Search

Background: In recent years, mRNA-based vaccines with promising safety and functional characteristics have gained significant momentum in cancer immunotherapy. However, stable immunological molecular subtypes of lung adenocarcinoma (LUAD) and novel tumor antigens for LUAD mRNA vaccine development remain elusive. Therefore, a novel approach is urgently needed to identify suitable LUAD subtypes and potential tumor antigens. Methods: The Cancer Genome Atlas (TCGA), the Genotype Tissue Expression (GTEx), and Gene Expression Omnibus (GEO) databases were utilized to retrieve gene expression data. The LUAD Immunological Multi-Omics Classification (LIMOC) system was developed using seven machine learning (ML) algorithms by performing integrative immunogenomic analysis of single-cell and bulk tissue transcriptome profiling. Subsequently, a panel of approaches was applied to identify novel tumor antigens. Results: First, the LIMOC system was construct to identify three subtypes: LIMOC1, LIMOC2, and LIMOC3. Second, we identified CHIT1, LILRA4, and MEP1A as novel tumor antigens in LUAD; these genes were up-regulated, amplified, and mutated, and showed a positive association with APC infiltration, making them promising candidates for designing mRNA vaccines. Notably, the LIMOC2 subtype had the worst prognosis and could benefit most from mRNA immunization. Furthermore, we performed a comprehensive in silico screening of approximately 2000 compounds and identified Sorafenib and Azacitidine as potential subtype-specific therapeutic agents. Conclusions: Overall, our study established a robust LIMOC system and identified CHIT1, LILRA4, and MEP1A as promising tumor antigen candidates for development of anti-LUAD mRNA vaccines, particularly for the LIMOC2 subtype.

Abstract Background Plant compactness (PC) is a crucial agronomic trait that affects plant density in wheat, which in turn influences biomass and grain yield potential. The canopy of high-yielding wheat varieties should exhibit appropriate aboveground plant architecture. In this study, three recombinant inbred line (RIL) populations were generated to identify and validate quantitative trait loci (QTL) related to plant compactness. The erect and compact tillering genotype SN05525 was used as a common parent. A total of 193 F8 RILs from the cross SN05525/SN22 were genotyped using the high-density Illumina iSelect 90 K single nucleotide polymorphism (SNP) assay. Results A linkage map with 7180 SNP loci was constructed, revealing six QTL on chromosomes 3B (Qpc.sdau-3B.1, Qpc.sdau-3B.2),5B (Qpc.sdau-5B), 5D (Qpc.sdau-5D), 2 A (Qpc.sdau-2 A), and 7 A (Qpc.sdau-7 A) that control compact tillers. Qpc.sdau-3B.1, Qpc.sdau-5D, and Qpc.sdau-5B accounted for up to 16.70%, 16.89%, and 14.56% of the phenotypic variance, respectively. Kompetitive allele-specific PCR (KASP) markers were developed for these QTL, and their effects were validated in two additional RIL populations, SN05525/Luyuan 502 and SN05525/Xinong 511. Significant effects of Qpc.sdau-3B.1 and Qpc.sdau-5D on compactness were observed in the validation populations. Conclusion Three major QTL loci closely related to plant compactness in wheat were successfully identified, and their effects were validated in two additional RIL populations across multi environments. Plant architecture plays a crucial role in enhancing yield and economic value in wheat. In the process of molecular marker-assisted selection breeding, the closely linked KASP markers could potentially be utilized in molecular marker-assisted selection for adjusting plant compactness and for further characterization of the underlying gene(s).

Abstract Liver-expressed antimicrobial peptide 2 (LEAP2) is a peptide that counteracts the hunger hormone ghrelin-induced functions. Recently, we showed that vertical sleeve gastrectomy (VSG) did not alter the serum LEAP2 concentration in individuals with obesity. Here, we investigated the effects of VSG in both chow diet (CD)-fed and high-fat diet (HFD)-fed mice. In CD-fed mice, VSG increased plasma LEAP2 levels and hepatic Leap2 mRNA levels while decreasing body weight, blood glucose levels, and ghrelin levels. Intraperitoneal (ip) administration of ghrelin reversed these changes. These effects were found in both male and female mice. In contrast, VSG or weight loss in HFD-induced obese mice decreased LEAP2 levels. After fasting, the plasma LEAP2 concentration was in the following order: hepatic vein > abdominal aorta > portal vein. A high glucose concentration robustly increased the plasma LEAP2 concentration in the hepatic vein and abdominal aorta but not in the portal vein. In addition, corn oil or palmitate increased LEAP2 expression and secretion. The increase in LEAP2 levels after the meal tolerance test was delayed in the human subjects with diabetes. Our data suggest that various factors (metabolic, hormonal, and nutritional) regulate LEAP2, and the liver is the predominant site for the production and secretion of LEAP2. Furthermore, the interaction between ghrelin and LEAP2 is involved in the pathogenesis of obesity and diabetes.

Programmed cell death ligand-1 (PD-L1) is a T cell inhibitory immune checkpoint molecule that interacts with programmed cell death-1 (PD-1) to promote immune escape of tumor cells. Compared with antibody therapies, small molecule drugs show better prospects due to their advantages such as higher bioavailability, better tissue penetration, and reduced risk of immunogenicity. Here, we found that the small molecule demethylzeylasteral (Dem) can significantly downregulate the expression of PD-L1 in colorectal cancer cells and enhance the killing effect of T cells on tumor cells. Mechanistically, Dem binds to the deubiquitinating enzyme USP22 and promotes its degradation, resulting in increased ubiquitination and degradation of PD-L1 through the proteasome pathway. In addition, Dem increased the activity of cytotoxic T cells and reduced the number of myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) in tumor-infiltrating lymphocytes (TILs), thereby activating the tumor immune microenvironment and inhibiting the growth of subcutaneous MC38 tumors in C57BL/6 mice. Moreover, we also found that the combination of Dem and CTLA4 antibodies can further improve the efficacy of antitumor therapy. Our study reveals the mechanism by which Dem promotes PD-L1 degradation and suggests that the combination of Dem and CTLA4 antibodies may improve the efficacy of immunotherapy.

To enhance the tribocorrosion resistance of 7075-T6 aluminum alloy in deep sea environments, TiB2–Ni coatings with varying La2O3 content were deposited on 7075-T6 aluminum alloy substrates using plasma spray technology. The effects of different La2O3 contents on the organization, structure, and properties of the coatings were analyzed. The results indicated that La2O3 incorporation suppressed brittle phase formation such as Ni3B; 1.0 wt% La2O3 addition reduced Ni3B by 16.9%. The coating's corrosion resistance significantly improved with La2O3 doping - the self-corrosion current density of the 1.0 wt% La2O3-doped coating decreased from 71.2 nA/cm2 to 30.2 nA/cm2.

Immunotherapies hold immense potential for achieving durable potency and long-term survival opportunities in cancer therapy. As vital biological mediators, peptides with high tissue penetration and superior selectivity offer significant promise for enhancing cancer immunotherapies (CITs). However, physicochemical peptide features such as conformation and stability pose challenges to their on-target efficacy. This review provides a comprehensive overview of recent advancements in therapeutic peptides targeting key steps of the cancer-immunity cycle (CIC), including tumor antigen presentation, immune cell regulation, and immune checkpoint signaling. Particular attention is given to the opportunities and challenges associated with these peptides in boosting CIC within the context of clinical progress. Furthermore, possible future developments in this field are also discussed to provide insights into emerging CITs with robust efficacy and safety profiles.

Abstract Coal pitch, an important by-product in the coal coking industry with a high output, is a low-cost and high-carbon yield precursor for the manufacturing of high-value carbon materials. Herein, N/O co-doped carbon fiber (CFCP), fabricated by electrospinning using pre-oxidized coal pitch as the precursor, was employed as the sulfur host for Li-S batteries. The presence of more pyrrolic N and graphic N in CFCP than carbon fiber made from polyacrylonitrile benefits the adsorption of lithium polysulfide and the battery’s life. Sulphur-CFCP cathode (S@CFCP) exhibited excellent specific capacity and cyclability, with a specific capacity of 701.1 mAh/g and a low capacity decay rate of 0.088% per cycle over 200 cycles at 2.0 C, respectively. The high ion diffusion rate, low charge transfer resistance, and effective conversion of lithium polysulfides enable the high electrochemical performance of S@CFCP.

Introduction Hypertension and rising serum uric acid (sUA) played a pivotal role in the development of Chronic Kidney Disease (CKD). This study investigates the interactive effect of sUA and hypertension on CKD and identifies the optimal threshold of sUA among individuals with and without hypertension in the Chinese community population.Materials and methods The study included 4180 individuals aged 45–85 years, derived from the China Health and Retirement Longitudinal Study (CHARLS) between 2011 and 2015. Additionally, a hospital-based study enrolled subjects in the Department of Nephrology at Zhongshan Hospital, China from January 1, 2019, to December 31, 2021. The interaction effect analysis were used to assess the impact of sUA and hypertension on CKD. We also compared the distribution of sUA and the CKD risk in community populations, distinguishing between those with and without hypertension. For the hospital-based population, kidney injury was marked by a KIM-1 positive area.Results Our results indicate a higher prevalence of CKD in the community population with hypertension (10.2% vs. 3.9%, p

The level of detail (LOD) modelling of vector and terrain data is individual, resulting in geometric and topological inconsistencies in simplification processes. The three dimension Douglas Peucker (3D_DP)algorithm can realize gradual discrete point selection through threshold, which is mainly used in DEM synthesis, and its simplified process is very suitable for the dynamic establishment of massive data sets. A new LOD modeling method based on 3D_DP algorithm is proposed to simplify the consistency of river network vector elements and DEM in this paper. The specific steps are as follows: Firstly, the “Bending Adjustment Index (BAI)” is introduced to improve the 3D_DP algorithm, called the improved 3D_DP algorithm; Secondly, the DEM data is extracted into a 3D discrete point dataset, and the river line vector data is also converted into a discrete point dataset, assigned with elevation attributes, and merges with the DEM’s 3D discrete points. The merged point datasets are equenced based on the importance of each point, which are computed by the improved 3D_DP algorithm. The order of deleting points is determined by the sequence and the corresponding model spatial errors are calculated with the deletion of points. Then, the DEM’s 3D discrete points are constructed a Delaunay network with the river line as a mandatory constraint condition. The required triangulation is called in real time with the change of sight distance depending on the simple correspondence between screen projection error and model space error, and the unified LOD model for river line vector and DEM is established. The results show that the river’s overall shape and the terrain’s main features can be reserved under the same simplified factor based on the improved 3D_DP algorithm. The unified LOD model for the river network and DEM is feasible under the importance sequence of merged point datasets by the improved 3D_DP algorithm. Under the proper operation of data blocking, the rendering frame rate can meet practical application requirements.

BackgroundPapillary thyroid cancer (PTC) with lymph node metastasis (LNM) is associated with an increased risk of postoperative recurrence. Understanding the clinical characteristics of PTC patients can help surgeons assess the likelihood of LNM. This study aims to identify risk factors for LNM in PTC patients.MethodsWe retrospectively analyzed clinical data from 2,428 patients diagnosed with PTC who underwent initial thyroid surgery in our single center. Risk factors related to central lymph node metastasis (CLNM), lateral lymph node metastasis (LLNM), and skip metastasis were investigated by univariate and multivariate binary logistic regression analyses.ResultsUnivariate analysis revealed that the following factors were associated with an increased likelihood of CLNM (P 1 cm, body mass index (BMI) ≥ 28 kg/m² and multifocality. Univariate analysis also revealed that patients with age < 45 years, MAD > 1 cm, BMI ≥ 28 kg/m², multifocality, and CLNM demonstrated a higher propensity for LLNM (P 1 cm, multifocality, and CLNM can help predict LNM. In specific cases, selective lymphadenectomy in the central or lateral neck area may be warranted.

Abstract To analyze the clinical characteristics and to improve clinicians’ understanding of multiple pulmonary sclerosing pneumocytoma (PSP) patients. A total of 36 PSP patients with multiple tumor characteristics were identified from the literature search. They were compared with 43 solitary PSP patients diagnosed and treated in our hospital in the past 5 years. Thus, the pathogenesis, clinical symptoms, diagnosis methods, treatment strategies, and prognosis of pulmonary sclerosing pneumocytoma (PSP) patients with multiple tumors were explored. Patients with multiple PSP are mostly distributed in Asia (88.89%) and are females (83.33%). PSP can be located in any one lobe (19.44%), or grow across ipsilateral lobes (44.44%), or even, bilateral lobes (36.11%). It can be accompanied by metastasis (9.09%) and is prone to misdiagnosis (27.78%). Compared with solitary PSP, the occurrence age of multiple PSP was younger (mean ± standard deviation [SD]: 40.36 ± 18.12: 51.28 ± 12.74 years), but there was no significant difference in sex, tumor size (mean ± SD: 43.54 ± 46.18: 30.56 ± 17.62 mm), or symptoms. Individualized surgical resection is required for treatment, including pneumonectomy (17.65%), lobectomy (23.53%), subpulmonary lobectomy (38.24%), or combined lobectomy (5.88%). Multiple PSP is relatively rare. Surgical resection within a limited time should be the main treatment for such patients. The prognosis of patients with multiple PSP is generally good, but inappropriate diagnosis and treatment plans may lead to poor prognosis.

Abstract Background Elevated interstitial fluid pressure within tumors, resulting from impaired lymphatic drainage, constitutes a critical barrier to effective drug penetration and therapeutic outcomes. Results In this study, based on the photosynthetic characteristics of algae, an active drug carrier (CP@ICG) derived from Chlorella pyrenoidosa (CP) was designed and constructed. Leveraging the hypoxia tropism and phototropism exhibited by CP, we achieved targeted transport of the carrier to tumor sites. Additionally, dual near-infrared (NIR) irradiation at the tumor site facilitated photosynthesis in CP, enabling the breakdown of excessive intratumoral interstitial fluid by generating oxygen from water decomposition. This process effectively reduced the interstitial pressure, thereby promoting enhanced perfusion of blood into the tumor, significantly improving deep-seated penetration of chemotherapeutic agents, and alleviating tumor hypoxia. Conclusions CP@ICG demonstrated a combined effect of photothermal/photodynamic/starvation therapy, exhibiting excellent in vitro/in vivo anti-tumor efficacy and favorable biocompatibility. This work provides a scientific foundation for the application of microbial-enhanced intratumoral drug delivery and tumor therapy. Graphical Abstract

PLCD3 belongs to the phospholipase C delta group and is involved in numerous biological functions, including cell growth, programmed cell death, and specialization. However, the role of PLCD3 in lung cancer still needs further investigation. This research aimed to investigate if PLCD3 influences glycolytic reprogramming and lung cancer development through the PKC-dependent Rap1 signaling pathway. This study found that PLCD3 was increased in lung cancer tissues. PLCD3 promotes the proliferation and invasion of lung cancer cells by activating the PKC-dependent Rap1 pathway. The detailed process involves PLCD3 triggering PKC, which subsequently stimulates the Rap1 pathway, leading to glycolytic reprogramming that supplies adequate energy and metabolic substrates necessary for the growth and spread of lung cancer cells. Moreover, PLCD3 can also promote the metastasis and invasion of lung cancer cells by activating the Rap1 pathway. This study reveals the mechanism of PLCD3 in lung cancer and provides new ideas for the treatment of lung cancer. Inhibiting PLCD3, PKC, and the Rap1 pathway may be an effective strategy for treating lung cancer.

Abstract Integrated multimodal imaging in theranostics nanomaterials offers extensive prospects for precise and noninvasive cancer treatment. Precisely controlling the structural evolution of plasmonic nanoparticles is crucial in the development of photothermal agents. However, previous successes have been limited to static assemblies and single‐component structures. Here, an activatable plasmonic theranostics system utilizing self‐assembled 1D silver‐coated gold nanochains (1D nanochains) is presented for precise tumor diagnosis and effective treatment. The absorbance of the adaptable core–shell chain structure can shift from visible to near‐infrared (NIR) regions due to the fusion between nearby Au@Ag nanoparticles induced by elevated H2O2 levels in the tumor microenvironment (TME), resulting in the creation of a novel 3D aggregates with strong NIR absorption. With a high photothermal conversion efficiency of 60.2% at 808 nm, nanochains utilizing the TME‐activated characteristics show remarkable qualities for photoacoustic imaging and significantly limit tumor growth in vivo. This study may pave the way for precise tumor diagnosis and treatment through customizable, optically tunable adaptive plasmonic nanostructures.

Abstract Targeting the programmed cell death 1/programmed cell death ligand 1 (PD‐1/PD‐L1) pathway has been identified as a successful approach for tumor immunotherapy. Here, we identified that the small molecule 5,7,4′‐trimethoxyflavone (TF) from Kaempferia parviflora Wall reduces PD‐L1 expression in colorectal cancer cells and enhances the killing of tumor cells by T cells. Mechanistically, TF targets and stabilizes the ubiquitin ligase HMG‐CoA reductase degradation protein 1 (HRD1), thereby increasing the ubiquitination of PD‐L1 and promoting its degradation through the proteasome pathway. In mouse MC38 xenograft tumors, TF can activate tumor‐infiltrating T‐cell immunity and reduce the immunosuppressive infiltration of myeloid‐derived suppressor cells and regulatory T cells, thus exerting antitumor effects. Moreover, TF synergistically exerts antitumor immunity with CTLA‐4 antibody. This study provides new insights into the antitumor mechanism of TF and suggests that it may be a promising small molecule immune checkpoint modulator for cancer therapy.

Abstract The binding of peroxisome proliferator‐activated receptor γ (PPARγ) to the orphan nuclear receptor Nur77 facilitates the ubiquitination and degradation of Nur77, and leads to aberrant fatty acid uptake for breast cancer progression. Because of its crucial role in clinical prognosis, the interaction between Nur77 and PPARγ is an attractive target for anti‐breast‐cancer therapy. However, developing an inhibitor of the Nur77‐PPARγ interaction poses a technical challenge due to the absence of the crystal structure of PPARγ and its corresponding interactive model with Nur77. Here, ST‐CY14, a stapled peptide, is identified as a potent modulator of Nur77 with a KD value of 3.247 × 10−8 M by in silico analysis, rational design, and structural modification. ST‐CY14 effectively increases Nur77 protein levels by blocking the Nur77‐PPARγ interaction, thereby inhibiting lipid metabolism in breast tumor cells. Notably, ST‐CY14 significantly suppresses breast cancer growth and bone metastasis in mice. The findings demonstrate the feasibility of exploiting directly Nur77‐PPARγ interaction in breast cancer, and generate what to the best knowledge is the first direct inhibitor of the Nur77‐PPARγ interaction available for impeding fatty acid uptake and therapeutic development.

NUAK2 is a member of the AMP-activated protein kinase (AMPK) family, which plays an essential role in cellular processes such as apoptosis, proliferation, and cell fate. Recent studies have already shown that silencing of NUAK2 blocks proliferation and promotes apoptosis of human melanoma cells and liver cancer cells. In addition, NUAK2 is involved in the development of glioblastoma via regulating the expression of cancer stem cell-related genes, and it promotes the cell cycle entry in the glioblastoma cells. However, the expression and the role of NUAK2 in the progress of peripheral nerve regeneration after injury are yet to be elucidated. We observed that NUAK2 was upregulated following distal sciatic nerve crush (SNC). Interestingly, we discovered that NUAK2 showed co-localization with S100 (Schwann cell marker). Furthermore, we found that the NUAK2 had a spatiotemporal protein expression, which was consistent with proliferating cell nuclear-antigen (PCNA). The protein level of NUAK2 and YAP was upregulated in the model of TNF-α-induced Schwann cell (SC) proliferation. Furthermore, flow cytometry analysis, CCK-8, transwell assays, and wound healing assays were all performed with the purpose of exploring the role of NUAK2 in the regulation of SC proliferation and migration. More importantly, we found that NUAK2-deficient SCs showed significantly reduced expression of Yes-associated protein (YAP). Bioinformatic analysis identified upstream regulators of NUAK2 and NUAK2-associated genes (e.g., YAP1). Finally, we investigated the recovery changes during regeneration progress through the walking track analysis. Thus, we speculated that NUAK2 was involved in biochemical and physiological responses of SCs after SNC via YAP-driven proliferation and migration, and this study determined the importance of NUAK2 as a potential target in peripheral nerve regeneration.