Search

Background: Acute-on-chronic liver failure (ACLF) is a common clinical type of liver failure, and patients with acute-on-chronic liver failure are prone to fungal infections, especially the increasing incidence of invasive pulmonary aspergillosis(IPA). Voriconazole is recommended as the first-line antifungal agent in the treatment of invasive aspergillosis, however, no recommendation has been given for patients with severe liver cirrhosis (Child-Pugh C) and liver failure. This trial aims to examine the therapeutic effects and safety of voriconazole in the treatment of IPA in patients with liver failure.Methods: This study is a non-double-blind randomized controlled trial. The 96 eligible acute-on-chronic liver failure patients complicated with invasive pulmonary aspergillosis will be randomly assigned to receive either the optimized voriconazole regimen or the recommended voriconazole regimen for patients with mild to moderate liver cirrhosis (Child-Pugh A and B), at a 1:1 ratio, with an 8-week follow-up period. The antifungal efficacy of voriconazole will be the primary outcome measure. Plasma voriconazole concentration; the laboratory examination(CRP, PCT, ESR, etc.); chest CT; adverse events; and mortality at week 4 and 8 will be the secondary outcome measures.Discussion: This trial aims to demonstrate the efficacy and safety of voriconazole in the treatment of IPA in patients with liver failure, which is expected to provide a reference for scientific optimization of voriconazole regimens and a realistic basis for the standardized treatment of acute-on-chronic liver failure patients complicated with invasive pulmonary aspergillosis.Trial registration: The trial was registered with the Chinese Clinical Trial Registry, ChiCTR2100048259. Registered on 5 July 2021.

The NLRP3 inflammasome plays a pro-tumorigenic role in various malignancies. However, its potential role in lymphomagenesis remains unclear. In this study, we identified an immunosuppressive state in patients with diffuse large B cell lymphoma (DLBCL), which was characterized by markedly elevated interleukin (IL)-18 levels in lymphoma tissues and positive correlation with programmed death ligand 1 (PD-L1) expression. Furthermore, NLRP3 inflammasome activation in DLBCL cell lines upregulated PD-L1 and reduced the proportion of cytotoxic T cells. NLRP3 inflammasome blockade in vivo suppressed lymphoma growth and ameliorated anti-tumor immunity by downregulating PD-L1 in the tumor microenvironment and decreasing the proportion of PD-1/TIM-3-expressing T cells, myeloid-derived suppressor cells, tumor-associated macrophages, and regulatory T cells. Further in vivo studies revealed IL-18 as the main effector cytokine involved in the negative regulation of anti-lymphoma immunity. Interestingly, NLRP3 blockers combined with anti-PD-L1 treatment exerted antagonistic effects during lymphoma therapy. Altogether, our findings indicate that NLRP3 inflammasome promotes immunosuppression by modulating PD-L1 and immune cells. Accordingly, this study highlights the prognostic and therapeutic values of the NLRP3 inflammasome in lymphoma.

Background Streptococcus suis is an emerging zoonotic pathogen that mainly causes meningitis, sepsis, arthritis, endocarditis, and endophthalmitis in human. To the best of our knowledge, Spinal canal infection caused by Streptococcus suis has rarely been reported. Case presentation Here we report a case of spinal canal infection caused by Streptococcus suis in a 50-year-old male patient. The patient had a history of close contact with sick pigs days before disease onset. Initially he presented with headache and fever. After admission, the patient began to experience lower back pain, which led physicians to perform a lumber puncture. Meta-genomic next generation sequencing helped identify Streptococcus suis in the cerebrospinal fluid. MRI imaging indicated a spinal canal infection caused by Streptococcus suis. Conclusions Spinal canal infection is an uncommon disease of Streptococcus suis infection. This case report indicates that people presented with fever, headache and lower back pain should also be suspected as Streptococcus suis infection, especially for those who have had a history of sick pig contact.

Background: Cadherin-23 (CDH23), which plays an important role in intercellular adhesion, is involved in the progression of several types of cancer. However, the biological functions and impact of CDH23 expression on the prognosis of patients with acute myeloid leukemia (AML) are yet to be explored. Herein, we aim to characterize the role and molecular functions of CDH23 in AML.Methods: The expression level of CDH23 were assessed in patients with AML by Gene Expression Profiling Interactive Analysis (GEPIA). The prognostic value of CDH23 was analyzed via GEPIA and LinkedOmics. Correlation analysis and biology function analysis were conducted by LinkedOmics and GeneMANIA database. Relationship of CDH23 with immune infiltration level was detected by TIMER. Results: In the present study, aberrant overexpression of CDH23 was first confirmed in patients with AML and contributed to poor prognosis. Notably, we observed a negative correlation between CDH23 mRNA expression and immune cell infiltration by calculating the ESTIMATE score. In addition, functional enrichment analysis confirmed that CDH23 plays a crucial role in tumor immunity. Conclusions: Our findings indicate that upregulation of CDH23 expression corresponded to shortened overall survival of patients with AML. CDH23 may be involved in mediating tumor immunity, and this highlights the potential of CDH23 as a therapeutic target in AML.

Additional file 1: Table S1. Transcription factors that bound around TNFAIP8 gene.

Helicobacter-induced chronic inflammation and immune disorders are closely associated with the development of gastric mucosa-associated lymphoid tissue (MALT) lymphoma. Myeloid-derived suppressor cells (MDSCs) exhibit strong immunosuppressive properties and promote the growth of various solid tumors. However, the role of MDSCs in the development of MALT lymphoma has not been elucidated so far. We detected significant infiltration and enrichment of MDSCs in patients with MALT lymphoma, as well in Helicobacter felis-infected mouse model of gastric MALT lymphoma. In addition, the expression of arginase-1 and inducible nitric oxide synthase was significantly elevated both in gastric MALT lymphoma tissues and H. felis-infected stomach. Persistent H. felis infection closely reproduced the development of gastric MALT lymphoma and was accompanied by increased numbers of γδT17 cells. Accumulation of γδT17 cells was also validated in the human gastric MALT lymphoma tissues. Furthermore, the elevated cytokines interleukin-23 and interleukin-1β, as well as chemokines CCL20/CCR6, may be involved in the accumulation of γδT17 cells and the subsequent immunosuppression. These findings highlight the role of MDSCs and γδT17 cells in immune dysregulation during gastric MALT lymphoma development and their potential as therapeutic targets.

Tyrosine kinase inhibitor treatment of chronic myeloid leukemia (CML) has demonstrated beneficial effects. However, resistance to tyrosine kinase inhibitors and disease relapse are still a challenge for CML therapy. In this study, we analyzed bone marrow samples from 149 CML patients and 15 control donors, and investigated the affect of AF1q on CML cell survival and engraftment in vitro and in vivo. We found that AF1q/MLLT11 expression was significantly upregulated in CML patients, especially in CD34+ CML cells. Elevated AF1q expression was associated with disease progression. Knockdown of AF1q enhanced imatinib sensitivity, induced apoptosis, and suppressed growth in CML cells. Moreover, AF1q deficiency sensitized CD34+ CML cells to imatinib. In contrast, upregulation of AF1q promoted cell survival, protected CML cells from imatinib-induced apoptosis, and increased engraftment of CML cells in vivo. We further identified a positive correlation between AF1q and CD44 expression in chronic phase CML patients and CD34+ CML cells. Importantly, AF1q contributes to imatinib-resistance in CML by regulating the expression of CD44. These findings reveal a novel BCR-ABL-independent pathway, AF1q/CD44, involves imatinib resistance in CML, thus representing a potential therapeutic target for imatinib-resistant CML patients.

Helicobacter-induced chronic inflammation and immune disorders are closely associated with the development of gastric mucosa-associated lymphoid tissue (MALT) lymphoma. Myeloid-derived suppressor cells (MDSCs) exhibit strong immunosuppressive properties and promote the growth of various solid tumors. However, the role of MDSCs in the development of MALT lymphoma has not been elucidated so far. We detected significant infiltration and enrichment of MDSCs in patients with MALT lymphoma, as well in Helicobacter felis-infected mouse model of gastric MALT lymphoma. In addition, the expression of arginase-1 and inducible nitric oxide synthase was significantly elevated both in gastric MALT lymphoma tissues and H. felis-infected stomach. Persistent H. felis infection closely reproduced the development of gastric MALT lymphoma and was accompanied by increased numbers of γδT17 cells. Accumulation of γδT17 cells was also validated in the human gastric MALT lymphoma tissues. Furthermore, the elevated cytokines interleukin-23 and interleukin-1β, as well as chemokines CCL20/CCR6, may be involved in the accumulation of γδT17 cells and the subsequent immunosuppression. These findings highlight the role of MDSCs and γδT17 cells in immune dysregulation during gastric MALT lymphoma development and their potential as therapeutic targets.

Action plan generation is essentially a planning problem, but the planning algorithm is not systematic, and it is difficult to effectively solve the problem of maritime rescue action plan generation. In this paper, a nested method for generating maritime rescue action plan is proposed. The specific steps are as follows. Firstly, a hierarchical scheme generation strategy is proposed. The scheme generation is mainly divided into two parts: task decomposition and resource scheduling. Then a task decomposition method based on genetic algorithm is established by learning the expert scheme. Through the mathematical modeling of the problem in the part of resource scheduling, a resource scheduling algorithm is proposed. Finally, the effectiveness of the proposed method is verified by simulation.

The new type of marine accident has the characteristics of multi-objective and time-critical, which puts forward higher requirements for the method of target allocation in maritime rescue, that is, more time must be saved while ensuring the allocation of rescue resources in place. The aim of the study was to propose a new target allocation method based on improved genetic algorithm. The method was called multi-string genetic algorithm and can select multiple targets to search for the global optimal solution based on the same platform. The simulation results showed that the proposed method can accomplish multi-objective assignment with fewer assignment times, and save more time than the traditional method.

To evaluate the efficacy and safety of tenofovir disoproxil fumarate (TDF) in patients with chronic hepatitis B (CHB) after failure of nucleoside-analogues (NAs).A total of 30 CHB patients who had been previously treated with NAs and had subsequently completed a 48-week course of TDF were retrospectively investigated. Patients' data of HBV DNA level (log10 copies/ml) and rate of undetectable HBV DNA at treatment weeks 0 (baseline), 4, 12, 24, 36 and 48 were collected for evaluation. The lower limit of HBV DNA detection was 100 IU/ml. The serum alanine aminotransferase (ALT) normalization rate, hepatitis B e antigen (HBeAg) seroconversion rate, viral breakthrough (VBT) rate, viral response (VR) rate, and adverse events were determined upon treatment completion. Statistical analyses were carried out using the Student's t-test, the x² test or the Kaplan-Meier method.Over the 48-week treatment period, HBV DNA levels declined significantly from baseline (week 4:(2.11 ± 0.38) log10 IU/ml, t =5.582; week 12:(0.93 ± 0.31) log10 IU/ ml, t =9.303; week 24:(0.75 ± 0.20) log10 IU/ml, t =3.123; week 36:(0.16 ± 0.19) log10 IU/ml, t =10.759; week 48:(0.14 ± 0.25) log10 IU/ml, t =12.202) (all P less than 0.01). However, the rates of HBV DNA reduction and of cumulative reduction were comparable at weeks 24, 36 and 48 (all P more than 0.05). The most robust decline in HBV DNA levels was observed at week 4 ((2.11 ± 0.38) log10 IU/ml) and the highest cumulative HBV DNA reduction was observed at week 24 ((3.79 ± 0.37) log10 IU/ml). The rate of undetectable HBV DNA at week 4 (26.7%) was significantly lower than that at weeks 24 (87.5%, P less than 0.01), 36 (80.0%, P=0.007), and 48 (88.9%, P=0.001). The median time to achieving undetectable HBV DNA was 10.4 weeks (range:3.43-34.0 weeks). At week 48, the rates of VR, HBeAg seroconversion, and VBT were 88.9% ,6.7%, and 0% respectively. During treatment, the levels of creatine kinase were more than two times the upper limit normal in 9.2% of the patients, and were comparable at each time point examined (all P more than 0.05). All patients showed a normal level of serum creatinine throughout the treatment period.For CHB patients with non-response to NAs, TDF can suppress HBV DNA replication very quickly and achieve a high rate of ALT normalization with a low rate of adverse events.

Objective: To analyze the efficacy and safety of entecavir (ETV) treatment for up to 5 years in nucleos(t)ide-naive chronic hepatitis B patients in real life. Methods: We retrospectively analyzed 230 nucleos(t)ide naive chronic hepatitis B patients who received ETV 0.5 mg/day monotherapy for at least 3 months, of whom 113 were HBeAg positive and 117 were HBeAg negative. The primary endpoints was cumulative probability of achieving a virological response (undetectable serum HBV DNA