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BackgroundOH2 is a genetically engineered oncolytic herpes simplex virus type 2 designed to selectively amplify in tumor cells and express granulocyte-macrophage colony-stimulating factor to enhance antitumor immune responses. We investigated the safety, tolerability and antitumor activity of OH2 as single agent or in combination with HX008, an anti-programmed cell death protein 1 antibody, in patients with advanced solid tumors.MethodsIn this multicenter, phase I/II trial, we enrolled patients with standard treatment-refractory advanced solid tumors who have injectable lesions. In phase I, patients received intratumoral injection of OH2 at escalating doses (106, 107 and 108CCID50/mL) as single agent or with fixed-dose HX008. The recommended doses were then expanded in phase II. Primary endpoints were safety and tolerability defined by the maximum-tolerated dose and dose-limiting toxicities (DLTs) in phase I, and antitumor activity assessed per Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) and immune-RECIST in phase II.ResultsBetween April 17, 2019 and September 22, 2020, 54 patients with metastatic cancers were enrolled. Forty patients were treated with single agent OH2, and 14 with OH2 plus HX008. No DLTs were reported with single agent OH2 in phase I. Four patients, having metastatic mismatch repair-proficient rectal cancer or metastatic esophageal cancer, achieved immune-partial response, with two from the single agent cohort and two from the combination cohort. The duration of response were 11.25+ and 14.03+ months for the two responders treated with single agent OH2, and 1.38+ and 2.56+ months for the two responders in the combination cohort. The most common treatment-related adverse event (TRAE) with single agent OH2 was fever (n=18, 45.0%). All TRAEs were of grade 1–2, except one case of grade 3 fever in the 108CCID50/mL group. No treatment-related serious AEs occurred. Single agent OH2 induced alterations in the tumor microenvironment, with clear increases in CD3+ and CD8+ cell density and programmed death-ligand 1 expression in the patients’ post-treatment biopsies relative to baseline.ConclusionsIntratumoral injection of OH2 was well-tolerated, and demonstrated durable antitumor activity in patients with metastatic esophageal and rectal cancer. Further clinical development of OH2 as single agent or with immune checkpoint inhibitors in selected tumor types is warranted.

BackgroundOH2 is an oncolytic virus derived from herpes simplex virus type 2. A phase Ia/Ib clinical trial in China was conducted in patients with unresected stage III–IV melanoma, the majority of whom had the acral type, to assess the safety and preliminary efficacy of OH2.MethodsThe trial enrolled patients with histologically confirmed unresectable stage III or advanced stage IV melanoma. In phase Ia, nine patients received OH2 single-dose treatment across three dose levels (106, 107, and 108 CCID50/mL, where CCID50 represents cell culture infectious dose 50%) while six patients underwent multidose therapy. Phase Ib expanded the proposed dose. Antitumor efficacy was evaluated using the Response Evaluation Criteria in Solid Tumors and immune-RECIST guidelines. NCT04386967 is the clinical trial identifier.ResultsAll 44 patients were enrolled. OH2 was well tolerated without serious adverse events (AEs) or deaths reported. No Grade 3 or higher treatment-related AEs occurred. In phase Ia, the 1-year survival rate was 92.9% (95% CI, 59.1% to 99.0%), with a median overall survival of 28.9 months (95% CI, 12.7 to not reached). In phase Ib, 10 patients achieved immune-partial response (iPR)/partial response (PR), yielding an objective response rate (ORR) of 37.0% (95% CI, 19.4% to 57.6%), with 6 patients still responding. The rate of the durable response (PR or complete response lasting at least 6 months) was at least 29.6% (8/27). Notably, 7 of 12 III–IVM1a patients who previously received programmed cell death protein-1 (PD-1) therapy achieved iPR/PR, with an ORR of 58.3% (95% CI, 27.7% to 84.8%) and a disease control rate of 75.0% (95% CI, 42.8% to 94.5%). Biomarker analysis indicated that elevated baseline neutrophil activation state correlated with poorer clinical outcomes. A phase III clinical trial is ongoing in China (NCT05868707).ConclusionsOH2 oncolytic virotherapy exhibited a favorable safety profile without dose-limiting toxicities (DLTs) and demonstrated durable antitumor efficacy in patients with melanoma, especially in those who had progressed on anti-PD-1 treatment.Trial registration numberClinicalTrials.gov identifier NCT04386967.

We propose a new deep neural network termed TRQ3DNet which combines convolutional neural network (CNN) and transformer for hyperspectral image (HSI) denoising. The network consists of two branches. One is built by 3D quasi-recurrent blocks, including convolution and quasi-recurrent pooling operation. Specifically, the 3D convolution can extract the spatial correlation within a band, and spectral correlation between different bands, while the quasi-recurrent pooling operation is able to exploit global correlation along the spectrum. The other branch is composed of a series of Uformer blocks. The Uformer block uses window-based multi-head self-attention (W-MSA) mechanism and the locally enhanced feed-forward network (LeFF) to exploit the global and local spatial features. To fuse the features extracted by the two branches, we develop a bidirectional integration bridge (BI bridge) for better preserving the image feature information. Experimental results on synthetic and real HSI data show the superiority of our proposed network. For example, in the case of Gaussian noise with sigma 70, the PSNR value of our method significantly increases about 0.8 compared with other state-of-the-art methods.

Hydrogen, ammonia, and methanol are typical carbon-neutral fuels. Combustion characteristics and pollutant formation problems can be significantly improved by their blending. In this paper, reactive molecular dynamics were used to investigate the pollutant formation characteristics of hydrogen/ammonia/methanol blended fuel combustion and to analyze the mechanisms of CO, CO2, and NOX formation at different temperatures and blending ratios. It was found that heating can significantly increase blending and combustion efficiency, leading to more active oxidizing groups and thus inhibiting N2 production. Blended combustion pollutant formation was affected by coupling effects. NH3 depressed the rate of CO production when CH4O was greater than 30%, but the amount of CO and CO2 was mainly determined by CH4O. This is because CH4O provides more OH, H, and carbon atoms for CO and CO2 to collide efficiently. CH4O facilitates the combustion of NH3 by simplifying the reaction pathway, making it easier to form NOX.

Abstract—Mesenchymal stem cells induce kidney transplant tolerance by increasing regulatory T (Treg) cells. Bone marrow mesenchymal stem cell exosomes (BMMSC-Ex) promote Treg cell differentiation. Long non-coding RNA differentiation antagonizing non-protein coding RNA (DANCR) is expressed in BMMSCs and can be encapsulated in exosomes. We aimed to explore the role of DANCR in BMMSC-Ex in immune tolerance after kidney transplantation and related mechanism. The isogenic/allograft kidney transplantation mouse model was established, and levels of serum creatinine (SCr) were determined. Hematoxylin–eosin staining was conducted to detect the inflammation, and immunohistochemistry was performed to detect the infiltration of CD4+ T cells. Levels of IFN-γ, IL-17, and IL-2 were examined by ELISA. Flow cytometry was conducted to determine Treg cells. In the allograft group, the inflammatory response was severe, CD4+ T cell infiltration, SCr levels, and plasma rejection-related factors were up-regulated, while injection of BMMSC-Ex reversed the results. BMMSC-Ex increased Treg cells in kidney transplantation mice. Interference with DANCR reversed the promoting effect of BMMSC-Ex on Treg cell differentiation. DANCR bound to SIRT1, promoted ubiquitination and accelerated its degradation. The injection of BMMSC-Ex (after interference with DANCR) promoted SIRT1 levels, inflammatory response, CD4+ T cell infiltration, SCr levels, and plasma rejection related factors’ expression, while Treg cells were decreased. LncRNA DANCR in BMMSC-Ex promoted Treg cell differentiation and induced immune tolerance of kidney transplantation by down-regulating SIRT1 expression in CD4+ T cells.

The ecological restoration of submerged plants is one of the most widely used technologies in the remediation of eutrophic water bodies. This technology mainly removes nitrogen, phosphorus, and other nutrients in water through the absorption effects of plant roots, stems, and leaves and the biotransformation of microorganisms attached to their surfaces. Root exudates can directly affect root-attached microorganisms and other aquatic organisms, thus significantly influencing water remediation by submerged plants. At present, there are few reviews on the root exudates of submerged plants and their effects on aquatic organisms. In this study, the composition, collection, and methods of detecting the root exudates of submerged plants are reviewed. Factors affecting the release of root exudates from submerged plants are analyzed, including abiotic (light, temperature, and nutritional status) and biotic factors (rhizosphere microorganisms). The positive or negative effects of root exudates on phytoplankton, zooplankton, and microorganisms are also discussed. The results show that plant species, growth stages, and environmental factors (light, temperature, and nutritional status) are crucial factors affecting root exudates. In addition, submerged plants can significantly influence phytoplankton, zooplankton, and microorganisms by releasing allelochemicals or other root exudates. Based on the results of this study, the influencing mechanisms of root exudates on ecological restoration processes by submerged plants are clarified. This review provides important guiding significance for applying submerged macrophytes in water restoration.

Transplant renal artery stenosis (TRAS) is a vascular complication after kidney transplantation associated with poor outcomes. This study aimed to analyze the efficacy and safety of low-dose aspirin for preventing TRAS. After kidney transplantation, patients were enrolled from January 2018 to December 2020 in Henan Provincial People's Hospital. A total of 351 enrolled recipients were randomized to an aspirin group with low-dose intake of aspirin in addition to standard treatment ( n = 178), or a control group with only standard treatment ( n = 173). The patients was initially diagnosed as TRAS (id-TRAS) by Doppler ultrasound, and confirmed cases were diagnosed by DSA (c-TRAS). In the aspirin and control groups, 15.7% (28/178) and 22.0% (38/173) of the recipients developed id-TRAS, respectively, with no statistical difference. However, for c-TRAS, the difference of incidence and cumulative incidence was statistically significant. The incidence of c-TRAS was lower in the aspirin group compared with the control group (2.8% [5/178] vs. 11.6% [20/173], P = 0.001). Kaplan-Meier estimates and Cox regression model identified the cumulative incidence and hazard ratio (HR) of TRAS over time in two groups, showing that recipients treated with aspirin had a significantly lower risk of c-TRAS than those who were not treated (log-rank P  = 0.001, HR = 0.23, 95% confidence interval [CI]: 0.09-0.62). The levels of platelet aggregation rate ( P  < 0.001), cholesterol ( P  = 0.028), and low-density lipoprotein cholesterol ( P  = 0.003) in the aspirin group were decreased compared with the control group in the third-month post-transplantation. For the incidence of adverse events, there was no statistical difference. Clinical application of low-dose aspirin after renal transplant could prevent the development of TRAS with no significant increase in adverse effects. Clinicaltrials.gov, NCT04260828.

Background/Aims Natural killer (NK) cell function is generally considered dampened in chronic hepatitis B virus (HBV) infection; however, the NK cell pool exhibits phenotypic and functional heterogeneity, and the antibody-mediated effect of NK cells remains less characterized. This study evaluated the dynamic changes in antibody-mediated NK cell responses and the involvement of distinct NK subsets across disease stages and during antiviral treatment. Methods A T-cell receptor-like antibody specific for the HBV core 18–27 peptide (cTCRL-Ab) was used to determine the antibody-mediated effect of NK cells, and an array of NK cell surface markers were analyzed in cross-sectional and longitudinal cohorts of patients with chronic HBV infection. Single-cell RNA sequencing (scRNA-seq) was performed to identify the heterogeneity of NK subsets. Results The cTCRL-Ab enabled the detection of NK cell cytolytic activity and IFNγ production. Notably, cTCRL-Ab-mediated NK cell responses were compromised in chronically HBV-infected patients, particularly in those receiving pegylated interferon-α (Peg-IFNα), which was associated with the downregulation of CD16 expression. Correspondingly, Peg-IFNα inhibited cTCRL-Ab-mediated NK cell function by reducing CD16 expression in vitro. scRNA-seq revealed that CD16 downregulation occurred mainly within a dysfunctional CD16hi NK subset exhibiting exhaustion properties. In contrast, an activated CD16hiNK subpopulation (CX3CR1⁺KLRC2–CD16hi) with high cytotoxicity was enriched in patients who experienced favorable treatment responses. Furthermore, the intrahepatic CX3CR1+KLRC2–CD16hi subset tended to exhibit functional restoration in HBsAg-loss individuals. Conclusions Our data contribute to the understanding of antibody-mediated responses of NK cells in chronic HBV infection, and highlight a previously unappreciated functional CX3CR1+KLRC2–CD16hiNK subset as a potential therapeutic target.

Objectives: There are significant differences in the composition of intestinal flora in renal transplant recipients before and after an operation, which has a great impact on the prognosis of renal transplantation. The purpose of this project is to study the effect of intestinal flora imbalance on renal transplantation.Methods: The animal model of renal transplantation was established after intestinal flora imbalance (mice pretreated with compound antibiotics), or the animal model of renal transplantation was established after being pretreated with single antibiotics. HE, PAS, and Masson staining was used to detecting the histopathological changes of transplanted renal. The expression of inflammatory factors and infiltration of inflammatory cells of renal tissue were respectively been detected by ELISA kit and flow cytometry.Results: Antibiotic pretreatment restored weight loss, and decreased serum creatinine level in mice after renal transplantation. The tissue staining, ELISA assay, and flow cytometry data showed that antibiotic pretreatment alleviated injury of the renal allograft, inhibited the inflammatory factors levels, and reduced inflammatory cell infiltration in mice after renal transplantation. Furthermore, single antibiotic, especially ampicillin pretreatment can also play the same role as compound antibiotics, such as restoring weight loss, decreasing serum creatinine level, alleviating renal allograft injury, inhibiting inflammatory factors levels, and reducing inflammatory cell infiltration in mice after renal transplantation.Conclusions: Antibiotic ampicillin may inhibit inflammatory cell infiltration after renal transplantation by regulating the proportion of intestinal flora in mice, to reduce renal injury and play a role in renal protection.

Renal ischemia-reperfusion injury (IRI) frequently occurs following kidney transplantation, and exosomes derived from umbilical cord mesenchymal stem cells (WJ-MSC-Exos) have shown promise in treating IRI in transplanted kidneys. Our study delved into the potential mechanism of WJ-MSC-Exos in ameliorating IRI in transplanted kidneys, revealing that miR-19b is abundantly present in WJ-MSC-Exos. Both in vivo and in vitro experiments demonstrated that the absence of miR-19b abolished the protective effects of WJ-MSC-Exos against renal IRI. Mechanistically, miR-19b suppressed glycogen synthase kinase-3β (GSK3β) expression, thereby stabilizing PDXK protein through direct binding. Treatment with WJ-MSC-Exos led to reduced PDXK levels and enhanced pyridoxine accumulation, ultimately mitigating IRI in transplanted kidneys and I/R-induced HK2 cell apoptosis. These findings elucidate the underlying mechanism of WJ-MSC-Exos in alleviating IRI in transplanted kidneys, unveiling novel therapeutic targets for post-kidney transplantation IRI and providing a solid theoretical foundation for the clinical application of WJ-MSC-Exos in IRI treatment post-transplantation. Graphical Abstract