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Background Novel immunotherapy combination therapies have improved outcomes for patients with hepatocellular carcinoma (HCC), but responses are limited to a subset of patients. Little is known about the inter- and intra-tumor heterogeneity in cellular signaling networks within the HCC tumor microenvironment (TME) that underlie responses to modern systemic therapy. Methods We applied spatial transcriptomics (ST) profiling to characterize the tumor microenvironment in HCC resection specimens from a prospective clinical trial of neoadjuvant cabozantinib, a multi-tyrosine kinase inhibitor that primarily blocks VEGF, and nivolumab, a PD-1 inhibitor in which 5 out of 15 patients were found to have a pathologic response at the time of resection. Results ST profiling demonstrated that the TME of responding tumors was enriched for immune cells and cancer-associated fibroblasts (CAF) with pro-inflammatory signaling relative to the non-responders. The enriched cancer-immune interactions in responding tumors are characterized by activation of the PAX5 module, a known regulator of B cell maturation, which colocalized with spots with increased B cell marker expression suggesting strong activity of these cells. HCC-CAF interactions were also enriched in the responding tumors and were associated with extracellular matrix (ECM) remodeling as there was high activation of FOS and JUN in CAFs adjacent to the tumor. The ECM remodeling is consistent with proliferative fibrosis in association with immune-mediated tumor regression. Among the patients with major pathologic responses, a single patient experienced early HCC recurrence. ST analysis of this clinical outlier demonstrated marked tumor heterogeneity, with a distinctive immune-poor tumor region that resembles the non-responding TME across patients and was characterized by HCC-CAF interactions and expression of cancer stem cell markers, potentially mediating early tumor immune escape and recurrence in this patient. Conclusions These data show that responses to modern systemic therapy in HCC are associated with distinctive molecular and cellular landscapes and provide new targets to enhance and prolong responses to systemic therapy in HCC.

A neoadjuvant immunotherapy platform clinical trial allows for rapid evaluation of treatment-related changes in tumors and identifying targets to optimize treatment responses. We enrolled patients with resectable pancreatic adenocarcinoma into such a platform trial (NCT02451982) to receive pancreatic cancer GVAX vaccine with low-dose cyclophosphamide alone (Arm A; n  = 16), with anti-PD-1 antibody nivolumab (Arm B; n  = 14), and with both nivolumab and anti-CD137 agonist antibody urelumab (Arm C; n  = 10), respectively. The primary endpoint for Arms A/B - treatment-related change in IL17A expression in vaccine-induced lymphoid aggregates - was previously published. Here, we report the primary endpoint for Arms B/C: treatment-related change in intratumoral CD8+ CD137+ cells and the secondary outcomes including safety, disease-free and overall survivals for all Arms. Treatment with GVAX+nivolumab+urelumab meets the primary endpoint by significantly increasing intratumoral CD8+ CD137+ cells ( p  = 0.003) compared to GVAX+Nivolumab. All treatments are well-tolerated. Median disease-free and overall survivals, respectively, are 13.90/14.98/33.51 and 23.59/27.01/35.55 months for Arms A/B/C. GVAX+nivolumab+urelumab demonstrates numerically-improved disease-free survival (HR = 0.55, p  = 0.242; HR = 0.51, p  = 0.173) and overall survival (HR = 0.59, p  = 0.377; HR = 0.53, p  = 0.279) compared to GVAX and GVAX+nivolumab, respectively, although not statistically significant due to small sample size. Therefore, neoadjuvant and adjuvant GVAX with PD-1 blockade and CD137 agonist antibody therapy is safe, increases intratumoral activated, cytotoxic T cells, and demonstrates a potentially promising efficacy signal in resectable pancreatic adenocarcinoma that warrants further study. GM-CSF-secreting whole-cell cancer vaccine (GVAX) promotes T-cell response against a range of tumor associated antigens in patients with pancreatic adenocarcinoma (PDA). Here the authors report the results of the initial three treatment arms of a platform trial of neoadjuvant and adjuvant GVAX alone or in combination with PD-1 antagonist and CD137 agonist antibodies in patients with resectable PDA.

With the advanced development of the intelligent transportation system, vehicular ad hoc networks have been observed as an excellent technology for the development of intelligent traffic management in smart cities. Recently, researchers and industries have paid great attention to the smart road-tolling system. However, it is still a challenging task to ensure geographical location privacy of vehicles and prevent improper behavior of drivers at the same time. In this paper, a reliable road-tolling system with trustworthiness evaluation is proposed, which guarantees that vehicle location privacy is secure and prevents malicious vehicles from tolling violations at the same time. Vehicle route privacy information is encrypted and uploaded to nearby roadside units, which then forward it to the traffic control center for tolling. The traffic control center can compare data collected by roadside units and video surveillance cameras to analyze whether malicious vehicles have behaved incorrectly. Moreover, a trustworthiness evaluation is applied to comprehensively evaluate the multiple attributes of the vehicle to prevent improper behavior. Finally, security analysis and experimental simulation results show that the proposed scheme has better robustness compared with existing approaches.

Accompanying the process of growth and development, plants are exposed to ever-changing environments, which consequently trigger abiotic or biotic stress responses. The large protein family known as receptor-like protein kinases (RLKs) is involved in the regulation of plant growth and development, as well as in the response to various stresses. Understanding the biological function and molecular mechanism of RLKs is helpful for crop breeding. Research on the role and mechanism of RLKs has recently received considerable attention regarding the balance between plant growth and environmental adaptability. In this paper, we systematically review the classification of RLKs, the regulatory roles of RLKs in plant development (meristem activity, leaf morphology and reproduction) and in stress responses (disease resistance and environmental adaptation). This review focuses on recent findings revealing that RLKs simultaneously regulate plant growth and stress adaptation, which may pave the way for the better understanding of their function in crop improvement. Although the exact crosstalk between growth constraint and plant adaptation remains elusive, a profound study on the adaptive mechanisms for decoupling the developmental processes would be a promising direction for the future research.

Commensal gut microbiota protects the immune defense of extra-intestinal organs. Gut microbiota depletion by antibiotics can impair host antiviral immune responses and alter hepatitis B virus (HBV) infection outcomes. However, how gut microbiota modulates antiviral immune response in the liver remains unclear. Here, mice were treated with broad-spectrum antibiotics to deplete gut microbiota. Gut integrity was evaluated, and translocation of live commensal gut bacteria and their components into the liver was investigated. An HBV infection model was established to evaluate impairment of antiviral immune response in the liver after gut microbiota depletion. We found that gut microbiota depletion was associated with impairment of colon epithelial integrity, and live commensal gut microbiota could translocate to the liver. Further, T cell antiviral function in the liver was impaired, partially relying on enhanced PD-1 expression, and HBV immune clearance was hampered. In conclusion, gut microbiota depletion by antibiotics can impair gut barrier function and suppress T cell antiviral immune response in the liver.

To get rid of the development dilemma of green credit, we constructed a stochastic evolutionary game model of local government, commercial banks, and loan enterprises. We gave sufficient conditions for the stability of strategy based on the stability discriminant theorem of Ito^'s stochastic differential equation (SDE). Then, we discussed the impacts of incentive and penalty parameters on green credit. Through the above analysis, we got the following conclusions: (1) rewards and punishments always benefit green production and green credit, but increasing incentives is not conducive to the governments’ performance of regulatory duties; (2) punishments can better improve the convergence rate of players’ strategy than rewards; and (3) both rewards and punishments can exert an obvious effect in improving the changing degree of players’ strategy. Finally, we put forward some suggestions to optimize the green credit mechanism.

Circulating tumor cell (CTC) detection in hepatocellular carcinoma (HCC) is limited not only by the rarity of CTCs but also by a heavy reliance on cell surface markers such as EpCAM, which are variably expressed or lost during tumor progression. Detecting intracellular markers, such as cytokeratin offers an important complementary and comprehensive strategy but remains technically limited in flow cytometry due to the need for fixation and permeabilization, which often lead to cell loss and surface epitope damage. In this study, we systematically evaluated the feasibility of using fixed samples for flow cytometry, using HepG2 cells, PBMCs, and CTCs from patients with HCC. Our results demonstrate that fixation enabled intracellular staining without compromising cell surface marker detection, even after short-term storage at 4 °C and long-term storage at -80 °C. Fixed samples, particularly fixed unfrozen, exhibited comparable staining performance to fresh samples with only a 7–10% reduction in cell recovery. Clinical validation in HCC patients confirmed successful CTC detection, and tumor-specific CTNNB1 mutations were identified in CTC-derived DNA but not in matched plasma cfDNA. These findings support fixed CTC sample workflows as a reliable and practical approach for CTC analysis in HCC.

Background Tumor regression following immune checkpoint blockade (ICB) is often associated with immune-related adverse events (irAEs), marked by inflammation in non-cancerous tissues. This study was undertaken to investigate the functional relationship between anti-tumor and anti-self immunity, to facilitate irAE management while promoting anti-tumor immunity. Methods Multiple biopsies from tumor and inflamed tissues were collected from a patient with melanoma experiencing both tumor regression and irAEs on ICB, who underwent rapid autopsy. Immune cells infiltrating melanoma lesions and inflamed normal tissues were subjected to gene expression profiling with multiplex qRT-PCR for 122 candidate genes. Subsequently, immunohistochemistry was conducted to assess the expression of 14 candidate markers of immune cell subsets and checkpoints. TCR-beta sequencing was used to explore T cell clonal repertoires across specimens. Results While genes involved in MHC I/II antigen presentation, IFN signaling, innate immunity and immunosuppression were abundantly expressed across specimens, irAE tissues over-expressed certain genes associated with immunosuppression ( CSF1R, IL10RA, IL27/EBI3, FOXP3, KLRG1, SOCS1, TGFB1 ), including those in the COX-2/PGE2 pathway ( IL1B, PTGER1/EP1 and PTGER4/EP4 ). Immunohistochemistry revealed similar proportions of immunosuppressive cell subsets and checkpoint molecules across samples. TCRseq did not indicate common TCR repertoires across tumor and inflammation sites, arguing against shared antigen recognition between anti-tumor and anti-self immunity in this patient. Conclusions This comprehensive study of a single patient with melanoma experiencing both tumor regression and irAEs on ICB explores the immune landscape across these tissues, revealing similarities between anti-tumor and anti-self immunity. Further, it highlights expression of the COX-2/PGE2 pathway, which is known to be immunosuppressive and potentially mediates ICB resistance. Ongoing clinical trials of COX-2/PGE2 pathway inhibitors targeting the major COX-2 inducer IL-1B, COX-2 itself, or the PGE2 receptors EP2 and EP4 present new opportunities to promote anti-tumor activity, but may also have the potential to enhance the severity of ICB-induced irAEs.

Gut microbiota composition is known to be associated with the progression of hepatitis B virus (HBV)-related liver cirrhosis in humans, outcome of HBV infection in mice, and seroconversion of HBV e-antigen in nucleot(s)ide analog-treated patients. The dynamic alteration of the gut microbiota following HBV infection is still unknown. In this study, a hydrodynamic injection mouse model mimicking acute or chronic HBV infection in humans with comparable virological and immunological features was used. The composition of gut microbiota in the control mice and mice with acute or chronic HBV infection was analyzed at different time points using the Illumina MiSeq platform. The expression of immune molecules in the colon was detected by real-time polymerase chain reaction. We found that the changes in gut microbiota composition, including the total operational taxonomic unit (OTU) count and Shannon-Weaver index, were significantly delayed in mice with HBV infection. Furthermore, the ratio of and was stable in the control mice, whereas remarkable dynamic patterns were observed in mice with HBV infection. Interestingly, the dynamic changes in and were found to differ in acute or chronic HBV infection. In addition, the expression of IFN-γ and PD-L1 in the colon was found to be up-regulated early in mice with acute HBV infection, whereas the expression of PD-L1 in the colon of mice with chronic HBV infection was up-regulated later. These data indicate that HBV infection could hamper the development of the gut microbiota community and dynamically change the gut / ratio. These data improve our understanding of the relationship between gut microbiota and HBV infection.

Aluminum nitride (AlN)-based ferroelectric films offer significant advantages, including compatibility with CMOS back-end processes, potential for sustainable miniaturization, and intrinsic stability in the ferroelectric phase. As promising emerging materials, they have attracted considerable attention for their broad application potential in nonvolatile ferroelectric memories. However, several key scientific and technological challenges remain, including the preparation of single-crystal materials, epitaxial growth, and doping, which hinder their progress in critical ferroelectric devices. To accelerate their development, further research is needed to elucidate the underlying physical mechanisms, such as growth dynamics and ferroelectric properties. This paper provides a comprehensive review of the preparation methods of AlN-based ferroelectric films, covering AlN, Al1−xScxN, Al1−xBxN, YxAl1−xN, and ScxAlyGa1−x−yN. We systematically analyze the similarities, differences, advantages, and limitations of various growth techniques. Furthermore, the ferroelectric properties of AlN and its doped variants are summarized and compared. Strategies for enhancing the ferroelectric performance of AlN-based films are discussed, with a focus on coercive field regulation under stress, suppression of leakage current, fatigue mechanism, and long-term stability. Then, a brief overview of the wide range of applications of AlN-based thin films in electronic and photonic devices is presented. Finally, the challenges associated with the commercialization of AlN-based ferroelectrics are presented, and critical issues for future research are outlined. By synthesizing insights on growth methods, ferroelectric properties, enhancement strategies, and applications, this review aims to facilitate the advancement and practical application of AlN-based ferroelectric materials and devices.