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Background: Ewing's sarcoma (EwS), a common pediatric bone cancer, is associated with poor survival due to a lack of therapeutic targets for immunotherapy or targeted therapy. Therefore, more effective treatment options are urgently needed. Methods: Since novel immunotherapies may address this need, we performed an integrative analysis involving single-cell RNA sequencing, cell function experiments, and humanized models to dissect the immunoregulatory interactions in EwS and identify strategies for optimizing immunotherapeutic efficacy. Results: EwS is infiltrated by immunosuppressive myeloid populations, T and B lymphocytes, and natural killer cells. We found that SLC40A1 and C1QA macrophages were associated with a poor prognosis, whereas CD8+ T-cell infiltration was associated with a good prognosis. A comparative analysis of paired samples revealed that in tumors with a good chemotherapeutic response, macrophages presented increased antigen presentation and reduced release of protumor cytokines, whereas CD8+ T cells presented increased cytotoxicity and reduced exhaustion. An interaction analysis revealed a vast immunoregulatory network and identified MIF-CD74 as a crucial immunoregulatory target that can simultaneously promote M2 polarization of macrophages and inhibit CD8+ T-cell infiltration. Importantly, MIF blockade effectively reshaped the tumor immune microenvironment, turning cold tumors hot and inhibiting tumor growth. Conclusions: Our integrative analysis revealed that the MIF/CD74 axis is a promising target for the treatment of Ewing sarcoma and provides a rationale for this novel immunotherapy. [ABSTRACT FROM AUTHOR]

Complete removal of all tumor tissue with a wide surgical margin is essential for the treatment of osteosarcoma (OS). However, it's difficult, sometimes impossible, to achieve due to the invisible small satellite lesions and blurry tumor boundaries. Besides, intraoperative frozen‐section analysis of resection margins of OS is often restricted by the hard tissues around OS, which makes it impossible to know whether a negative margin is achieved. Any unresected small tumor residuals will lead to local recurrence and worse prognosis. Herein, based on the high expression of B7H3 in OS, a targeted probe B7H3‐IRDye800CW is synthesized by conjugating anti‐B7H3 antibody and IRDye800CW. B7H3‐IRDye800CW can accurately label OS areas after intravenous administration, thereby helping surgeons identify and resect residual OS lesions (<2 mm) and lung metastatic lesions. The tumor‐background ratio reaches 4.42 ± 1.77 at day 3. After incubating fresh human OS specimen with B7H3‐IRDye800CW, it can specifically label the OS area and even the microinvasion area (confirmed by hematoxylin‐eosin [HE] staining). The probe labeled area is consistent with the tumor area shown by magnetic resonance imaging and complete HE staining of the specimen. In summary, B7H3‐IRDye800CW has translational potential in intraoperative resection guidance and rapid pathological diagnosis of OS. [ABSTRACT FROM AUTHOR]

Phototropism movement is crucial for plants to adapt to various environmental changes. Plant P‐type H+‐ATPase (HA) plays diverse roles in signal transduction during cell expansion, regulation of cellular osmotic potential and stomatal opening, and circadian movement. Despite numerous studies on the genome‐wide analysis of Vitis vinifera, no research has been done on the P‐type H+‐ATPase family genes, especially concerning pulvinus‐driven leaf movement. In this study, 55 VvHAs were identified and classified into nine distinct subgroups (1 to 9). Gene members within the same subgroups exhibit similar features in motif, intron/exon, and protein tertiary structures. Furthermore, four pairs of genes were derived by segmental duplication in grapes. Cis‐acting element analysis identified numerous light/circadian‐related elements in the promoters of VvHAs. qRT‐PCR analysis showed that several genes of subgroup 7 were highly expressed in leaves and pulvinus during leaf movement, especially VvHA14, VvHA15, VvHA16, VvHA19, VvHA51, VvHA52, and VvHA54. Additionally, we also found that the VvHAs genes were asymmetrically expressed on both sides of the extensor and flexor cell of the motor organ, the pulvinus. The expression of VvHAs family genes in extensor cells was significantly higher than that in flexor cells. Overall, this study serves as a foundation for further investigations into the functions of VvHAs and contributes to the complex mechanisms underlying grapevine pulvinus growth and development. [ABSTRACT FROM AUTHOR]

Down syndrome (DS), or trisomy 21, is one of the critical risk factors for early-onset Alzheimer's disease (AD), implicating key roles for chromosome 21-encoded genes in the pathogenesis of AD. We previously identified a role for the deubiquitinase USP25, encoded on chromosome 21, in regulating microglial homeostasis in the AD brain; however, whether USP25 affects amyloid pathology remains unknown. Here, by crossing 5*FAD AD and Dp16 DS mice, we observed that trisomy 21 exacerbated amyloid pathology in the 5*FAD brain. Moreover, bacterial artificial chromosome (BAC) transgene-mediated USP25 overexpression increased amyloid deposition in the 5*FAD mouse brain, whereas genetic deletion of Usp25 reduced amyloid deposition. Furthermore, our results demonstrate that USP25 promoted p cleavage of APP and Ap generation by reducing the ubiquitination and lysosomal degradation of both APP and BACE1. Importantly, pharmacological inhibition of USP25 ameliorated amyloid pathology in the 5*FAD mouse brain. In summary, we identified the DS-related gene USP25 as a critical regulator of AD pathology, and our data suggest that USP25 serves as a potential pharmacological target for AD drug development., Introduction Down syndrome (DS), the most common form of intellectual disability, arises from total or partial triplication of chromosome 21. As one of the critical risk factors for early-onset Alzheimer's [...]

Negative pressure wound therapy (NPWT) is a popular treatment to heal infected wounds. This meta‐analysis aimed to determine if NPWT was more effective than conventional wound dressings for surgical site infections (SSI) in varied orthopaedic surgeries. Literature was retrieved from seven electronic databases (Medline, Web of Science, PubMed, Embase, Google Scholar, Cochrane Library, and CNKI). Randomised control trials (RCT) and retrospective cohort studies (RS) involving arthroplasty, fracture, and spinal surgery were extracted. SSI was our primary outcome, while total complications and length of hospital stay were secondary outcomes. We carried out the risk of bias assessment and meta‐analysis using the Cochrane Risk of Bias 2.0 tool and Stata 17.0. Among the 798 studies retrieved, 18 of them met our inclusion criteria. We identified 13 RCTs and 5 RSs. The results of meta‐analysis showed that the incidence of SSI in the NPWT group was significantly lower relative to the control group (OR = 0.60, 95% CI 0.47 to 0.77, P < 0.001). Subgroup analyses revealed that the incidences of SSI involving arthroplasty, fracture, and spinal surgery in the NPWT group accounted for 46%, 69%, and 37% relative to the control group, respectively. The incidence of SSI in RS (OR = 0.27, 95% CI 0.13 to 0.56) was significantly lower than that in RCT (OR = 0.69, 95% CI 0.54 to 0.90) (P = 0.02). Moreover, patients in the NPWT group had a lower total complication rate (OR = 0.51, 95% CI 0.34 to 0.76) and shorter hospital stays (SMD = −0.42, 95% CI −0.83 to −0.02), although high heterogeneity existed. NPWT may be an efficient alternative to help prevent the incidence of SSI and total complications as well as achieved shorten hospital stay in varied orthopaedic surgeries. The rational use of NPWT should be based on the presence of patients' clinical conditions and relevant risk factors. [ABSTRACT FROM AUTHOR]