Design, synthesis, and evaluation of pyranochromene derivatives as membrane targeting antibacterials against Gram-positive bacteria.

The rapid growth of bacterial resistance has created obstacles for the effective treatment with conventional antibiotics, simultaneously posing a major threat to public health. In this study, a class of novel amphipathic pyranochromene derivatives were designed and synthesized by mimicking the amphiphilic characteristics of AMPs. Bioactivity screening identified a lead compound 5a with broad-spectrum antibacterial activity against Gram-positive stains (MICs = 1-4 µg/mL) and low hemolytic toxicity (HC50 = 111.6 µg/mL). Additionally, compound 5a displayed rapid bactericidal action, and was unlikely to induce bacterial resistance. Mechanistic investigation further demonstrated that compound 5a was able to disrupt the transmembrane potential and increased membrane permeability of S. aureus, which in turn causes leakage of cell contents such as DNA and proteins, ultimately leading to bacterial death. These findings indicated that compound 5a is a promising lead to combat bacterial infection caused by Gram-positive bacteria.

Administration of turmeric kombucha ameliorates lipopolysaccharide-induced sepsis by attenuating inflammation and modulating gut microbiota.

Our research team previously reported the immunomodulatory effects of kombucha fermentation liquid. This study investigated the protective effects of turmeric kombucha (TK) against lipopolysaccharide (LPS)-induced sepsis and its impact on the intestinal microbiota of mice. A turmeric culture medium without kombucha served as the control (TW). Non-targeted metabolomics analysis was employed to analyze the compositional differences between TK and TW. Qualitative analysis identified 590 unique metabolites that distinguished TK from TW. TK improved survival from 40 to 90%, enhanced thermoregulation, and reduced pro-inflammatory factor expression and inflammatory cell infiltration in the lung tissue, suppressing the NF-κB signaling pathway. TK also altered the microbiome, promoting Allobaculum growth. Our findings shed light on the protective effects and underlying mechanisms of TK in mitigating LPS-induced sepsis, highlighting TK as a promising anti-inflammatory agent and revealing new functions of kombucha prepared through traditional fermentation methods.

Delineation of features, responses, outcomes, and prognostic factors in pediatric PDGFRB-positive acute lymphoblastic leukemia patients: A retrospective multicenter study.

BACKGROUND: PDGFRB fusions in acute lymphoblastic leukemia (ALL) is rare. The authors identified 28 pediatric PDGFRB-positive ALL. They analyzed the features, outcomes, and prognostic factors of this disease. METHODS: This multicenter, retrospective study included 6457 pediatric patients with newly diagnosed PDGFRB fusion ALL according to the CCCG-ALL-2015 and CCCG-ALL-2020 protocols from April 2015 to April 2022 in 20 hospitals in China. Of these patients, 3451 were screened for PDGFRB fusions. RESULTS: Pediatric PDGFRB-positive ALL accounted for only 0.8% of the 3451 cases tested for PDGFRB. These patients included 21 males and seven females and 24 B-ALL and 4 T-ALL; the median age was 10 years; and the median leukocyte count was 29.8 × 109/L at baseline. Only one patient had eosinophilia. Three patients had an IKZF1 deletion, three had chromosome 5q31-33 abnormalities, and one suffered from a complex karyotype. The 3-year event-free survival (EFS), overall survival (OS), and cumulative incidence of relapse (CIR) were 33.1%, 65.5%, and 32.1%, respectively, with a median follow-up of 25.5 months. Twenty patients were treated with chemotherapy plus tyrosine-kinase inhibitors (TKIs) and eight were treated without TKI. Complete remission (CR) rates of them were 90.0% and 63.6%, respectively, but no differences in EFS, OS, or CIR. Univariate analyses showed patients with IKZF1 deletion or measurable residual disease (MRD) ≥0.01% after induction had inferior outcomes (p < .05). CONCLUSIONS: Pediatric PDGFRB-positive ALL has a poor outcome associated with high-risk features. Chemotherapy plus TKIs can improve the CR rate, providing an opportunity for lower MRD levels and transplantation. MRD ≥0.01% was a powerful adverse prognostic factor, and stratified treatment based on MRD may improve survival for these patients. PLAIN LANGUAGE SUMMARY: Pediatric acute lymphoblastic leukemia patients with PDGFRB fusions are associated with high-risk clinical features such as older age, high white blood cell count at diagnosis, high measurable residual disease after induction therapy, and increased risk of leukemia relapse. Chemotherapy plus tyrosine-kinase inhibitors can improve the complete remission rate and provide an opportunity for lower measurable residual disease (MRD) levels and transplantation for pediatric PDGFRB-positive acute lymphoblastic leukemia (ALL) patients. The MRD level was also a powerful prognostic factor for pediatric PDGFRB-positive ALL patients.

Combining Aloin with TIENAM ameliorates cecal ligation and puncture-induced sepsis in mice by attenuating inflammation and modulating abdominal cavity microbiota.

Despite the high mortality rate, sepsis lacks specific and effective treatment options. Conventional antibiotics, such as TIENAM (TIE; imipenem and cilastatin sodium for injection), face challenges owing to the emergence of bacterial resistance, which reduces their effectiveness and causes adverse effects. Addressing resistance and judicious drug use is crucial. Our research revealed that aloin (Alo) significantly boosts survival rates and reduces inflammation and bacterial load in mice with sepsis, demonstrating strong antimicrobial activity. Using a synergistic Alo + TIE regimen in a cecal ligation and puncture (CLP)-induced sepsis model, we observed a remarkable increase in survival rates from 10 % to 75 % within 72 h compared with the CLP group alone. This combination therapy also modulated inflammatory markers interleukin (IL)-6, IL-1ß, and tumor necrosis factor (TNF)-α, mitigated tissue damage, regulated immune cells by lowering NK, activated CD8+ and CD4+ T cells while increasing peritoneal macrophages, and decreased the bacterial load in the peritoneal cavity. We noted a significant shift in the abdominal cavity microbiota composition post-treatment, with a decrease in harmful bacteria, such as Lachnospiraceae_NK4A136_group, Klebsiella, Bacillus, and Escherichia, and an increase in beneficial bacteria, such as Lactobacillus and Mucispirillum. Our study emphasizes the efficacy of combining Alo with TIE to combat sepsis, and paves the way for further investigations and potential clinical applications aiming to overcome the limitations of TIE and enhance the therapeutic prospects of Alo.

Huperzine a ameliorates sepsis-induced acute lung injury by suppressing inflammation and oxidative stress via α7 nicotinic acetylcholine receptor.

Sepsis, characterized by high mortality rates, causes over 50 % of acute lung injury (ALI) cases, primarily due to the heightened susceptibility of the lungs during this condition. Suppression of the excessive inflammatory response is critical for improving the survival of patients with sepsis; nevertheless, no specific anti-sepsis drugs exist. Huperzine A (HupA) exhibits neuroprotective and anti-inflammatory properties; however, its underlying mechanisms and effects on sepsis-induced ALI have yet to be elucidated. In this study, we demonstrated the potential of HupA for treating sepsis and explored its mechanism of action. To investigate the in vivo impacts of HupA, a murine model of sepsis was induced through cecal ligation and puncture (CLP) in both wild-type (WT) and α7 nicotinic acetylcholine receptor (α7nAChR) knockout mice. Our results showed that HupA ameliorates sepsis-induced acute lung injury by activating the α7nAChR. We used the CLP sepsis model in wild-type and α7nAChR -/- mice and found that HupA significantly increased the survival rate through α7nAChR, reduced the pro-inflammatory cytokine levels and oxidative stress, ameliorated histopathological lung injury, altered the circulating immune cell composition, regulated gut microbiota, and promoted short-chain fatty acid production through α7nAChR in vivo. Additionally, HupA inhibited Toll-like receptor NF-κB signaling by upregulating the α7nAChR/protein kinase B/glycogen synthase kinase-3 pathways. Our data elucidate HupA's mechanism of action and support a "new use for an old drug" in treating sepsis. Our findings serve as a basis for further in vivo studies of this drug, followed by application to humans. Therefore, the findings have the potential to benefit patients with sepsis.

Combining ulinastatin with TIENAM improves the outcome of sepsis induced by cecal ligation and puncture in mice by reducing inflammation and regulating immune responses.

Despite the high mortality associated with sepsis, effective and targeted treatments remain scarce. The use of conventional antibiotics such as TIENAM (imipenem and cilastatin sodium for injection, TIE) is challenging because of the increasing bacterial resistance, which diminishes their efficacy and leads to adverse effects. Our previous studies demonstrated that ulinastatin (UTI) exerts a therapeutic impact on sepsis by reducing systemic inflammation and modulating immune responses. In this study, we examined the possibility of administering UTI and TIE after inducing sepsis in a mouse model using cecal ligation and puncture (CLP). We assessed the rates of survival, levels of inflammatory cytokines, the extent of tissue damage, populations of immune cells, microbiota in ascites, and important signaling pathways. The combination of UTI and TIE significantly improved survival rates and reduced inflammation and bacterial load in septic mice, indicating potent antimicrobial properties. Notably, the survival rates of UTI+TIE-treated mice increased from 10 % to 75 % within 168 h compared to those of mice that were subjected to CLP. The dual treatment successfully regulated the levels of inflammatory indicators (interleukin [IL]-6, IL-1ß, and tumor necrosis factor [TNF]-α) and immune cell numbers by reducing B cells, natural killer cells, and TNFR2+ Treg cells and increasing CD8+ T cells. Additionally, the combination of UTI and TIE alleviated tissue damage, reduced bacterial load in the peritoneal cavity, and suppressed the NF-κB signaling pathway. Our findings indicate that UTI and TIE combination therapy can significantly enhance sepsis outcomes by reducing inflammation and boosting the immune system. The results offer a promising therapeutic approach for future sepsis treatment.

Protective effects of DcR3-SUMO on lipopolysaccharide-induced inflammatory cells and septic mice.

Despite the high mortality rate associated with sepsis, no specific drugs are available. Decoy receptor 3 (DcR3) is now considered a valuable biomarker and therapeutic target for managing inflammatory conditions. DcR3-SUMO, an analog of DcR3, has a simple production process and high yield. However, its precise underlying mechanisms in sepsis remain unclear. This study investigated the protective effects of DcR3-SUMO on lipopolysaccharide (LPS)-induced inflammatory cells and septic mice. We evaluated the effects of DcR3 intervention and overexpression on intracellular inflammatory cytokine levels in vitro. DcR3-SUMO significantly reduced cytokine levels within inflammatory cells, and notably increased DcR3 protein and mRNA levels in LPS-induced septic mice, confirming its anti-inflammatory efficacy. Our in vitro and in vivo results demonstrated comparable anti-inflammatory effects between DcR3-SUMO and native DcR3. DcR3-SUMO protein administration in septic mice notably enhanced tissue morphology, decreased sepsis scores, and elevated survival rates. Furthermore, DcR3-SUMO treatment effectively lowered inflammatory cytokine levels in the serum, liver, and lung tissues, and mitigated the extent of tissue damage. AlphaFold3 structural predictions indicated that DcR3-SUMO, similar to DcR3, effectively interacts with the three pro-apoptotic ligands, namely TL1A, LIGHT, and FasL. Collectively, DcR3-SUMO and DcR3 exhibit comparable anti-inflammatory effects, making DcR3-SUMO a promising therapeutic agent for sepsis.

The Effect of Hydroxy Silicone Oil Emulsion on the Waterproof Performance of Cement.

The hydrophilic and porous structure of cement-based concrete materials makes it vulnerable to various harmful ions dissolved in water in the environment or during the freeze-thaw cycle, resulting in a significant decline in durability. Therefore, the introduction of hydrophobic hydroxyl silicone oil with good chemical stability and excellent hydrophobic properties during the process of concrete preparation to achieve the hydrophobic modification of its internal holes has very positive significance in terms of improving its durability. In order to disperse the hydrophobic hydroxyl silicone oil evenly in the internal pores of the concrete, synthetic non-ionic polyether-modified silicone oil was used as an emulsifier to make it a water-soluble emulsion. The influences of the composition of the emulsifier on the dispersion, water contact angle, water absorption, porosity, and compressive strength of cement mortar were investigated. The results show that when the emulsion content is 0.5%, the pore volume of the cement mortar decreases by 15%, and the maximum contact angle reaches 128°, which is conducive to improving the anti-erosion and anti-freezing properties of concrete and provides a new solution for the preparation of high-durability concrete. However, the introduction of polyether-modified silicone oil increases the number of large holes in the cement mortar, and leads to an increase in water absorption and a decrease in compressive strength. It is necessary to further optimize the composition of emulsifier in future work.

The efficacy and safety of Gukang Capsule for primary osteoporosis: a systematic review and meta-analysis of randomized clinical trial.

Background: Gukang Capsule has been used as a complementary and alternative medicine (CAM) for the treatment of primary osteoporosis (POP) in China. The primary aim of this study was to assess the clinical effectiveness and safety of Gukang Capsule in POP patients. Methods: A systematic search was conducted across multiple academic databases including PubMed, Web of science, Cochrane Library, China National Knowledge Infrastructure, Chongqing VIP Information, and Wanfang database to identify randomized controlled trials investigating the Gukang Capsule in the treatment of POP. The screening process, data extraction, and assessment of methodological quality were conducted independently by two reviewers. Statistical analysis was performed using the Rev Man 5.3 software. Subgroup analysis was carried out through the combination of OPF. Subgroup analysis was performed according to whether OPF were combined. Stata 12.0 was used for sensitivity and bias analysis. Results: Nineteen studies were assessed that included 1804 participants. It was found that compared with the control group, the total effective rate (RR = 1.26, 95% CI, 1.20, 1.33), the Medical Outcomes Study Short-form 36 [RR = 1.26, 95% CI(1.20, 1.33)], the bone mineral density (BMD) of lumbar vertebra (SMD = 0.77, 95% CI, 0.48, 1.07), the BMD of femoral neck [SMD = 0.84, 95% CI(0.53, 1.14)], and the BMD of Ward's triangle (SMD = 0.64, 95% CI, 0.44, 0.85) of the Gukang Capsule experimental group were higher. Compared with the control group, the fracture healing time (SMD = -2.14, 95% CI, -2.45, -1.84), the bone specific alkaline phosphatase (BALP) levels in serum (SMD = -2.00, 95% CI, -2.83, -1.17), the tartrate resistant acid phosphatase 5b (TRACP-5b) levels in serum (SMD = -2.58, 95% CI, -3.87, -1.29) of the Gukang Capsule experimental group were lower. The bone glaprotein (BGP) levels in serum (SMD = -0.22, 95% CI, -1.86, 1.43) and the adverse events (RR = 0.80, 95% CI, 0.40, 1.63) of the experimental group and the control group have no difference. Conclusion: Gukang Capsule, as a CAM for the management of POP, exhibits the potential to enhance BMD and quality of life, expedite the healing time of OPF, diminish levels of BALP and TRACP-5b, and improve the total effective rate without increasing the adverse events. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023477774, PROSPERO CRD42023477774.

Is better readiness the key to deeper learning in distance education? A cross-sectional online study.

Background: The COVID-19 pandemic has required teachers and students to suddenly transition from face-to-face formats to distance education (DE). The uniqueness of nursing discipline is that it requires both theoretical and skills-based learning. Therefore, it is necessary to explore the influencing factors and effectiveness of DE in nursing education. This exploration can guide teaching practice and provide a basis for the future application of DE in nursing education. Aims: To describe the current distance education readiness and depth of learning among undergraduate nursing students and explore possible influencing factors. To determine the relationship between students' distance education readiness and the depth of learning. Design: This is a descriptive and cross-sectional online study. Settings: School of Nursing in a traditional Chinese medicine university, Beijing, China. Participants: A total of 222 undergraduate nursing students from a traditional Chinese medicine university were recruited. Methods: A questionnaire, which is composed of information form, the Online Learning Readiness Scale, and the Scale of Students Making Deep Learning, was used for data collection. Frequency, percentage, arithmetic mean, standard deviation, t-test, one-way ANOVA, and Pearson correlations were used in the analysis of the data. Result: Undergraduate nursing students have lower averages in distance education readiness and higher averages in the depth of learning. Significant differences in distance education readiness and depth of learning between different grade groups. A positive correlation was found between distance education readiness and depth of learning (r = 0.894, p < 0.001). Conclusion: Distance education is a feasible approach to learning today. Undergraduate nursing students have exhibited poor readiness for distance education but demonstrated deeper learning conditions. Upper grades may lead to better learning outcomes. Better distance education readiness can lead to deeper learning. These conclusions prompt teachers and students to be prepared before participating in distance education to obtain better academic performance.

Inhibitory mechanisms of decoy receptor 3 in cecal ligation and puncture-induced sepsis.

Despite its high mortality, specific and effective drugs for sepsis are lacking. Decoy receptor 3 (DcR3) is a potential biomarker for the progression of inflammatory diseases. The recombinant human DcR3-Fc chimera protein (DcR3.Fc) suppresses inflammatory responses in mice with sepsis, which is critical for improving survival. The Fc region can exert detrimental effects on the patient, and endogenous peptides are highly conducive to clinical application. However, the mechanisms underlying the effects of DcR3 on sepsis are unknown. Herein, we aimed to demonstrate that DcR3 may be beneficial in treating sepsis and investigated its mechanism of action. Recombinant DcR3 was obtained in vitro. Postoperative DcR3 treatment was performed in mouse models of lipopolysaccharide- and cecal ligation and puncture (CLP)-induced sepsis, and their underlying molecular mechanisms were explored. DcR3 inhibited sustained excessive inflammation in vitro, increased the survival rate, reduced the proinflammatory cytokine levels, changed the circulating immune cell composition, regulated the gut microbiota, and induced short-chain fatty acid synthesis in vivo. Thus, DcR3 protects against CLP-induced sepsis by inhibiting the inflammatory response and apoptosis. Our study provides valuable insights into the molecular mechanisms associated with the protective effects of DcR3 against sepsis, paving the way for future clinical studies. IMPORTANCE: Sepsis affects millions of hospitalized patients worldwide each year, but there are no sepsis-specific drugs, which makes sepsis therapies urgently needed. Suppression of excessive inflammatory responses is important for improving the survival of patients with sepsis. Our results demonstrate that DcR3 ameliorates sepsis in mice by attenuating systematic inflammation and modulating gut microbiota, and unveil the molecular mechanism underlying its anti-inflammatory effect.

Automatic height measurement of central serous chorioretinopathy lesion using a deep learning and adaptive gradient threshold based cascading strategy.

Accurately quantifying the height of central serous chorioretinopathy (CSCR) lesion is of great significance for assisting ophthalmologists in diagnosing CSCR and evaluating treatment efficacy. The manual measurement results dominated by single optical coherence tomography (OCT) B-scan image in clinical practice face the dilemma of weak reference, poor reproducibility, and experience dependence. In this context, this paper constructs two schemes: Scheme Ⅰ draws on the idea of ensemble learning, namely, integrating multiple models for locating starting key point in the height direction of lesion in the inference stage, which appropriately improves the performance of a single model. Scheme Ⅱ designs an adaptive gradient threshold (AGT) technique, followed by the construction of cascading strategy, which involves preliminary location of starting key point through deep learning, and then employs AGT for precise adjustment. This strategy not only achieves effective location for starting key point, but also significantly reduces the large appetite of deep learning model for training samples. Subsequently, AGT continues to play a crucial role in locating the terminal key point in the height direction of lesion, further demonstrating its feasibility and effectiveness. Quantitative and qualitative key point location experiments in the height direction of lesion on 1152 samples, as well as the final height measurement display, consistently conveys the superiority of the constructed schemes, especially the cascading strategy, expanding another potential tool for the comprehensive analysis of CSCR.

Targeting autophagy overcomes cancer-intrinsic resistance to CAR-T immunotherapy in B-cell malignancies.

BACKGROUND: Chimeric antigen receptor T (CAR-T) therapy has substantially revolutionized the clinical outcomes of patients with hematologic malignancies, but the cancer-intrinsic mechanisms underlying resistance to CAR-T cells remain yet to be fully understood. This study aims to explore the molecular determinants of cancer cell sensitivity to CAR-T cell-mediated killing and to provide a better understanding of the underlying mechanisms and potential modulation to improve clinical efficacy. METHODS: The human whole-genome CRISPR/Cas9-based knockout screening was conducted to identify key genes that enable cancer cells to evade CD19 CAR-T-cell-mediated killing. The in vitro cytotoxicity assays and evaluation of tumor tissue and bone marrow specimens were further conducted to confirm the role of the key genes in cancer cell susceptibility to CAR-T cells. In addition, the specific mechanisms influencing CAR-T cell-mediated cancer clearance were elucidated in mouse and cellular models. RESULTS: The CRISPR/Cas9-based knockout screening showed that the enrichment of autophagy-related genes (ATG3, BECN1, and RB1CC1) provided protection of cancer cells from CD19 CAR-T cell-mediated cytotoxicity. These findings were further validated by in vitro cytotoxicity assays in cells with genetic and pharmacological inhibition of autophagy. Notably, higher expression of the three autophagy-related proteins in tumor samples was correlated with poorer responsiveness and worse survival in patients with relapsed/refractory B-cell lymphoma after CD19 CAR-T therapy. Bulk RNA sequencing analysis of bone marrow samples from B-cell leukemia patients also suggested the clinical relevance of autophagy to the therapeutic response and relapse after CD19 CAR-T cell therapy. Pharmacological inhibition of autophagy and knockout of RB1CC1 could dramatically sensitize tumor cells to CD19 CAR-T cell-mediated killing in mouse models of both B-cell leukemia and lymphoma. Moreover, our study revealed that cancer-intrinsic autophagy mediates evasion of CAR-T cells via the TNF-α-TNFR1 axis-mediated apoptosis and STAT1/IRF1-induced chemokine signaling activation. CONCLUSIONS: These findings confirm that autophagy signaling in B-cell malignancies is essential for the effective cytotoxic function of CAR-T cells and thereby pave the way for the development of autophagy-targeting strategies to improve the clinical efficacy of CAR-T cell immunotherapy.

Comparison of oral aprepitant and intravenous fosaprepitant for prevention of chemotherapy-induced nausea and vomiting in pediatric oncology patients: a randomized phase III trial.

Background: Neurokinin-1 receptor antagonists have improved the management of chemotherapy-induced nausea and vomiting (CINV), but to date there has been no prospective comparison between oral aprepitant and intravenous fosaprepitant in pediatric oncology patients. Methods: Our study was a double-parallel study, and the distribution ratio was 1:1. Children aged 2-12 years who were undergoing moderate or highly emetogenic chemotherapy (MEC or HEC) were randomly assigned to receive ondansetron and dexamethasone combined with either a single dose of intravenous fosaprepitant (arm A), or 3 days of oral aprepitant (arm B). The primary outcome measure was the rate of complete response (CR) of CINV within the acute phase, defined as from the start through 24 hours after the last chemotherapy dose. Response during the delayed phase, overall response, and use of rescue antiemetics were also assessed. Results: We prospectively evaluated 108 eligible patients, including 55 receiving fosaprepitant. Study observations were made during a single cycle for each patient. The occurrence of CR in the acute phase was statistically higher for patients receiving fosaprepitant (95% vs. 79%, P=0.018<0.05). Modest differences were seen in CR rates during the delayed phase (71% vs. 66%, P=0.586), and overall response rate (69% vs. 57%, P=0.179). The use of antiemetic rescue medicines was similar between arms A (11%) and B (7%). Conclusions: Fosaprepitant produced more CRs of CINV in the acute phase than did aprepitant, although there were no statistical differences in delayed phase response, overall response, or use of rescue antiemetics. This study confirms the safety, efficacy, and potential advantages of fosaprepitant in reducing CINV in pediatric oncology patients. Trial Registration: ClinicalTrials.gov identifier: NCT04873284.

A nanoluciferase SFTSV for rapid screening antivirals and real-time visualization of virus infection in mice.

BACKGROUND: Severe fever with thrombocytopenia syndrome virus (SFTSV) is an emerging tick-borne pathogen that causes severe hemorrhagic fever in humans, but no FDA-approved specific antivirals or vaccines are available to treat or prevent SFTS. METHODS: The plasmids construction and transfection were performed to generate the recombinant SFTSV harboring the nanoluciferase gene (SFTSV-Nluc). Immunostaining plaque assay was performed to measure viral titers, and DNA electrophoresis and Sanger sequencing were performed to evaluate the genetic stability. Luciferase assay and quantitative RT-PCR were performed to evaluate the efficacy of antivirals in vitro. Bioluminescence imaging, titration of virus from excised organs, hematology, and histopathology and immunohistochemistry were performed to evaluate the efficacy of antivirals in vivo. FINDINGS: SFTSV-Nluc exhibited high genetic stability and replication kinetics similar to those of wild-type virus (SFTSVwt), then a rapid high-throughput screening system for identifying inhibitors to treat SFTS was developed, and a nucleoside analog, 4-FlU, was identified to effectively inhibit SFTSV in vitro. SFTSV-Nluc mimicked the replication characteristics and localization of SFTSVwt in counterpart model mice. Bioluminescence imaging of SFTSV-Nluc allowed real-time visualization and quantification of SFTSV replication in the mice. 4-FlU was demonstrated to inhibit the replication of SFTSV with more efficiency than T-705 and without obvious adverse effect in vivo. INTERPRETATION: The high-throughput screening system based on SFTSV-Nluc for use in vitro and in vivo revealed that a safe and effective antiviral nucleoside analog, 4-FlU, may be a basis for the strategic treatment of SFTSV and other bunyavirus infections, paving the way for the discovery of antivirals. FUNDING: This work was supported by grants from the National Key Research and Development Plan of China (2021YFC2300700 to L. Zhang, 2022YFC2303300 to L. Zhang), Strategic Priority Research Program of Chinese Academy of Sciences (XDB0490000 to L. Zhang), National Natural Science Foundation of China (31970165 to L. Zhang, U22A20379 to G. Xiao), the Science and Technology Commission of Shanghai Municipality (21S11903100 to Y. Xie), Hubei Natural Science Foundation for Distinguished Young Scholars (2022CFA099 to L. Zhang).

Association between lactate-to-albumin ratio and 28-days all-cause mortality in patients with sepsis-associated liver injury: a retrospective cohort study.

BACKGROUND: The mortality rate of sepsis-associated liver injury (SALI) is relatively high, but there is currently no authoritative prognostic criterion for the outcome of SALI. Meanwhile, lactate-to-albumin ratio (LAR) has been confirmed to be associated with mortality rates in conditions such as sepsis, heart failure, and respiratory failure. However, there is a scarcity of research reporting on the association between LAR and SALI. This study aimed to elucidate the association between LAR and the 28-day mortality rate of SALI. METHODS: In this retrospective cohort study, data were obtained from the Medical Information Mart for Intensive Care IV (v2.2). Adult patients with SALI were admitted to the intensive care unit in this study. The LAR level at admission was included, and the primary aim was to assess the relationship between the LAR and 28-day all-cause mortality. RESULTS: A total of 341 patients with SALI (SALI) were screened. They were divided into a survival group (241) and a non-survival group (100), and the 28-day mortality rate was 29.3%. Multivariable Cox regression analysis revealed that for every 1-unit increase in LAR, the 28-day mortality risk for SALI patients increased by 21%, with an HR of 1.21 (95% CI 1.11 ~ 1.31, p < 0.001). CONCLUSIONS: This study indicates that in patients with SALI, a higher LAR is associated with an increased risk of all-cause mortality within 28 days of admission. This suggests that LAR may serve as an independent risk factor for adverse outcomes in SALI patients.

Decreased Nrf2 protein level and low sperm quality in intractable spermatocystitis.

ABSTRACT: To investigate the molecular etiology of low sperm quality in patients with intractable spermatocystitis, spermatozoa samples from patients with persistent hematospermia undergoing transurethral seminal vesiculoscopy and healthy volunteers were utilized. Spermatozoa samples were collected from the seminal vesicles through transurethral seminal vesiculoscopy or by masturbation ejaculation. Sperm quality was analyzed by a WLJY-9000 color semen analysis system. Measurement of tumor necrosis factor alpha (TNFα) and interleukin-6 (IL-6) in the seminal plasma was performed using enzyme-linked immunosorbent assay (ELISA). Measurement of H2O2 in the seminal plasma was performed with a hydrogen peroxide kit. The protein levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and phosphorylated-Nrf2 (p-Nrf2) were measured by western blot analysis and immunofluorescence assays. Low sperm quality parameters and increased levels of inflammatory cytokines (TNFα, IL-6, and H2O2) in the seminal plasma were detected among the semen samples from the patients with persistent hematospermia. Nrf2 and p-Nrf2 were strongly expressed in the nucleus and periphery of human sperm cells, according to the results of the immunofluorescence assays. The protein levels of Nrf2 and p-Nrf2 were significantly lower in the spermatozoa samples from patients with persistent hematospermia than in those from healthy volunteers with normal sperm motility. The results suggested that Nrf2 signaling might play a role in the low sperm quality of patients with intractable spermatocystitis.

Effect of the tyrosine kinase inhibitors on the growth in children with Philadelphia chromosome-positive acute lymphoblastic leukemia: a case-control study.

Background: First-generation ABL-targeted tyrosine kinase inhibitor (TKI) imatinib is known to retard growth in children but it is not known if the second-generation ABL-targeted TKI dasatinib has the same effect. We aimed to determine the impact of the first- or second-generation TKI on the growth of children treated for Philadelphia chromosome-positive (Ph+) childhood acute lymphoblastic leukemia (ALL). Methods: We evaluated the longitudinal growth changes in 140 children with Ph+ ALL treated with imatinib or dasatinib in additional to intensive cytotoxic chemotherapy and 280 matched controls treated with the same intensity of cytotoxic chemotherapy without TKI on Chinese Children's Cancer Group ALL-2015 protocol between 2015 and 2019. We retrospectively reviewed the height data obtained during routine clinic visits at 4 time points: at diagnosis, the end of therapy, 1 year and 2 years off therapy. Height z Scores were derived with the aid of WHO Anthro version 3.2.2 and WHO AnthroPlus version 1.0.4, global growth monitoring tool. Findings: This study consisted only patients who have completed all treatment in continuous complete remission without major events, including 33 patients randomized to receive imatinib, 43 randomized to receive dasatinib, and 64 assigned to receive dasatinib. Similar degree of loss of height z scores from diagnosis to the end of therapy was observed for the 33 imatinib- and the 107 dasatinib-treated patients (median △ = -0.84 vs. -0.88, P = 0.41). Adjusting for height z score at diagnosis, puberty status, and sex, there was no significant difference in the longitudinal mean height z scores between patients treated with imatinib and those with dasatinib (0.08, 95% CI, -0.22 to 0.38, P = 0.60). The degree of loss of height z scores from diagnosis to end of therapy was significantly greater in the 140 TKI-treated patients than the 280 controls (median △ = -0.88 vs. -0.18, P < 0.001). The longitudinal mean height z scores in the TKI-treated patients were significantly lower than those of the controls (-0.84, 95% CI, -0.98 to -0.69; P < 0.001). Interpretation: These data suggest that dasatinib and imatinib have the similar adverse impact on the growth of children with Ph+ ALL. Funding: This study was supported by the National Natural Science Foundation of China (grant 81670136 [JCai and JT]), the fourth round of Three-Year Public Health Action Plan (2015-2017; GWIV-25 [SS]), Shanghai Health Commission Clinical Research Project (202140161 [JCai]), the US National Cancer institute (CA21765 [C-H Pui]), and the American Lebanese Syrian Associated Charities (CC, JJY, and C-HP). The content of this paper is solely the responsibility of the authors and does not necessarily represent the official views of the US National Institutes of Health.