotic RSV-infected epithelial cells, 2) neutrophil-containing inflammatory infiltrates, and 3) MUC5B dominated mucus secretions. We also show that treatment of LoM with a small molecule antiviral (ribavirin) or a neutralizing antibody (palivizumab) significantly suppressed and/or prevented RSV infection in vivo. Together, our data show that RSV infection of human lung implants in vivo has appropriate cellular tropism and results in hallmark pathological characteristics of severe bronchiolitis and bronchopneumonia in humans. They also offer proof-of-principle of the utility of this model to evaluate novel approaches for the prevention/treatment of RSV infection.

Severe Organ Impairment Was Common in Elderly Individuals with Dengue in Guangdong, China.

Guangdong, China, has experienced several dengue epidemics involving thousands of confirmed cases in recent decades, and elderly individuals suffered severe dengue (SD) most seriously. However, the clinical characteristics and risk factors for SD among elderly patients in Guangdong have not been investigated. Patients older than 65 years were recruited and divided into a dengue fever (DF) group and an SD group according to the 2009 Dengue Guidelines of the WHO. We analyzed the clinical manifestations of the elderly patients with dengue and then assessed the risk factors for SD. Of a total of 1,027 patients, 868 patients were diagnosed as having DF and 159 as having SD. Of the 159 elderly patients with SD, 129 (81%) had comorbidities, with hypertension being the most common. Severe organ impairment (SOI) (115, 54%) was the most common presentation in SD patients, followed by severe plasma leakage (52, 24.4%) and severe hemorrhage (46, 21.6%). The most common symptom of SOI was kidney injury, followed by heart injury and central nervous system injury. Furthermore, multivariate regression revealed that the presence of chronic obstructive pulmonary disease (COPD), a lower red blood cell (RBC) count (≤3.5 × 1012/L; odds ratio [OR], 0.35; 95% CI, 0.17-0.55; P <0.001), lower serum albumin (ALB) (≤35 U/L; OR, 0.18; 95% CI, 0.09-0.32; P <0.001), and hyperpyrexia (body temperature ≥39°C; OR, 1.8; 95% CI, 1.2-2.6, P <0.001) were risk factors for SD. Severe organ impairment was the predominant manifestation in elderly individuals with SD characterized by kidney injury. The potential risk factors of SD such as presence of COPD and hyperpyrexia and lower RBC and ALB levels might help clinicians identify patients with SD early.

The clinical prognostic risk stratification system for HIV infected hepatocellular carcinoma.

BACKGROUND: Patients with human immunodeficiency virus (HIV) are more susceptible to liver cancer because of their compromised immune system. There is no specific prognostic model for HIV-infected hepatocellular carcinoma (HCC) patients. METHODS: Clinical data of 85 patients with HIV-infected HCC was divided into a 7:3 ratio for training and internal validation sets, while the data of 23 patients with HIV-infected HCC was served as the external validation set. Data of 275 HIV-negative HCC patients was considered as external HIV-negative validation set. Variables associated with overall survival (OS) in the training set were used to develop the HIV-infected HCC prognosis (HIHP) model. The model was tested in the internal and external validation sets. The predictive accuracy of the model was assessed with conventional HIV-negative HCC prognostic scoring systems. RESULTS: In the training set, variables independently associated with OS in multivariable analysis were organ involvement and tumor number. The HIHP model demonstrated a significant association with OS in the training set, with a median OS of 13 months for low risk, 7 months for medium risk, and 3 months for high risk (p < 0.001). The HIHP model showed a significant association with OS, and exhibited greater discriminative abilities compared to conventional HIV-negative HCC prognostic models both in the internal and external validation sets. In the external HIV-negative validation set, the HIHP model did not show better discrimination than conventional HIV-negative HCC scores. CONCLUSION: The new model presented in the work provided a more accurate prognostic prediction of OS in HIV-infected HCC patients. However, the model is not applicable to patients with HIV-negative HCC.

Clinical Characteristics and Outcomes of AIDS-Related Burkitt Lymphoma in China: A Retrospective Single-Center Study.

Objectives: Studies on the prognosis and risk stratification of patients with acquired immune deficiency syndrome (AIDS) - related Burkitt lymphoma (AR-BL) are rare. We aim to construct a novel model to improve the risk assessment of these patients. Methods: We retrospectively analyzed the clinical data of 34 patients over the past 10 years and the factors associated with progression-free survival (PFS) and overall survival (OS) were evaluated in univariate and multivariate Cox models. Then, the novel model consisting of screened factors was compared with the existing models. Results: With a 37-month median follow-up, the overall 2-year PFS and OS rates were 40.50% and 36.18%, respectively. The OS of patients who received chemotherapy was better compared with those without chemotherapy (P = .0012). Treatment with an etoposide, prednisone, oncovin, cyclophosphamide, and hydroxydaunorubicin-based regimen was associated with longer OS and PFS compared with a cyclophosphamide, doxorubicin, vincristine, and prednisone-based regimen (OS, P = .0002; PFS, P = .0158). Chemotherapy (hazard ratio [HR] = 0.075; 95% confidence interval [CI], 0.009-0.614) and Eastern Cooperative Oncology Group Performance Status (ECOG PS) 2 to 4 (HR = 4.738; 95% CI, 1.178-19.061) were independent prognostic factors of OS in multivariate analysis and we established a novel prognostic risk stratification model named GZ8H model with chemotherapy and ECOG PS. Conclusion: GZ8H showed better stratification ability than the international prognostic index (IPI) or Burkitt lymphoma IPI (BL-IPI). Furthermore, the C-index of the nomogram used to predict OS was 0.884 in the entire cohort and the calibration curve showed excellent agreement between the predicted and actual results of OS. No human immunodeficiency virus-related factors were found to be associated with OS and PFS of AR-BL patients in our study. Overall, the clinical characteristics and outcomes in AR-BL were shown and prognostic factors for OS and PFS were identified in this study.

Gut microbial co-metabolite 2-methylbutyrylcarnitine exacerbates thrombosis via binding to and activating integrin α2ß1.

Thrombosis represents the leading cause of death and disability upon major adverse cardiovascular events (MACEs). Numerous pathological conditions such as COVID-19 and metabolic disorders can lead to a heightened thrombotic risk; however, the underlying mechanisms remain poorly understood. Our study illustrates that 2-methylbutyrylcarnitine (2MBC), a branched-chain acylcarnitine, is accumulated in patients with COVID-19 and in patients with MACEs. 2MBC enhances platelet hyperreactivity and thrombus formation in mice. Mechanistically, 2MBC binds to integrin α2ß1 in platelets, potentiating cytosolic phospholipase A2 (cPLA2) activation and platelet hyperresponsiveness. Genetic depletion or pharmacological inhibition of integrin α2ß1 largely reverses the pro-thrombotic effects of 2MBC. Notably, 2MBC can be generated in a gut-microbiota-dependent manner, whereas the accumulation of plasma 2MBC and its thrombosis-aggravating effect are largely ameliorated following antibiotic-induced microbial depletion. Our study implicates 2MBC as a metabolite that links gut microbiota dysbiosis to elevated thrombotic risk, providing mechanistic insight and a potential therapeutic strategy for thrombosis.

Effects of microplastic combined with Cr(III) on apoptosis and energy pathway of coral endosymbiont.

The combined effect of polyethylene (PE) microplastics and chromium (Cr(III)) on the scleractinian coral Acropora pruinosa (A. pruinosa) was investigated. The endpoints analysed in this study included the endosymbiont density, the chlorophyll a + c content, and the activity of enzymes involved in apoptosis (caspase-1, caspase-3), glycolysis (lactate dehydrogenase, LDH), the pentose phosphate pathway (glucose-6-phosphate dehydrogenase, G6PDH) and electron transfer coenzyme (nicotinamide adenine dinucleotide, NAD+/NADH). During the 7-day exposure to PE and Cr(III) stress, the endosymbiont density and chlorophyll content decreased gradually. The caspase-1 and caspase-3 activities increased in the high-concentration Cr(III) exposure group. Furthermore, the LDH and G6PDH activities decreased significantly, and the NAD+/NADH was decreased significantly. In summary, the results showed that PE and Cr(III) stress inhibited the endosymbiont energy metabolism enzymes and further led to endosymbiont apoptosis in coral. In addition, under exposure to the combination of stressors, when the concentration of Cr(III) remained at 1 × 10-2 mg/L, the toxic effects of heavy metals on the endosymbiont were temporarily relieved with elevated PE concentrations. In contrast, when coral polyps were exposed to 5 mg/L PE and increasing Cr(III) concentrations, their metabolic activities were seriously disturbed, which increased the burden of energy consumption. In the short term, the toxic effect of Cr(III) was more obvious than that of PE because Cr(III) exposure leads to endosymbiont apoptosis and irreversible damage. This is the first study to provide insights into the combined effect of microplastic and Cr(III) stress on the apoptosis and energy pathways of coral endosymbionts. This study suggested that microplastics combined with Cr(III) are an important factor affecting the apoptosis and energy metabolism of endosymbionts, accelerating the collapse of the balance between the coral host and symbiotic endosymbiont.

New insights into microbial and metabolite signatures of coral bleaching.

Coral bleaching and coral reef degradation have been severely increased due to anthropogenic impacts, especially global warming. Studies have indicated the key role of host-microbiome symbiotic relationships for the coral holobiont health and development, although not all of the mechanisms of interaction have been fully explored. Here, we explore bacterial and metabolic shifts within coral holobionts under thermal stress, and its correlation with bleaching. Our results showed obvious signs of coral bleaching after 13 days of heating treatment, and a more-complex co-occurrence network was observed in the coral-associated bacterial community of the heating group. The bacterial community and metabolites changed significantly under thermal stress, and genera Flavobacterium, Shewanella and Psychrobacter increased from <0.1 % to 43.58 %, 6.95 % and 6.35 %, respectively. Bacteria potentially associated with stress tolerance, biofilm formation and mobile elements decreased from 80.93 %, 62.15 % and 49.27 % to 56.28 %, 28.41 % and 18.76 %, respectively. The differentially expressed metabolites of corals after heating treatment, such as Cer(d18:0/17:0), 1-Methyladenosine, Trp-P-1 and Marasmal, were associated with cell cycle regulation and antioxidant properties. Our results can contribute to our current understanding on the correlations between coral-symbiotic bacteria, metabolites and the coral physiological response to thermal stress. These new insights into the metabolomics of heat-stressed coral holobionts may expand our knowledge on the mechanisms underlying bleaching.

Assessing the chronic hepatitis B adaptive immune response by profiling specific T-cell receptor repertoire.

Challenges in assessing hepatitis B virus (HBV)-specific T cell immunity as an immunological biomarker still remain in chronic hepatitis B (CHB), such as the requirement of large quantities of cells. This study aims to conveniently assess HBV-specific T cells immunity in chronic HBV infected patients. We obtained T cell receptor ß chains (TCRßs) from public databases and six acute hepatitis B patients to establish an HBV-specific TCRßs dataset. For some TCRs from one acute patient, their specificities and epitopes were verified. The potential HBV-specific TCRßs from CHB patients were analyzed using GLIPH2 and established dataset. By analyzing two antiviral therapy cohorts including 42 CHB patients, we showed that individuals with better therapy response may depend more on newly emerging potential HBV-specific TCRßs. In a cross-sectional study containing 207 chronic HBV infected patients, the results exhibited that the characteristics of potential HBV-specific clusters were divergent between CHB and hepatocellular carcinoma patients. Our strategy could profile potential HBV-specific TCRß repertoire using a small blood sample, which will complement traditional methods for assessing the HBV-specific T cell immunity.

Evaluating SARS-CoV-2 antibody reactivity to natural exposure and inactivated vaccination with peptide microarrays.

Objective: Vaccination is effective tool for preventing and controlling SARS-CoV-2 infections, and inactivated vaccines are the most widely used type of vaccine. In order to identify antibody-binding peptide epitopes that can distinguish between individuals who have been vaccinated and those who have been infected, this study aimed to compare the immune responses of vaccinated and infected individuals. Methods: SARS-CoV-2 peptide microarrays were used to assess the differences between 44 volunteers inoculated with the inactivated virus vaccine BBIBP-CorV and 61 patients who were infected with SARS-CoV-2. Clustered heatmaps were used to identify differences between the two groups in antibody responses to peptides such as M1, N24, S15, S64, S82, S104, and S115. Receiver operating characteristic curve analysis was used to determine whether a combined diagnosis with S15, S64, and S104 could effectively distinguish infected patients from vaccinated individuals. Results: Our findings showed that the specific antibody responses against S15, S64, and S104 peptides were stronger in vaccinators than in infected persons, while responses to M1, N24, S82, and S115 were weaker in asymptomatic patients than in symptomatic patients. Additionally, two peptides (N24 and S115) were found to correlate with the levels of neutralizing antibodies. Conclusion: Our results suggest that antibody profiles specific to SARS-CoV-2 can be used to distinguish between vaccinated individuals and those who are infected. The combined diagnosis with S15, S64, and S104 was found to be more effective in distinguishing infected patients from those who have been vaccinated than the diagnosis using individual peptides. Moreover, the specific antibody responses against the N24 and S115 peptides were found to be consistent with the changing trend of neutralizing antibodies.