Development of an mRNA-based therapeutic vaccine mHTV-03E2 for high-risk HPV-related malignancies.

Human papillomavirus (HPV) 16 and 18 infections are related to many human cancers. Despite several preventive vaccines for high-risk (hr) HPVs, there is still an urgent need to develop therapeutic HPV vaccines for targeting pre-existing hrHPV infections and lesions. In this study, we developed a lipid nanoparticle (LNP)-formulated mRNA-based HPV therapeutic vaccine (mHTV)-03E2, simultaneously targeting the E2/E6/E7 of both HPV16 and HPV18. mHTV-03E2 dramatically induced antigen-specific cellular immune responses, leading to significant CD8+ T cell infiltration and cytotoxicity in TC-1 tumors derived from primary lung epithelial cells of C57BL/6 mice expressing HPV E6/E7 antigens, mediated significant tumor regression, and prolonged animal survival, in a dose-dependent manner. We further demonstrated significant T cell immunity against HPV16/18 E6/E7 antigens for up to 4 months post-vaccination in immunological and distant tumor rechallenging experiments, suggesting robust memory T cell immunity against relapse. Finally, mHTV-03E2 synergized with immune checkpoint blockade to inhibit tumor growth and extend animal survival, indicating the potential in combination therapy. We conclude that mHTV-03E2 is an excellent candidate therapeutic mRNA vaccine for treating malignancies caused by HPV16 or HPV18 infections.

Ferroptosis mediated by TNFSF9 interferes in acute ischaemic stroke reperfusion injury with the progression of acute ischaemic stroke.

In this study, we investigated the potential involvement of TNFSF9 in reperfusion injury associated with ferroptosis in acute ischaemic stroke patients, mouse models and BV2 microglia. We first examined TNFSF9 changes in peripheral blood from stroke patients with successful reperfusion, and constructed oxygen-glucose deprivation-reperfusion (OGD-R) on BV2 microglia, oxygen-glucose deprivation for 6 h followed by reoxygenation and re-glucose for 24 h, and appropriate over-expression or knockdown of TNFSF9 manipulation on BV2 cells and found that in the case of BV2 cells encountering OGD-R over-expression of TNFSF9 resulted in increased BV2 apoptosis. Still, the knockdown of TNFSF9 ameliorated apoptosis and ferroptosis. In an in vivo experiment, we constructed TNFSF9 over-expression or knockout mice by intracerebral injection of TNFSF9-OE or sh-TNFSF9 adenovirus. We performed the middle cerebral artery occlusion (MCAO) model on day four, 24 h after ligation of the proximal artery, for half an hour to recanalize. As luck would have it, over-expression of TNFSF9 resulted in increased brain infarct volumes, neurological function scores and abnormalities in TNFSF9-related TRAF1 and ferroptosis-related pathways, but knockdown of TNFSF9 improved brain infarcts in mice as well as reversing TNFSF9-related signalling pathways. In conclusion, our data provide the first evidence that TNFSF9 triggers microglia activation by activating the ferroptosis signalling pathway following ischaemic stroke, leading to brain injury and neurological deficits.

CircGLIS3 promotes gastric cancer progression by regulating the miR-1343-3p/PGK1 pathway and inhibiting vimentin phosphorylation.

BACKGROUND: Circular RNAs (circRNAs) have been proved to play crucial roles in the development of various cancers. However, the molecular mechanism of circGLIS3 involved in gastric cancer (GC) tumorigenesis has not been elucidated. METHODS: The higher expression level of circGLIS3 was identified in GC through RNA sequencing and subsequent tissue verification using Quantitative real-time PCR (qRT-PCR). A series of functional experiments in vitro and in vivo were performed to evaluated the effects of circGLIS3 on tumor growth and metastasis in GC. The interaction and regulation of circGLIS3/miR-1343-3p/PGK1 axis was confirmed by RNA pulldown, western blot, and rescue experiments. RIP and western blot were performed to demonstrate the role of circGLIS3 in regulating phosphorylation of VIMENTIN. We then used qRT-PCR and co culture system to trace circGLIS3 transmission via exosomal communication and identify the effect of exosomal circGLIS3 on gastric cancer and macrophages. Finally, RIP experiments were used to determine that EIF4A3 regulates circGLIS3 expression. RESULTS: CircGLIS3(hsa_circ_0002874) was significantly upregulated in GC tissues and high circGLIS3 expression was associated with advanced TNM stage and lymph node metastasis in GC patients. We discovered that overexpression of circGLIS3 promoted GC cell proliferation, migration, invasion in vitro and in vivo, while suppression of circGLIS3 exhibited the opposite effect. Mechanistically, circGLIS3 could sponge miR-1343-3p and up-regulate the expression of PGK1 to promote GC tumorigenesis. We also found that circGLIS3 reduced the phosphorylation of VIMENTIN at ser 83 site by binding with VIMENTIN. Moreover, it was proven that exosomal circGLIS3 could promote gastric cancer metastasis and the M2 type polarization of macrophages. In the final step, the mechanism of EIF4A3 regulating the generation of circGLIS3 was determined. CONCLUSION: Our findings demonstrate that circGLIS3 promotes GC progression through sponging miR-1343-3p and regulating VIMENTIN phosphorylation. CircGLIS3 is a potential therapeutic target for GC patients.

Recent Advances of Neoadjuvant Immunotherapy for Urothelial Bladder Cancer.

Urothelial bladder cancer is one of the most common malignant tumors of the urinary system, which accounts for 90~95% of urothelial carcinoma. Despite the current standard neoadjuvant management for localized urothelial MIBC (T2-4cN0M0) is cisplatin-based chemotherapy before radical cystectomy, there still had poor performances and less overall survival benefits in patients with localized urothelial MIBC. Moreover, nearly half of MIBC patients were ineligible for receiving cisplatin because of chronic kidney disease and performance status. Although immunotherapy, immune checkpoint inhibitors (ICIs) has been identified as first or second-line treatments for localized and metastasis bladder cancer based on less adverse reactions and favorable outcomes, neoadjuvant immunotherapy had rarely used for the treatment of these patients because of less large-scale clinical randomized studies and limited outcomes. Therefore, we reviewed the advances of efficacy and safety with neoadjuvant immunotherapy for urothelial bladder cancer depended on published articles and clinical studies, which could provide more theoretical evidences and promising strategy for clinical therapeutic development.

eIF4A3-mediated circEHMT1 regulation in retinal microvascular endothelial dysfunction in diabetic retinopathy.

BACKGROUND AND OBJECTIVE: Literature has reported that circular RNAs (circRNAs) are crucially associated with diabetic retinopathy (DR). Furthermore, circEHMT1 has been identified to maintain endothelial cell barrier function. This study aimed to investigate the mechanisms that regulate aberrant circEHMT1 expression and its role in the pathogenesis of DR. METHODS: In this study, retinal microvascular endothelial cells were exposed to a high glucose (HG) environment, and subsequently, tube formation and intercellular junction proteins were evaluated. Furthermore, the biological functions of circEHMT1 and its potential regulatory factor, eIF4A3, in microvascular endothelial cells under HG conditions were also assessed. In addition, the regulatory role of eIF4A3 on circEHMT1 expression was confirmed. Moreover, to elucidate the in vivo functions of eIF4A3 and circEHMT1, streptozotocin (STZ) was used to establish a DR model in rats. RESULTS: It was revealed that HG condition decreased circEHMT1 and eIF4A3 expressions and reduced ZO-1, Claudin-5, and Occludin levels in retinal microvascular endothelial cells. Furthermore, it was observed that eIF4A3 could regulate the expression of circEHMT1. Overexpression of eIF4A3 or circEHMT1 under HG conditions improved endothelial cell injury and decreased tube-formation ability. Additionally, in the DR rat model, eIF4A3 overexpression restored circEHMT1 levels and ameliorated retinal vasculature changes. CONCLUSION: Altogether, eIF4A3 regulates circEHMT1 expression, thereby affecting microvascular endothelial cell injury and tube formation. Further understanding the regulatory effect of eIF4A3 on circEHMT1 may provide novel therapeutic targets for DR.

Energy-transfer Enabled Divergent Synthesis of Polycyclic γ-Sultines.

A visible-light-initiated energy-transfer enabled radical cyclization for the divergent synthesis of polycyclic γ-sultine derivatives has been developed. The reaction provides an alternative and expeditious access to benzofused γ-sultine frameworks, the analogues of γ-lactones and γ-sultones, and features good functional group compatibility, mild reaction conditions and excellent diastereoselectivity. The robustness and application potential of this method have also been successfully displayed by two gram-scale reactions and the synthesis of polycyclic sultones. Mechanistic studies indicated the transformations through a possible energy-transfer enabled intramolecular radical homolytic substitution or hydrogen atom transfer process mainly.

Oxidation behavior and atomic structural transition of size-selected coalescence-resistant tantalum nanoclusters.

Herein a series of size-selected TaN(N = 147, 309, 561, 923, 1415, 2057, 6525, 10 000, 20 000) clusters are generated using a gas-phase condensation cluster beam source equipped with a lateral time-of-flight mass-selector. Aberration-corrected scanning transmission electron microscopy (AC-STEM) imaging reveals good thermal stability of TaNclusters in this study. The oxidation-induced amorphization is observed from AC-STEM imaging and further demonstrated through x-ray photoelectron spectroscopy and energy-dispersive spectroscopy. The oxidized Ta predominantly exists in the +5 oxidation state and the maximum spontaneous oxidation depth of the Ta cluster is observed to be 5 nm under prolonged atmosphere exposure. Furthermore, the size-dependent sintering and crystallization processes of oxidized TaNclusters are observed with anin situheating technique, and eventually, ordered structures are restored. As the temperature reaches 1300 °C, a fraction of oxidized Ta309clusters exhibit decahedral and icosahedral structures. However, the five-fold symmetry structures are absent in larger clusters, instead, these clusters exhibit ordered structures resembling those of the crystalline Ta2O5films. Notably, the sintering and crystallization process occurs at temperatures significantly lower than the melting point of Ta and Ta2O5, and the ordered structures resulting from annealing remain well-preserved after six months of exposure to ambient conditions.

FXR activation remodels hepatic and intestinal transcriptional landscapes in metabolic dysfunction-associated steatohepatitis.

The escalating obesity epidemic and aging population have propelled metabolic dysfunction-associated steatohepatitis (MASH) to the forefront of public health concerns. The activation of FXR shows promise to combat MASH and its detrimental consequences. However, the specific alterations within the MASH-related transcriptional network remain elusive, hindering the development of more precise and effective therapeutic strategies. Through a comprehensive analysis of liver RNA-seq data from human and mouse MASH samples, we identified central perturbations within the MASH-associated transcriptional network, including disrupted cellular metabolism and mitochondrial function, decreased tissue repair capability, and increased inflammation and fibrosis. By employing integrated transcriptome profiling of diverse FXR agonists-treated mice, FXR liver-specific knockout mice, and open-source human datasets, we determined that hepatic FXR activation effectively ameliorated MASH by reversing the dysregulated metabolic and inflammatory networks implicated in MASH pathogenesis. This mitigation encompassed resolving fibrosis and reducing immune infiltration. By understanding the core regulatory network of FXR, which is directly correlated with disease severity and treatment response, we identified approximately one-third of the patients who could potentially benefit from FXR agonist therapy. A similar analysis involving intestinal RNA-seq data from FXR agonists-treated mice and FXR intestine-specific knockout mice revealed that intestinal FXR activation attenuates intestinal inflammation, and has promise in attenuating hepatic inflammation and fibrosis. Collectively, our study uncovers the intricate pathophysiological features of MASH at a transcriptional level and highlights the complex interplay between FXR activation and both MASH progression and regression. These findings contribute to precise drug development, utilization, and efficacy evaluation, ultimately aiming to improve patient outcomes.

The cost of "snubbing": the effect of parental phubbing on filial piety behavior in children and adolescents.

Background: Although numerous studies have used Chinese samples to examine the consequences of parental phubbing, these studies focused on children's mental health and peer interaction. No research to date has directly explored the association between parental phubbing and child-parent interaction. Since parental phubbing is a way how parents interact with their children (parent-child), it might be associated with the way how children interact with their parents (child-parent), such as filial piety behavior, which prescribes how children behave toward their parents and remains one of the goals of parents in educating their children in modern Chinese society. Based on social exchange theory and social gender theory, this study investigated the impact of parental phubbing on filial piety behavior and tested its mediation of perceived parental rejection, its moderation of gender among children and adolescents. Methods: This study was conducted using a questionnaire method. A total of 753 students from Grade 4 to 9 (Mage = 12.28 years, SD = 1.81 years) was surveyed using the Parental Phubbing Scale, Perceived Parental Rejection Questionnaire, and the revised Dual Filial Piety Scale. Results: First, parental phubbing was negatively correlated with reciprocal filial piety (RFP) behavior, but not correlated with authoritarian filial piety (AFP) behavior. Second, perceived parental rejection played a mediating role between parental phubbing and RFP behavior. Third, this direct effect was moderated by gender, in that it was stronger for boys than for girls. Conclusion: These findings suggest that there are intergenerational costs of phubbing, such as reducing children and adolescents' RFP behavior. The present study is the first to combine parent-child interaction in the digital media era (parental phubbing) with traditional Chinese child-parent interaction (RFP behavior), which expands the research topic on the influence of parental phubbing on children and adolescents' psychological development.

Regulation and mechanistic insights into tensile strain in mesenchymal stem cell osteogenic differentiation.

Bone marrow mesenchymal stem cells (BMSCs) are integral to bone remodeling and homeostasis, as they are capable of differentiating into osteogenic and adipogenic lineages. This differentiation is substantially influenced by mechanosensitivity, particularly to tensile strain, which is a prevalent mechanical stimulus known to enhance osteogenic differentiation. This review specifically examines the effects of various cyclic tensile stress (CTS) conditions on BMSC osteogenesis. It delves into the effects of different loading devices, magnitudes, frequencies, elongation levels, dimensionalities, and coculture conditions, providing a comparative analysis that aids identification of the most conducive parameters for the osteogenic differentiation of BMSCs. Subsequently, this review delineates the signaling pathways activated by CTS, such as Wnt/ß-catenin, BMP, Notch, MAPK, PI3K/Akt, and Hedgehog, which are instrumental in mediating the osteogenic differentiation of BMSCs. Through a detailed examination of these pathways, this study elucidates the intricate mechanisms whereby tensile strain promotes osteogenic differentiation, offering valuable guidance for optimizing therapeutic strategies aimed at enhancing bone regeneration.

Analysis of water quality and the response of phytoplankton in the low-temperature environment of Majiagou Urban River, China.

Majiagou River, a crucial urban river in Harbin, traverses densely populated areas including agricultural, suburban, and main urban areas, presenting highly intricate habitat characteristics. In recent years, urbanization has significantly intensified human interference, fundamentally reshaping the phytoplankton community. Understanding the response mechanism of phytoplankton to environmental factors is of paramount importance as they serve as primary producers in aquatic ecosystems. To investigate this, we established 25 sampling sites to analyze the phytoplankton community and 14 key physicochemical parameters, such as total phosphorus (TP) and total nitrogen (TN). Utilizing hierarchical clustering analysis (HCA) and One-way Analysis of Variance (ANOVA), we identified distinct river segments, revealing spatial distribution differences and environmental factor variations among phytoplankton species across segments. By adopting redundancy analysis (RDA), we pinpointed the primary environmental factors impacting phytoplankton communities and examined the correlation between phytoplankton and these factors to elucidate the driving mechanisms governing phytoplankton dynamics. The outcomes demonstrated that the phytoplankton community in Majiagou River was predominantly composed of Bacillariophyta and Chlorophyta, however, notable disparities in spatial distribution and species composition resulting from human interference were evident. Areas with intense human disturbance were dominated by diatoms and exhibited trends of homogenization and reduced biodiversity. RDA showed that pH, NH4+-N, NH3-N, chemical oxygen demand (COD), and TP were key environmental factors influencing phytoplankton communities. We have confirmed that due to variations in environment conditions and different levels of human disturbance, there will be some differences in the critical limiting factors affecting phytoplankton. Our study offers valuable insights for governing urban rivers during the low-temperature period.

Arbuscular Mycorrhizal Fungi Improve Lycium barbarum Potassium Uptake by Activating the Expression of LbHAK.

Arbuscular mycorrhizal (AM) fungi can establish a mutualistic relationship with the roots of most terrestrial plants to increase plant nutrient uptake. The effects of potassium uptake and transport by AM symbiosis are much less reported compared to other nutrients. In this research, a heterologous yeast system was used to verify that the LbHAK has capacity for potassium uptake. The split-roots system implemented using seedlings of Lycium barbarum confirmed that R. irregularis locally induced LbHAK expression, which means that LbHAK is only expressed in mycorrhizal roots. Furthermore, the impacts of overexpression of LbHAK on the growth, nutrients and water uptake, and transport of mycorrhizal tobacco (inoculation with Rhizophagus irregularis) at 0.2 mM and 2 mM K conditions were assessed. The mycorrhizal tobacco growth and potassium accumulation were significantly enhanced through LbHAK overexpression in tobacco. In addition, overexpression of LbHAK substantially enhanced phosphorus content, while stimulating the expression of NtPT4, Rir-AQP1, and Rir-AQP2 in mycorrhizal tobacco. Moreover, LbHAK overexpression greatly promoted AM colonization. LbHAK has a potential role in facilitating potassium absorption through the mycorrhizal pathway, and overexpression of LbHAK in tobacco may promote the transport of potassium, phosphorus, and water from AM fungi to tobacco. These data imply the important roles played by the LbHAK in AM-fungi-induced potassium uptake in L. barbarum and in improving plant nutrients and AM colonization.

A Rat Dry Eye Model with Lacrimal Gland Dysfunction Induced by Scopolamine.

Aqueous-deficient dry eye (ADDE) is a type of dry eye disease that can result in the reduction of tear secretion quantity and quality. Prolonged abnormal tear production can lead to a disturbance in the ocular surface environment, including corneal damage and inflammation. In severe cases, ADDE can cause vision loss or even blindness. Currently, dry eye treatment is limited to eye drops or physical therapy, which can only alleviate eye discomfort symptoms and cannot fundamentally cure dry eye syndrome. To restore the function of the lacrimal gland in dry eye, we have created an animal model of lacrimal gland dysfunction in rats induced by scopolamine. Through the comprehensive evaluation of the lacrimal gland, corneas, conjunctivas, and other factors, we aim to provide a full understanding of the pathological changes of ADDE. Compared with the current dry eye mouse model, this ADDE animal model includes a functional evaluation of the lacrimal gland, providing a better platform for studying lacrimal gland dysfunction in ADDE.

16S rRNA sequencing in chronic dacryocystitis.

CLINICAL RELEVANCE: The pathogenesis of chronic dacryocystitis (CDC) is associated with a variety of bacteria. Investigating microflora has the potential to provide a theoretical basis for preventing and treating CDC. BACKGROUND: 16S rRNA sequencing is a sequence-based bacterial analysis. The application of 16S rRNA sequencing in CDC is rarely reported. METHODS: A case-control study of infected and healthy eyes diagnosed as CDC patients was conducted. Seventy-eight patients were divided into A (conjunctival sac secretions from healthy eyes), B (conjunctival sac secretions from affected eyes), and C (lacrimal sac secretions from affected eyes) groups. The flora of samples was analysed with 16S rRNA sequencing, and the data was analysed using QIIME, R, LefSE and other software. The potential functions were analysed by PICRUSt. RESULTS: A total of 1440 operational taxonomic units (OTUs) were obtained, 139 specific to group A, 220 specific to group B, and 239 specific to group C. There was no significant difference in α index between the three groups. The beta diversity and grouping analysis data indicated that the three groups of flora were similar in species richness and diversity, but there were some differences in composition. In group A, the abundance of Pseudomonadaceae, Chlorobacteria, Moraceae, Staphylococcaceae, Bacillariophyceae, Immunobacterium spp. and Bacillus spp. was higher; in group B, the abundance of Burkholderiaceae, Sphingomonas, Rhizobia, Stalked Bacteria, Sphingomonadaceae, Enterobacteriaceae, Shortwaveomonas spp. was higher; in group C, the abundance of Streptococcus digestiveis, Propionibacterium, Enterobacteriaceae, Anaerobacteriaceae, Propionibacteriaceae, Bacillus spp. Neisseria spp. and Shortactomonas spp. was higher. Six pathways were identified to assess the potential microbial functions. CONCLUSION: Alterations in the microbiota of the conjunctiva and lacrimal sac are associated with the pathogenesis of CDC, which may provide certain guidance for antibiotic treatment of CDC.

Ubiquitous occurrence of 1,4-dioxane in drinking water of China and its ecological and human health risk.

The occurrence and distribution of 1,4-dioxane was investigated in 280 source and finished drinking water samples from 31 Chinese cities, based on which its ecological and health risks were systematically evaluated. The findings demonstrated that 1,4-dioxane was detected in about 80.0 % samples with values ranging from n.d. to 7757 ng/L in source water and n.d. to 2918 ng/L in drinking water. 1,4-Dioxane showed limited removal efficiency using conventional coagulation-sedimentation-filtration processes (14 % ± 48 %), and a removal efficiency of 35 % ± 44 % using ozonation-biological activated carbon advanced treatment processes. Relatively higher concentrations, detection frequency and environmental risk were observed in Taihu Lake, Yellow River, Yangtze River, Zhujiang River, and Huaihe River mainly in the eastern and southern regions, where there are considerable industrial activities and comparatively high population densities. The widespread presence as by-products during manufacturing consumer products e.g., ethoxylated surfactants, suggested municipal wastewater discharges were the dominant source for the ubiquitous occurrence of 1,4-dioxane, while industrial activities, e.g. resin manufacturing, also contribute considerably to the elevated concentrations of 1,4-dioxane. The estimated risk quotients were in the range of <1.5 × 10-4 for ecological risk, <5.0 × 10-3 by oral exposure and < 5.0 × 10-2 by inhalation exposure for health risk, illustrating limited ecological harm to water environment or chronic toxicity to human health. For carcinogenic risk, 1,4-Dioxane presented a mean risk of 1.8 × 10-6 by oral exposure, which slightly surpassed the recommended acceptable levels of U.S. EPA (<10-6), and risk from inhalation exposure could be negligible. The pervasiveness in drinking water, low removal efficiencies during water treatment processes, and suspected health impacts, highlighted the necessity to set related water quality standards of 1,4-dioxane in order to improve water environment in China.

Immunogenicity and effectiveness of an mRNA therapeutic vaccine for HPV-related malignancies.

Human papillomavirus (HPV) infections account for several human cancers. There is an urgent need to develop therapeutic vaccines for targeting preexisting high-risk HPV (such as HPV 16 and 18) infections and lesions, which are insensitive to preventative vaccines. In this study, we developed a lipid nanoparticle-formulated mRNA-based HPV therapeutic vaccine (mHTV), mHTV-02, targeting the E6/E7 of HPV16 and HPV-18. mHTV-02 dramatically induced antigen-specific cellular immune response and robust memory T-cell immunity in mice, besides significant CD8+ T-cell infiltration and cytotoxicity in TC-1 tumors expressing HPV E6/E7, resulting in tumor regression and prolonged survival in mice. Moreover, evaluation of routes of administration found that intramuscular or intratumoral injection of mHTV-02 displayed significant therapeutic effects. In contrast, intravenous delivery of the vaccine barely showed any benefit in reducing tumor size or improving animal survival. These data together support mHTV-02 as a candidate therapeutic mRNA vaccine via specific administration routes for treating malignancies caused by HPV16 or HPV18 infections.

A cell-based assay to discover inhibitors of Zika virus RNA-dependent RNA polymerase.

Zika virus (ZIKV) belongs to Flaviviridae, the Flavivirus genus. Its infection causes congenital brain abnormalities and Guillain-Barré syndrome. However, there are no effective vaccines, no FDA-approved drugs to manage ZIKV infection. The non-structural protein NS5 of ZIKV has been recognized as a valuable target of antivirals because of its RNA-dependent RNA polymerase (RdRp) and methyltransferase (MTase) activities essential for viral RNA synthesis. Here, we report a cell-based assay for discovering inhibitors of ZIKV NS5 and found that 5-Azacytidine potently inhibits ZIKV NS5, with EC50 of 4.9 µM. Furthermore, 5-Azacytidine suppresses ZIKV replication by inhibiting NS5-mediated viral RNA transcription. Therefore, we have developed a cell-based ZIKV NS5 assay which can be deployed to discover ZIKV NS5 inhibitors and demonstrated the potential of 5-Azacytidine for further development as a ZIKV NS5 inhibitor.

ITGB5 facilitates gastric cancer metastasis by promoting TGFBR2 endosomal recycling.

TGFBR2, a key regulator of the TGFß signaling pathway, plays a crucial role in gastric cancer (GC) metastasis through its endosomal recycling process. Despite its importance, the mechanisms governing this process remain unclear. Here, we identify integrin ß5 (ITGB5) as a critical mediator that promotes TGFBR2 endosomal recycling. Our study reveals elevated expression of ITGB5 in GC, particularly in metastatic cases, correlating with poor patient outcomes. Knockdown of ITGB5 impairs GC cell metastasis both in vitro and in vivo. Mechanistically, ITGB5 facilitates epithelial-mesenchymal transition mediated by TGFß signaling, thereby enhancing GC metastasis. Acting as a scaffold, ITGB5 interacts with TGFBR2 and SNX17, facilitating SNX17-mediated endosomal recycling of TGFBR2 and preventing lysosomal degradation, thereby maintaining its surface distribution on tumor cells. Notably, TGFß signaling directly upregulates ITGB5 expression, establishing a positive feedback loop that exacerbates GC metastasis. Our findings shed light on the role of ITGB5 in promoting GC metastasis through SNX17-mediated endosomal recycling of TGFBR2, providing insights for the development of targeted cancer therapies.

Controlled Refolding of Denatured IL-12 Using In Situ Antigen-Capturing Nanochaperone Remarkably Reduces the Systemic Toxicity and Enhances Cancer Immunotherapy.

Cytokines are powerful in cancer immunotherapy, however, their therapeutic potential is limited by the severe systemic toxicity. Here a potent strategy to reduce the toxicity of systemic cytokine therapy by delivering its denatured form using a finely designed nanochaperone, is described. It is demonstrated that even if the denatured protein cargos are occasionally released under normal physiological conditions they are still misfolded, while can effectively refold into native states and release to function in tumor microenvironment. Consequently, the systemic toxicity of cytokines is nearly completely overcome. Moreover, an immunogenic cell death (ICD)-inducing chemotherapeutic is further loaded and delivered to tumor using this nanochaperone to trigger the release of tumor-associated antigens (TAAs) that are subsequently captured in situ by nanochaperone and then reflows into lymph nodes (LNs) to promote antigen cross-presentation. This optimized personalized nanochaperone-vaccine demonstrates unprecedented suppressive effects against large, advanced tumors, and in combination with immune checkpoint blockade (ICB) therapy results in a significant abscopal effect and inhibition of postoperative tumor recurrence and metastasis. Hence, this approach provides a simple and universal delivery strategy to reduce the systemic toxicities of cytokines, as well as provides a robust personalized cancer vaccination platform, which may find wide applications in cancer immunotherapy.

Evaluation of the flavor profiles of Yanbian-style sauced beef from differently treated raw beef samples.

In this study, we investigated the volatile flavor compounds and sensory perceptions of Yanbian-style sauced beef prepared from raw meats subjected to different treatments (hot fresh, chilled, and frozen beef). The results indicated that the treatment of raw beef significantly impacted the quality and flavor of sauced beef. Sauced chilled beef (CRSB) exhibited the highest content of fatty acids and total amino acids. A total of 48 volatile compounds were identified. Moreover, a relative odor activity value analysis identified hexanal, nonanal, heptanal, 1-octen-3-ol, and 2,3-octanedione as the characteristic flavor compounds in Yanbian-style sauced beef. The sensory evaluation demonstrated that CRSB was the most palatable and flavorful. Additionally, correlation loading plot analysis indicated strong correlations between sensory evaluation, fatty acids, amino acids, and volatile flavor compounds. These results suggest that chilled beef meat is the best raw material for the production of Yanbian-style sauced beef.