Transcriptomic and metabolomic analysis of poplar response to feeding by Hyphantria cunea.

Populus cathayana × canadansis 'Xinlin 1' ('P.'xin lin 1') with the characteristics of rapid growth and high yield, is frequently attacked by herbivorous insects. However, little is known about how it defenses against Hyphantria cunea (H. cunea) at molecular and biochemical levels. Differences in the transcriptome and metabolome were analyzed after 'P. 'xin lin 1' leaves were fed to H. cunea for 0h, 2h, 4h, 8h, 16h and 24h. In the five comparison groups including 2h vs. CK, 4h vs. CK, 8h vs. CK, 16h vs. CK, and 24h vs. CK, a total of 8925 genes and 842 metabolites were differentially expressed. A total of 825 transcription factors (TFs) were identified, which encoded 56 TF families. The results showed that the top four families with the highest number of TFs were AP2/ERF, MYB, C2C2, bHLH. Analyses of leaves which were fed to H. cunea showed that the differentially expressed genes (DEGs) and differentially accumulated metabolites (DAMs) were significantly enriched in plant hormone signal transduction pathway, MAPK signaling pathway, flavonoid, flavone and flavonol and anthocyanin biosynthesis pathway. Additionally, there were a number of genes significantly up-regulated in MAPK signaling pathway. Some compounds involved in plant hormone signal transduction and flavonoid/flavone and flavonol/ anthocyanin pathways such as jasmonic acid (JA), jasmonoyl-L-Isoleucine (JA-Ile), kaempferol and cyanidin-3-O-glucoside were induced in infested 'P.'xin lin 1'. This study provides a new understanding for exploring the dynamic response mechanism of poplar to the infestation of H. cunea.

Risk Factors for Progression of Vitreomacular Traction to Macular Hole.

Purpose: To evaluate the clinical and optical coherence tomography (OCT) characteristics associated with progression of vitreomacular traction (VMT) to a full-thickness macular hole (FTMH) and lamellar macular hole (LMH). Methods: A retrospective cohort study of patients with an OCT-confirmed diagnosis of idiopathic VMT and 6 or more months of follow-up was performed. Clinical data included age, sex, race, systemic comorbidities, hormone replacement therapy, corrected visual acuity (VA), subjective visual symptoms, OCT signs, and the presence of or progression to FTMH or LMH. Results: Of the 287 eyes with VMT, 48 (16.7%) progressed to MH. Twelve eyes (4.2%) progressed to LMH, and 36 eyes (12.5%) progressed to FTMH. Female sex (P = .02), myopic refractive status in phakic eyes (P = .02), subjective decreased VA (P = .01), and the presence of an inner segment-outer segment junction disruption on OCT (P = .003) were risk factors for progression from VMT to FTMH. Subjective metamorphopsia was a risk factor for progression to FTMH (P = .001) and LMH (P = .01). In a subgroup analysis, patients who had an FTMH in the fellow eye were significantly more likely to have VMT progress to FTMH in the study eye (24.0% vs 8.7%; P = .04). Having an LMH in the fellow eye was not a risk factor for progression to LMH in the study eye (P = .47). Conclusions: Risk factors were found for the progression of VMT to MH that may be clinically relevant for risk-stratifying patients presenting with VMT.

Confined Gelation Synthesis of Flexible Barium Aluminate Nanofibers as a High-Performance Refractory Material.

Barium aluminate (BAO) ceramics are highly sought after as a kind of high-temperature refractory material due to their exceptional thermal stability in both vacuum and oxygen atmospheres, but their inherent brittleness results in rapid hardening, imposing a negative impact on the overall construction performance. Here, we report a strategy to synthesize flexible BAO nanofibers with a needle-like structure through confined-gelation electrospinning followed by in situ mineralization. The confined gelation among the colloidal particles promotes the formation of precursor nanofibers with high continuity and a large aspect ratio. The resulting flexible BAO nanofiber membranes are bendable, stretchable, and can even be woven, exhibiting a softness (12 mN) that is lower than that of tissue paper (27 mN). Additionally, they are capable of withstanding hundreds to thousands of continuous buckling and bending at 50% deformation without tearing. More importantly, the low emissivity of the flexible BAO nanofiber membranes ensures excellent thermal insulation at 1300 °C while preserving structural integrity and performance stability. In this sense, our strategy can be easily scaled up to produce flexible yet tough oxide ceramic membranes for a wider range of applications.

Cardiovascular adverse events associated with targeted therapies for multiple myeloma: a pharmacovigilance study.

Introduction: Multiple myeloma (MM) is a leading cause of hematopoietic cancer-related mortality, accounting for 20% of deaths. MM-targeted therapies have demonstrated efficacy, and since 2015, the United States Food and Drug Administration (FDA) has approved five targeted drugs. However, their cardiovascular safety has not been comprehensively evaluated. Objective: This study aimed to investigate the association between MM-targeted therapy and cardiovascular adverse events (AEs). Methods: Disproportionality analysis was conducted on reports from the FDA AE Reporting System database from 2014 to the second quarter of 2023. Cardiovascular AEs were grouped into nine narrow categories using the Standardized Medical Dictionary for Regulatory Activities Queries (SMQs). Results: A total of 3,228 cardiovascular AE cases involving MM-targeted therapy were extracted and analyzed. Significant disproportionality was identified for daratumumab, elotuzumab, and isatuximab. Among the nine narrow SMQ categories, the three most reported cardiovascular AEs were cardiomyopathy, cardiac arrhythmias, and embolic and thrombotic events. Noninfectious myocarditis/pericarditis, cardiac arrhythmias, and embolic and thrombotic events exhibited the strongest signal strengths. The cardiovascular AE risk was higher within the first month and gradually decreased thereafter; however, it increased rapidly again after 1 year. This trend was observed for all cardiovascular AEs. The Kaplan-Meier curve and the log-rank test revealed that isatuximab and elotuzumab exhibited a significantly lower probability of cardiovascular AEs than daratumumab (p < 0.001). Conclusions: MM-targeted therapy is significantly associated with an increased risk of previously unknown cardiovascular AE profiles, with the range and onset differing among various drugs, thereby warranting specific monitoring and appropriate management.

BCL-XL-targeting antibody-drug conjugates are active in preclinical models and mitigate on-mechanism toxicity of small-molecule inhibitors.

Overexpression of the antiapoptotic protein B-cell lymphoma-extra large (BCL-XL) is associated with drug resistance and disease progression in numerous cancers. The compelling nature of this protein as a therapeutic target prompted efforts to develop selective small-molecule BCL-XL inhibitors. Although efficacious in preclinical models, we report herein that selective BCL-XL inhibitors cause severe mechanism-based cardiovascular toxicity in higher preclinical species. To overcome this liability, antibody-drug conjugates were constructed using altered BCL-XL-targeting warheads, unique linker technologies, and therapeutic antibodies. The epidermal growth factor receptor-targeting antibody-drug conjugate AM1-15 inhibited growth of tumor xenografts and did not cause cardiovascular toxicity nor dose-limiting thrombocytopenia in monkeys. While an unprecedented BCL-XL-mediated toxicity was uncovered in monkey kidneys upon repeat dosing of AM1-15, this toxicity was mitigated via further drug-linker modification to afford AM1-AAA (AM1-25). The AAA drug-linker has since been incorporated into mirzotamab clezutoclax, the first selective BCL-XL-targeting agent to enter human clinical trials.

Asymptomatic thrombocytopenia after nintedanib initiation in a patient with progressive pulmonary fibrosis: a case report and review of literature.

BACKGROUND: Nintedanib is a primary antifibrosing medication available for idiopathic pulmonary fibrosis, systemic sclerosis-interstitial lung disease, and progressive pulmonary fibrosis, with scattered report of drug-induced thrombocytopenia. CASE REPORT: A 60-year-old Asian male with no history of thrombocytopenia was administered with nintedanib to treat progressive pulmonary fibrosis. The platelet count dropped rapidly after introduction of nintedanib and resolved gradually by withdrawal of the medication along with thrombopoietin receptor agonist. CONCLUSION: Based on experience from the limited reports, nintedanib-induced thrombocytopenia is typically reversible and manageable. Close monitoring of platelet counts in patients receiving this medication should be warranted.

Impact of exercise type, duration, and intensity on depressive symptoms in older adults: a systematic review and meta-analysis.

Objective: This systematic review and meta-analysis assessed the effects of three types of physical exercise (resistance exercise, aerobic exercise, and group exercise), different exercise intervention times (3 months, 6 months), and different exercise intensities (low, moderate, and high) on the improvement of depressive symptoms in older adults aged ≥60 years, as well as to explore the impact of the sustainability of these physical exercise intervention programs on depressive symptoms in older adults. Methods: The randomized controlled trials (RCTs) on the effect of physical exercise on depressive symptoms in older adults were retrieved from Cochrane Library, Web of Science, PubMed, and Embase Data. The retrieval time limit is from establishing the database to January 7, 2024. We conducted a meta-analysis using a 95% confidence interval (95% CI) and the standardized mean differences (SMD). The I2 statistic was used to assess the heterogeneity of the outcomes of the studies. When I 2 < 50%, we used the fixed-effects model, and when I 2 > 50%, we used the random-effects model. Subgroup and sensitivity analyses investigated heterogeneity origins. Results: There are 15 articles reported 20 studies, with a total of 1,346 patients, including 689 in the control group and 657 in the experimental group. The findings demonstrated a notable improvement in depression symptoms among older persons as an immediate result of engaging in physical exercise [SMD = -0.82, 95% CI (-1.19, -0.45)]. The subgroup analysis showed that moderate-intensity physical exercise [SMD = -0.25, 95% CI (-0.47, -0.03)], high-intensity physical exercise [SMD = -0.94, 95% CI (-1.37, -0.51)], resistance exercise [SMD = -0.70, 95% CI (-1.20, -0.20)], and group exercise [SMD = -0.97, 95% CI (-1.89, -0.05)], and the exercise intervention time was 3 months [SMD = -0.81, 95% CI (-1.38, -0.23)] or 6 months [SMD = -0.93, 95% CI (-1.46, -0.41)] were more effective in improving depressive symptoms in older adults. Conclusion: The sustainable resistance and group exercise have a better effect on improving depressive symptoms in older adults. Appropriate exercise intervention time can also ensure the sustainable improvement effect of exercise. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/record_email.php, identifier CRD42023405525.

Identification of an Endogenous Strong Promoter in Burkholderia sp. JP2-270.

Burkholderia is the second largest source of natural product bacteria after Actinomyces and can produce many secondary metabolites including pyrrolnitrin (PRN). Natural products of microbial origin are usually found in trace amounts, so in metabolic engineering, promoter engineering is often used to regulate gene expression to increase yield. In this study, an endogenous strong promoter was identified based on RNA-seq to overexpress biosynthetic genes to increase the production of PRN. By analyzing the transcriptomic data of the antagonistic bacterium Burkholderia sp. JP2-270 in three different development periods, we screened 50 endogenous promoters with high transcriptional activity, nine of which were verified by an obvious fluorescent signal via fluorescence observation. Then, combined with RT-qPCR analysis, Php, the promoter of a hypothetical protein, was found to be significantly expressed in all three periods. In order to increase the suitability of endogenous promoters, the promoter Php was shortened at different lengths, and the results show that a sequence length of 173 bp was necessary for its activity. Moreover, this promoter was used to overexpress the PRN biosynthesis genes (prnA, prnB, prnC and prnD) in JP2-270, resulting in a successful increase in gene expression levels by 40-80 times. Only the overexpression of the prnB gene successfully increased PRN production to 1.46 times that of the wild type. Overall, the endogenous strong promoters screened in this study can improve gene expression and increase the production of secondary metabolites in JP2-270 and other strains.

Effects of body weight support training on balance and walking function in stroke patients: a systematic review and meta-analysis.

Objective: To comprehensively and quantitatively evaluate the impact of body weight support training (BWST) on balance and gait function in stroke patients based on an evidence-based basis and to identify the most effective intervention strategies. Methods: PubMed, Web of Science, The Cochrane Library, CNKI, Wanfang, and Chinese SinoMed Database were searched until November 25, 2023. Quality assessment and meta-analysis were performed using RevMan 5.2 and Stata 14.0 software. Results: A total of 31 randomized controlled trials involving 1,918 patients were included in the study. The meta-analysis demonstrated that body weight support training (BWST) significantly improved Berg Balance Scale (BBS) scores (MD = 3.60; 95% CI: 1.23 to 5.98; p = 0.003), gait speed (SMD = 0.77; 95% CI: 0.38 to 1.15; p < 0.0001), and step length (SMD = 0.46; 95% CI: 0.19 to 0.72; p = 0.0008) in stroke patients compared to conventional rehabilitation. For enhancing balance function, the most effective interventions were identified as a disease duration of 3-6 months (MD = 5.16; 95% CI: 0.76 to 9.57; p = 0.02), intervention time of 4-8 weeks (MD = 5.70; 95% CI: 2.90 to 8.50; p < 0.0001), a maximum body weight support level above 30% (MD = 3.80; 95% CI: 1.48 to 6.13; p = 0.001), and a maximum training walking speed of 0.2 m/s or more (MD = 4.66; 95% CI: 0.37 to 9.70; p = 0.03). For improving walking function, the optimal interventions were also a disease duration of 3-6 months (gait speed: SMD = 0.59; 95% CI: 0.15 to 1.03; p = 0.008; step length: SMD = 0.27; 95% CI: 0.06 to 0.56; p = 0.04), intervention time of 4-8 weeks (gait speed: SMD = 1.01; 95% CI: 0.44 to 1.59; p = 0.0006; step length: SMD = 0.83; 95% CI: 0.54 to 1.12; p < 0.00001), a maximum body weight support level above 30% (gait speed: SMD = 0.79; 95% CI: 0.36 to 1.22; p = 0.0003; step length: SMD = 0.79; 95% CI: 0.47 to 1.11; p < 0.00001), and a maximum training walking speed of 0.2 m/s or more (gait speed: SMD = 1.26; 95% CI: 0.62 to 1.90; p = 0.0001; step length: SMD = 0.85; 95% CI: 0.38 to 1.31; p = 0.0003). Conclusion: Compared with conventional rehabilitation training, BWST demonstrates superior efficacy in enhancing balance and walking function in stroke patients, with a consistent optimal intervention strategy. The most effective program includes a disease duration of 3-6 months, an intervention period of 4-8 weeks, a maximum body weight support of 30% or more, and a maximum training walking speed of 0.2 m/s or greater. Systematic review registration: http://www.crd.york.ac.uk/PROSPERO/, identifier: CRD42022358963.

Simultaneous detection of multiple urinary biomarkers in patients with early-stage diabetic kidney disease using Luminex liquid suspension chip technology.

Background: Several urinary biomarkers have good diagnostic value for diabetic kidney disease (DKD); however, the predictive value is limited with the use of single biomarkers. We investigated the clinical value of Luminex liquid suspension chip detection of several urinary biomarkers simultaneously. Methods: The study included 737 patients: 585 with diabetes mellitus (DM) and 152 with DKD. Propensity score matching (PSM) of demographic and medical characteristics identified a subset of 78 patients (DM = 39, DKD = 39). Two Luminex liquid suspension chips were used to detect 11 urinary biomarkers according to their molecular weight and concentration. The biomarkers, including cystatin C (CysC), nephrin, epidermal growth factor (EGF), kidney injury molecule-1 (KIM-1), retinol-binding protein4 (RBP4), α1-microglobulin (α1-MG), ß2-microglobulin (ß2-MG), vitamin D binding protein (VDBP), tissue inhibitor of metalloproteinases-1 (TIMP-1), tumor necrosis factor receptor-1 (TNFR-1), and tumor necrosis factor receptor-2 (TNFR-2) were compared in the DM and DKD groups. The diagnostic values of single biomarkers and various biomarker combinations for early diagnosis of DKD were assessed using receiver operating characteristic (ROC) curve analysis. Results: Urinary levels of VDBP, RBP4, and KIM-1 were markedly higher in the DKD group than in the DM group (p < 0.05), whereas the TIMP-1, TNFR-1, TNFR-2, α1-MG, ß2-MG, CysC, nephrin, and EGF levels were not significantly different between the groups. RBP4, KIM-1, TNFR-2, and VDBP reached p < 0.01 in univariate analysis and were entered into the final analysis. VDBP had the highest AUC (0.780, p < 0.01), followed by RBP4 (0.711, p < 0.01), KIM-1 (0.640, p = 0.044), and TNFR-2 (0.615, p = 0.081). However, a combination of these four urinary biomarkers had the highest AUC (0.812), with a sensitivity of 0.742 and a specificity of 0.760. Conclusions: The urinary levels of VDBP, RBP4, KIM-1, and TNFR-2 can be detected simultaneously using Luminex liquid suspension chip technology. The combination of these biomarkers, which reflect different mechanisms of kidney damage, had the highest diagnostic value for DKD. However, this finding should be explored further to understand the synergistic effects of these biomarkers.

A hypothalamus-lateral periaqueductal gray GABAergic neural projection facilitates arousal following sevoflurane anesthesia in mice.

BACKGROUND: The lateral hypothalamus (LHA) is an evolutionarily conserved structure that regulates basic functions of an organism, particularly wakefulness. To clarify the function of LHAGABA neurons and their projections on regulating general anesthesia is crucial for understanding the excitatory and inhibitory effects of anesthetics on the brain. The aim of the present study is to investigate whether LHAGABA neurons play either an inhibitory or a facilitatory role in sevoflurane-induced anesthetic arousal regulation. METHODS: We used fiber photometry and immunofluorescence staining to monitor changes in neuronal activity during sevoflurane anesthesia. Opto-/chemogenetic modulations were employed to study the effect of neurocircuit modulations during the anesthesia. Anterograde tracing was used to identify a GABAergic projection from the LHA to a periaqueductal gray (PAG) subregion. RESULTS: c-Fos staining showed that LHAGABA activity was inhibited by induction of sevoflurane anesthesia. Anterograde tracing revealed that LHAGABA neurons project to multiple arousal-associated brain areas, with the lateral periaqueductal gray (LPAG) being one of the dense projection areas. Optogenetic experiments showed that activation of LHAGABA neurons and their downstream target LPAG reduced the burst suppression ratio (BSR) during continuous sevoflurane anesthesia. Chemogenetic experiments showed that activation of LHAGABA and its projection to LPAG neurons prolonged the anesthetic induction time and promoted wakefulness. CONCLUSIONS: In summary, we show that an inhibitory projection from LHAGABA to LPAGGABA neurons promotes arousal from sevoflurane-induced loss of consciousness, suggesting a complex control of wakefulness through intimate interactions between long-range connections.

Development of a Modular miRNA-Responsive Biosensor for Organ-Specific Evaluation of Liver Injury.

MicroRNAs (miRNAs) are increasingly being considered essential diagnostic biomarkers and therapeutic targets for multiple diseases. In recent years, researchers have emphasized the need to develop probes that can harness extracellular miRNAs as input signals for disease diagnostics. In this study, we introduce a novel miRNA-responsive biosensor (miR-RBS) designed to achieve highly sensitive and specific detection of miRNAs, with a particular focus on targeted organ-specific visualization. The miR-RBS employs a Y-structured triple-stranded DNA probe (Y-TSDP) that exhibits a fluorescence-quenched state under normal physiological conditions. The probe switches to an activated state with fluorescence signals in the presence of high miRNA concentrations, enabling rapid and accurate disease reporting. Moreover, the miR-RBS probe had a modular design, with a fluorescence-labeled strand equipped with a functional module that facilitates specific binding to organs that express high levels of the target receptors. This allowed the customization of miRNA detection and cell targeting using aptameric anchors. In a drug-induced liver injury model, the results demonstrate that the miR-RBS probe effectively visualized miR-122 levels, suggesting it has good potential for disease diagnosis and organ-specific imaging. Together, this innovative biosensor provides a versatile tool for the early detection and monitoring of diseases through miRNA-based biomarkers.

Risk predictive model for the development of hepatocellular carcinoma before initiating long-term antiviral therapy in patients with chronic hepatitis B virus infection.

It is generally acknowledged that antiviral therapy can reduce the incidence of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), there remains a subset of patients with chronic HBV infection who develop HCC despite receiving antiviral treatment. This study aimed to develop a model capable of predicting the long-term occurrence of HCC in patients with chronic HBV infection before initiating antiviral therapy. A total of 1450 patients with chronic HBV infection, who received initial antiviral therapy between April 2006 and March 2023 and completed long-term follow-ups, were nonselectively enrolled in this study. Least absolute shrinkage and selection operator (LASSO) and Cox regression analysis was used to construct the model. The results were validated in an external cohort (n = 210) and compared with existing models. The median follow-up time for all patients was 60 months, with a maximum follow-up time of 144 months, during which, 32 cases of HCC occurred. The nomogram model for predicting HCC based on GGT, AFP, cirrhosis, gender, age, and hepatitis B e antibody (TARGET-HCC) was constructed, demonstrating a good predictive performance. In the derivation cohort, the C-index was 0.906 (95% CI = 0.869-0.944), and in the validation cohort, it was 0.780 (95% CI = 0.673-0.886). Compared with existing models, TARGET-HCC showed promising predictive performance. Additionally, the time-dependent feature importance curve indicated that gender consistently remained the most stable predictor for HCC throughout the initial decade of antiviral therapy. This simple predictive model based on noninvasive clinical features can assist clinicians in identifying high-risk patients with chronic HBV infection for HCC before the initiation of antiviral therapy.

Long-working-distance high-collection-efficiency three-photon microscopy for in vivo long-term imaging of zebrafish and organoids.

Zebrafish and organoids, crucial for complex biological studies, necessitate an imaging system with deep tissue penetration, sample protection from environmental interference, and ample operational space. Traditional three-photon microscopy is constrained by short-working-distance objectives and falls short. Our long-working-distance high-collection-efficiency three-photon microscopy (LH-3PM) addresses these challenges, achieving a 58% fluorescence collection efficiency at a 20 mm working distance. LH-3PM significantly outperforms existing three-photon systems equipped with the same long working distance objective, enhancing fluorescence collection and dramatically reducing phototoxicity and photobleaching. These improvements facilitate accurate capture of neuronal activity and an enhanced detection of activity spikes, which are vital for comprehensive, long-term imaging. LH-3PM's imaging of epileptic zebrafish not only showed sustained neuron activity over an hour but also highlighted increased neural synchronization and spike numbers, marking a notable shift in neural coding mechanisms. This breakthrough paves the way for new explorations of biological phenomena in small model organisms.

Deciphering the spatial organization of fibrotic microenvironment in silica particles-induced pulmonary fibrosis.

Silicosis represents a form of interstitial lung disease induced by the inhalation of silica particles in production environments. A key pathological characteristic of silica-induced pulmonary fibrosis is its localized tissue heterogeneity, which presents significant challenges in analyzing transcriptomic data due to the loss of important spatial context. To address this, we integrate spatial gene expression data with single-cell analyses and achieve a detailed mapping of cell types within and surrounding fibrotic regions, revealing significant shifts in cell populations in normal and diseased states. Additionally, we explore cell interactions within fibrotic zones using ligand-receptor mapping, deepening our understanding of cellular dynamics in these areas. We identify a subset of fibroblasts, termed Inmt fibroblasts, that play a suppressive role in the fibrotic microenvironment. Validating our findings through a comprehensive suite of bioinformatics, histological, and cell culture studies highlights the role of monocyte-derived macrophages in shifting Inmt fibroblast populations into profibrotic Grem1 fibroblast, potentially disrupting lung homeostasis in response to external challenges. Hence, the spatially detailed deconvolution offered by our research markedly advances the comprehension of cell dynamics and environmental interactions pivotal in the development of pulmonary fibrosis.

Recent research progress in tetrodotoxin detection and quantitative analysis methods.

Tetrodotoxin (TTX) is a highly potent and widely distributed ion-channel marine neurotoxin; it has no specific antidote and poses a great risk to human health. Therefore, detecting and quantifying TTX to effectively implement prevention strategies is important for food safety. The development of novel and highly sensitive, highly specific, rapid, and simple techniques for trace TTX detection has attracted widespread attention. This review summarizes the latest advances in the detection and quantitative analysis of TTX, covering detection methods based on biological and cellular sensors, immunoassays and immunosensors, aptamers, and liquid chromatography-mass spectrometry. It further discusses the advantages and applications of various detection technologies developed for TTX and focuses on the frontier areas and development directions of TTX detection, providing relevant information for further investigations.

PegIFN alpha-2a reduces relapse in HBeAg-negative patients after nucleo(s)tide analogue cessation: A randomized-controlled trial.

BACKGROUND & AIMS: Nucleo(s)tide analogue (NUC) cessation can lead to hepatitis B surface antigen (HBsAg) clearance but also a high rate of virological relapse. However, the effect of pegylated interferon alpha-2a (PegIFN-α-2a) on virological relapse after NUC cessation is unknown. Therefore, this study aimed to evaluate the effect of switching from NUC to PegIFN-α-2a treatment for 48 weeks on virological relapse up to week 96. METHODS: In this multicenter randomized-controlled clinical trial, 180 non-cirrhotic patients with HBeAg-negative chronic hepatitis B on continuous NUC therapy for ≥2.5 years, with HBV DNA levels <60 IU/ml, were randomized to discontinue NUC therapy (n = 90) or receive 48 weeks of PegIFN-α-2a treatment (n = 90). Patients were followed up for up to 96 weeks. The primary endpoint was the virological relapse rate up to week 96. RESULTS: Intention-to-treat analysis revealed patients in the interferon monotherapy group had significantly lower cumulative virological relapse rates than the NUC cessation group until week 96 (20.8% vs. 53.6%, p <0.0001). Consistently, a significantly lower proportion of patients in the interferon monotherapy group had virological relapse than those in the NUC cessation group at 48 weeks off treatment (17.8% vs. 36.7%, p = 0.007). The virological relapse rate positively correlated with HBsAg levels in the NUC cessation group. The interferon monotherapy group had a lower cumulative clinical relapse rate (7.8% vs. 20.9%, p = 0.008) and a higher HBsAg loss rate (21.5% vs. 9.0%, p = 0.03) than the NUC cessation group. CONCLUSIONS: Switching from NUC to PegIFN-α-2a treatment for 48 weeks significantly reduces virological relapse rates and leads to higher HBsAg loss rates than NUC treatment cessation alone in patients with HBeAg-negative chronic hepatitis B. IMPACT AND IMPLICATIONS: Nucleo(s)tide analogue (NUC) cessation can lead to HBsAg clearance but also a high rate of virological relapse, but an optimized scheme to reduce the virological relapse rate after NUC withdrawal is yet to be reported. This randomized-controlled trial investigated the effect of switching from NUC to PegIFN-α-2a treatment for 48 weeks on virological relapse up to week 96 in patients with HBeAg-negative chronic hepatitis B. The interferon monotherapy group had a significantly lower cumulative virological relapse rate (20.8% vs. 53.6%, p <0.0001) and higher HBsAg loss rate (21.5% vs. 9.0%, p = 0.03) than the NUC cessation group up to week 96. This provides an optimized strategy for NUC cessation in HBeAg-negative patients. TRIAL REGISTRATION NUMBER: NCT02594293.

A ß-1,3/1,6-glucan enhances anti-tumor effects of PD1 antibody by reprogramming tumor microenvironment.

Checkpoint blockades have emerged as a frontline approach in cancer management, designed to enhance the adaptive immune response against tumors. However, its clinical efficacy is limited to a narrow range of tumor types, which necessitates the exploration of novel strategies that target another main branch of the immune system. One such potential strategy is the therapeutic modulation of pattern recognition receptors (PRRs) pathways in innate immune cells, which have shown promise in tumor eradication. Previously, a ß-1,3/1,6-glucan with high purity from Durvillaea antarctica (BG136) was reported by our group to exhibit pan-antitumor effects. In the current study, we systemically studied the antitumor activity of BG136 in combination with anti-PD1 antibody in MC38 syngeneic tumor model in vivo. Integrated transcriptomic and metabolomic analyses suggested that BG136 enhanced the antitumor immunity of anti-PD1 antibody by reprogramming the tumor microenvironment to become more proinflammatory. In addition, an increase in innate and adaptive immune cell infiltration and activation, enhanced lipid metabolism, and a decrease in ascorbate and aldarate metabolism were also found. These findings provide mechanistic insights that support the potent antitumor efficacy of BG136 when combined with immune checkpoint inhibitor antibodies.

Exploring gut microbiota and metabolite alterations in patients with thyroid-associated ophthalmopathy using high-throughput sequencing and untargeted metabolomics.

Introduction: Thyroid-associated ophthalmopathy (TAO) is an autoimmune-driven orbital inflammatory disease. Despite research efforts, its exact pathogenesis remains unclear. This study aimed to characterize the intestinal flora and metabolic changes in patients with TAO to identify the flora and metabolites associated with disease development. Methods: Thirty patients with TAO and 29 healthy controls were included in the study. The intestinal flora and metabolites were analyzed using high-throughput sequencing of the 16S rRNA gene and non-targeted metabolomics technology, respectively. Fresh fecal samples were collected from both populations for analysis. Results: Reduced gut richness and diversity were observed in patients with TAO. Compared to healthy controls, significant differences in relative abundance were observed in patients with TAO at the order level Clostridiales, family level Staphylococcaceae, genus level Staphylococcus, Fournierella, Eubacterium siraeum, CAG-56, Ruminococcus gnavus, Intestinibacter, Actinomyces, and Erysipelotrichaceae UCG-003 (logFC>1 and P<0.05). Veillonella and Megamonas were closely associated with clinical symptoms in patients with TAO. Among the 184 significantly different metabolites, 63 were upregulated, and 121 were downregulated in patients with TAO compared to healthy controls. The biosynthesis of unsaturated fatty acids was the significantly enriched metabolic pathway. Correlation analysis revealed Actinomyces was positively correlated with NAGlySer 15:0/16:0, FAHFA 3:0/20:0, and Lignoceric Acid, while Ruminococcus gnavu was positively correlated with Cer 18:0;2O/16:0; (3OH) and ST 24:1;O4/18:2. Conclusion: Specific intestinal flora and metabolites are closely associated with TAO development. Further investigation into the functional associations between these flora and metabolites will enhance our understanding of TAO pathogenesis.

A single-cell and spatially resolved atlas of human osteosarcomas.

Osteosarcomas are intricate cellular ecosystems, where heterotypic interactions significantly influence disease progression and therapeutic outcomes. Despite their importance, a detailed understanding of their cellular composition and organizational structure remains elusive. In this study, we provide a comprehensive single-cell and spatially resolved transcriptomics analysis of human osteosarcomas. We construct a cellular meta-map to dissect spatial transcriptomic data, unveiling a detailed atlas of osteosarcoma compositional subgroups. We meticulously characterize the unique gene signatures and functional states of each subgroup and investigate the impact of chemotherapy on these cellular subpopulations. Additionally, our spatial transcriptomics analysis identifies a distinct spatial niche, located at the forefront of tumor necrotic zones, potentially associated with chemotherapy resistance. We also delve into the crosstalk between different cellular subgroups. This study furnishes a comprehensive transcriptional atlas of osteosarcoma's cellular architecture, enriching our comprehension of its complexity and laying the groundwork for more targeted therapeutic approaches.