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Multidimensional solitary states (MDSS)—self-sustained wavepackets—have attracted renewed interest in many different fields of physics. They are of particular importance in nonlinear optics, especially for the nonlinear propagation of ultrashort pulses in multimode fibres, which contain rich spatiotemporal intermodal interactions and dynamics, albeit often in an unstable manner. Here, we report the observation of the formation of highly stable multidimensional solitary states in a molecular gas-filled large-core hollow-core fibre. We experimentally and numerically demonstrate the creation of MDSS by multimillijoule, subpicosecond near-infrared pulses and the underlying physics. We find that the MDSS have a broadband redshifted spectra with an uncommon negative quadratic spectral phase at the output of the hollow-core fibre, originating from Raman enhancement due to the strong intermodal nonlinear interactions. The spatial and temporal localization of MDSS enables the compression of the broadened pulses at the output to 10.8 fs by simple linear propagation in a piece of fused silica. The high spatiotemporal quality of MDSS is further verified by high-harmonic generation. Our results present new opportunities for studying multimodal spatiotemporal dynamics in the high-energy regime. This work also presents a route toward a new class of compact, tunable and high-energy spatiotemporally engineered coherent light sources based on picosecond ytterbium technology.The formation of multidimensional solitary states through the nonlinear propagation of high-energy pulses in a molecular gas-filled large-core hollow-core fibre is demonstrated, offering new opportunities for studying multimodal spatiotemporal dynamics in the high-energy regime.

In hepatocellular carcinoma (HCC), classical cancer stem cells (CSC) markers were shared by normal stem cells, targeting which may hinder hepatic regeneration and cause liver failure. Additionally, the spatial structure of CSC still remained elusive. To address these limitations, we undertook a comprehensive study combining single-cell data (56,022 cells from 20 samples) and spatial data (38,191 spots from eight samples) to obtain CSC signature and uncover its spatial structure. Utilizing the CytoTRACE algorithm, we discretely identified CSC, which displayed upregulated proliferation pathways regulated by HIF1A. A CSC signature of 107 genes was then developed using Weighted Gene Co-expression Network Analysis (WGCNA). Notably, HCC patients with high CSC levels exhibited an accumulation of SPP1+ macrophages (Macro_SPP1) expressing metalloproteinases (MMP9, MMP12, and MMP7) regulated by HIF1A, suggesting a hypoxic tumor region connecting Macro_SPP1 and CSC. Both CSC and Macro_SPP1 correlated with worse prognosis and undesirable immunotherapy response. Spatial analysis revealed the co-location of CSC and Macro_SPP1, with CD8 T cells excluded from the tumor region. The co-location area and non-tumor area of boundary exhibited a high level of hypoxia, with the HAVRC2 checkpoint highly expressed. Within the co-location area, the SPP1 signaling pathway was most active in cell-cell communication, with SPP1-CD44 and SPP1-ITGA/ITGB identified as the main ligand-receptor pairs. This study successfully constructed a CSC signature and demonstrated the co-location of CSC and Macro_SPP1 in a hypoxic region that exacerbates the tumor microenvironment in HCC.

Generating intense ultrashort pulses with high-quality spatial modes is crucial for ultrafast and strong-field science and can be achieved by nonlinear supercontinuum generation (SCG) and pulse compression. In this work, we propose that the generation of quasi-stationary solitons in periodic layered Kerr media can greatly enhance the nonlinear light-matter interaction and fundamentally improve the performance of SCG and pulse compression in condensed media. With both experimental and theoretical studies, we successfully identify these solitary modes and reveal their unified condition for stability. Space-time coupling is shown to strongly influence the stability of solitons, leading to variations in the spectral, spatial and temporal profiles of femtosecond pulses. Taking advantage of the unique characteristics of these solitary modes, we first demonstrate single-stage SCG and the compression of femtosecond pulses from 170 to 22 fs with an efficiency >85%. The high spatiotemporal quality of the compressed pulses is further confirmed by high-harmonic generation. We also provide evidence of efficient mode self-cleaning, which suggests rich spatiotemporal self-organization of the laser beams in a nonlinear resonator. This work offers a route towards highly efficient, simple, stable and highly flexible SCG and pulse compression solutions for state-of-the-art ytterbium laser technology.

BackgroundExisting biomarkers and models for predicting response to programmed cell death protein 1 monoclonal antibody in advanced squamous-cell non-small cell lung cancer (sqNSCLC) did not have enough accuracy. We used data from the ORIENT-3 study to construct artificial neural network (ANN) systems to predict the response to sintilimab for sqNSCLC.MethodsFour ANN systems based on bulk RNA data to predict disease control (DC), immune DC (iDC), objective response (OR) and immune OR (iOR) were constructed and tested for patients with sqNSCLC treated with sintilimab. The mechanism exploration on the bulk and the spatial level were performed in patients from the ORIENT-3 study and the real world, respectively.FindingssqNSCLC patients with different responses to sintilimab showed each unique transcriptomic spectrum. Four ANN systems showed high accuracy in the test cohort (AUC of DC, iDC, OR and iOR were 0.83, 0.89, 0.93 and 0.94, respectively). The performance of ANN systems was better than that of linear model systems and showed high stability. The mechanism exploration on the bulk level suggested that patients with lower ANN system scores (worse response) had a higher ratio of immune-related pathways enrichment. The mechanism exploration on the spatial level indicated that patients with better response to immunotherapy had fewer clusters of both tumor and cytotoxicity T cell spots.InterpretationThe four ANN systems showed high accuracy, robustness and stability in predicting the response to sintilimab for patients with sqNSCLC.

Inspired by natural organisms, biomimetic materials with exceptional biocompatibility, degradability, and multifunctionality have emerged as promising candidates for biomedical applications. Lignin, a plant-derived organic polymer, has gained attention due to its intrinsic antioxidant activity, adhesive properties, and biocompatibility. Despite its structural advantages, challenges in stability, biodegradability, and practical implementation hinder its utilization. Structural modifications through chemical/physical treatments or microbial/enzymatic can optimize lignin’s bioactivity, mechanical strength, and adhesion, enabling applications in drug delivery, Ultraviolet (UV) shielding, sensing, and wound healing. This review outlines lignin sources, modification principles, and adhesion of biomaterials mechanisms, while showcasing innovative lignin-based materials in biomedical contexts. We highlight their roles in therapeutic delivery systems, tissue engineering & regenerative medicine, and functional biomedical devices, emphasizing lignin’s low toxicity and environmental adaptability. By addressing current limitations in processing techniques and clinical translation, we discuss lignin’s potential to bridge laboratory research and practical medical solutions. The analysis concludes with an evaluation of lignin’s untapped value in sustainable biomedicine, proposing strategies to overcome scalability and standardization barriers. This synthesis provides critical insights for advancing lignin-based technologies toward clinical implementation while maintaining ecological sustainability.

Intra-tumor immune infiltration plays a pivotal role in the interaction with tumor cells in hepatocellular carcinoma (HCC). However, its phenotype and related spatial structure remained elusive. To address these limitations, we conducted a comprehensive study combining spatial data (38,191 spots from eight samples) and single-cell data (56,022 cells from 20 samples). Our analysis revealed two distinct infiltration patterns: immune exclusion and immune activation. Plasma cells emerged as the primary cell type within intra-tumor immune clusters. Notably, we observed the co-location of CCL19+ fibroblasts with plasma cells, which secrete chemokines and promote T-cell activation and leukocyte migration. Conversely, in immune-exclusion samples, this co-location was primarily observed in the adjacent normal area. This co-localization correlated with T cell infiltration and the formation of tertiary lymphoid structures, validated by multiplex immunofluorescence conducted on twenty HCC samples. Both CCL19+ fibroblasts and plasma cells were associated with favorable survival outcomes. In an immunotherapy cohort, HCC patients who responded favorably exhibited higher infiltration of CCL19+ fibroblasts and plasma cells. Additionally, we observed the accumulation of DKK1+ tumor cells within the tumor area in immune-exclusion samples, particularly at the tumor boundary, which inhibited the infiltration of CCL19+ fibroblasts and plasma cells into the tumor area. Furthermore, in immune-exclusion samples, the SPP1 signaling pathway demonstrated the highest activity in communication between tumor and immune clusters, and CCL19-CCR7 played a pivotal role in the self-communication of immune clusters. This study elucidates immune exclusion and immune activation patterns in HCC and identifies relevant factors contributing to immune resistance.

Spread through air spaces (STAS) is a recognized aggressive pattern in lung cancer, serving as a crucial risk factor for postoperative recurrence. However, its phenotype and related spatial structure have remained elusive. To address these limitations, we conducted a comprehensive study based on spatial data, analyzing over 30,000 spots from 14 non-STAS samples and one STAS sample. We observed increased proliferation activities and angiogenesis in STAS, identifying S100P as a potential biomarker for STAS. Furthermore, our investigation into the heterogeneity of STAS tumor cells revealed a subset identified as S100P + TFF1 +, exhibiting a negative impact on patients' survival in public datasets. This subtype exhibited the highest activities in the TGFb and hypoxia, suggesting its potential pro-tumor role within the tumor microenvironment. To assess the role of S100P + TFF1 + tumor cells in therapy response, we included data from two clinical trial cohorts (BPI-7711 for EGFR-TKI therapy and ORIENT-3 for immunotherapy). The presence of S100P + TFF1 + tumor cells correlated with worse responses to both EGFR-TKI therapy and immunotherapy. Notably, TFF1 emerged as a serum marker for predicting EGFR-TKI response. Cell–cell communication analysis revealed that the TGFb signaling pathway was the most activated in S100P + TFF1 + tumor cells, with TGFB2-TGFBR2 identified as the main ligand-receptor pair. This was further validated by multiplex immunofluorescence performed on twenty NSCLC samples. In summary, our study identified S100P as the biomarker for STAS and highlighted the adverse role of S100P + TFF1 + tumor cells in survival outcomes.

Background Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous malignancy characterized by varied responses to treatment and prognoses. Understanding the metabolic characteristics driving DLBCL progression is crucial for developing personalized therapies. Methods This study utilized multiple omics technologies including single-cell transcriptomics ( n  = 5), bulk transcriptomics ( n  = 966), spatial transcriptomics ( n  = 10), immunohistochemistry ( n  = 34), multiple immunofluorescence ( n  = 20) and to elucidate the metabolic features of highly malignant DLBCL cells and tumor-associated macrophages (TAMs), along with their associated tumor microenvironment. Metabolic pathway analysis facilitated by scMetabolism, and integrated analysis via hdWGCNA, identified glycolysis genes correlating with malignancy, and the prognostic value of glycolysis genes ( STMN1, ENO1, PKM , and CDK1 ) and TAMs were verified. Results High-glycolysis malignant DLBCL tissues exhibited an immunosuppressive microenvironment characterized by abundant IFN_TAMs (CD68 + CXCL10 + PD-L1 + ) and diminished CD8 + T cell infiltration. Glycolysis genes were positively correlated with malignancy degree. IFN_TAMs exhibited high glycolysis activity and closely communicating with high-malignancy DLBCL cells identified within datasets. The glycolysis score, evaluated by seven genes, emerged as an independent prognostic factor ( HR  = 1.796, 95% CI : 1.077–2.995, p  = 0.025 and HR  = 2.631, 95% CI : 1.207–5.735, p  = 0.015) along with IFN_TAMs were positively correlated with poor survival ( p  < 0.05) in DLBCL. Immunohistochemical validation of glycolysis markers ( STMN1, ENO1, PKM , and CDK1 ) and multiple immunofluorescence validation of IFN_TAMs underscored their prognostic value ( p  < 0.05) in DLBCL. Conclusions This study underscores the significance of glycolysis in tumor progression and modulation of the immune microenvironment. The identified glycolysis genes and IFN_TAMs represent potential prognostic markers and therapeutic targets in DLBCL.

Cholecalciferol (VDC), a vital form of vitamin D, is essential for maintaining calcium-phosphorus balance, promoting bone health, and regulating the immune system; however, its therapeutic potential is limited by low oral bioavailability and poor aqueous solubility. To address these issues, a multifunctional nanoparticle (NPS) was developed: VDC was first encapsulated in -cyclodextrin (βCD) to form a stable βCD/VDC inclusion complex, improving solubility and physicochemical stability, and then coated with gallic acid (GA) to yield the core-shell nanovehicle GA/βCD/VDC-NPS, which leverages GA's intestinal mucoadhesive and mesenteric adipose retention. GA/βCD/VDC-NPS exhibited a particle size of 234.1 ± 5.23 nm, high encapsulation efficiency (81.2 ± 0.13%), and drug-loading capacity (20.10 ± 0.50%), and showed sustained release, with a cumulative release of 86.06 ± 2.35% at 72 h. MDCK (Madin-Darby Canine Kidney cells) cell experiments showed its cellular uptake was significantly higher than βCD/VDC or free VDC, mediated by multiple endocytic mechanisms. Pharmacokinetic analysis supported markedly enhanced oral absorption: relative to free VDC, the bioavailability of GA/βCD/VDC-NPS increased 2.87-fold in plasma, 6.75-fold in the small intestine, 3.40-fold in adipose tissue, and 3.50-fold in the stomach. Tissue distribution studies verified its enhanced accumulation and prolonged retention in intestinal regions and associated adipose depots. These findings highlight polyphenols like GA as bioactive shells that enhance intestinal adhesion and regional retention, improving oral hydrophobic drugs' pharmacokinetics. In conclusion, GA/βCD/VDC-NPS is a promising nanoplatform that resolves VDC's solubility and bioavailability issues via polyphenol-mediated surface functionalization, offering great potential for oral delivery of various hydrophobic active compounds.

Conventional therapy for the treatment of melanoma often results in poor therapeutic efficacy, and long-term and systemic administration of cancer chemotherapy is accompanied by unpredictable side effects. Graphene oxide (GO)-based photothermal therapy (PTT) combined with chemotherapy has emerged as a rapid and immunogenic alternative, where near-infrared (NIR) irradiation triggers localized hyperthermia via tumor-targeting photothermal immunomodulatory nanomaterials. However, pristine GO nanosheets tend to aggregate under physiological conditions, compromising their photothermal performance. This study aims to develop a combinatorial regimen integrating GO-enhanced photothermal immunotherapy with chemotherapy for synergistic melanoma treatment. We fabricated a novel photothermal nanomaterial through gallic acid(GA) modification of GO (GAGO), with comprehensive characterization including UV-Vis spectroscopy, FTIR, XRD, and TEM to verify successful synthesis. The photothermal conversion efficiency was systematically evaluated, along with an investigation of the combined therapeutic efficacy and underlying mechanisms of GAGO with paclitaxel for melanoma treatment. In this study, GAGO was developed as a novel photothermal nanomaterial with enhanced dispersibility, superior stability, and reduced biotoxicity, which significantly improved the photothermal conversion efficiency of pristine GO. The synergistic combination of GA-GO-mediated photothermal therapy and paclitaxel chemotherapy effectively activated immune cells and potentiated T cell-mediated antitumor immunity, ultimately achieving remarkable tumor growth suppression. We construct a synergistic platform of photothermal therapy, immunotherapy and chemotherapy, which provides a promising strategy for effective melanoma treatment.