Disassembly of the TRIM56-ATR complex promotes cytoDNA/cGAS/STING axis-dependent intervertebral disc inflammatory degeneration.

As the leading cause of disability worldwide, low back pain (LBP) is recognized as a pivotal socioeconomic challenge to the aging population and is largely attributed to intervertebral disc degeneration (IVDD). Elastic nucleus pulposus (NP) tissue is essential for the maintenance of IVD structural and functional integrity. The accumulation of senescent NP cells with an inflammatory hypersecretory phenotype due to aging and other damaging factors is a distinctive hallmark of IVDD initiation and progression. In this study, we reveal a mechanism of IVDD progression in which aberrant genomic DNA damage promoted NP cell inflammatory senescence via activation of the cyclic GMP-AMP synthase/stimulator of IFN genes (cGAS/STING) axis but not of absent in melanoma 2 (AIM2) inflammasome assembly. Ataxia-telangiectasia-mutated and Rad3-related protein (ATR) deficiency destroyed genomic integrity and led to cytosolic mislocalization of genomic DNA, which acted as a powerful driver of cGAS/STING axis-dependent inflammatory phenotype acquisition during NP cell senescence. Mechanistically, disassembly of the ATR-tripartite motif-containing 56 (ATR-TRIM56) complex with the enzymatic liberation of ubiquitin-specific peptidase 5 (USP5) and TRIM25 drove changes in ATR ubiquitination, with ATR switching from K63- to K48-linked modification, c thereby promoting ubiquitin-proteasome-dependent dynamic instability of ATR protein during NP cell senescence progression. Importantly, an engineered extracellular vesicle-based strategy for delivering ATR-overexpressing plasmid cargo efficiently diminished DNA damage-associated NP cell senescence and substantially mitigated IVDD progression, indicating promising targets and effective approaches to ameliorate the chronic pain and disabling effects of IVDD.

Spatial mapping of corneal biomechanical properties using wave-based optical coherence elastography.

Quantifying the mechanical properties of the cornea can provide valuable insights into the occurrence and progression of keratoconus, as well as the effectiveness of corneal crosslinking surgery. This study presents a non-contact and non-invasive wave-based optical coherence elastography system that utilizes air-pulse stimulation to create a two-dimensional map of corneal elasticity. Homogeneous and dual concentration phantoms were measured with the sampling of 25 × 25 points over a 6.6 × 6.6 mm2 area, to verify the measurement capability for elastic mapping and the spatial resolution (0.91 mm). The velocity of elastic waves distribution of porcine corneas before and after corneal crosslinking surgery were further mapped, showing a significant change in biomechanics in crosslinked region. This system features non-invasiveness and high resolution, holding great potential for application in ophthalmic clinics.

Resveratrol prevents age-related heart impairment through inhibiting the Notch/NF-κB pathway.

Resveratrol (RSV) is a natural polyphenol compound found in various plants that has been shown to have potential benefits for preventing aging and supporting cardiovascular health. However, the specific signal pathway by which RSV protects the aging heart is not yet well understood. This study aimed to explore the protective effects of RSV against age-related heart injury and investigate the underlying mechanisms using a D-galactose-induced aging model. The results of the study indicated that RSV provided protection against age-related heart impairment in mice. This was evidenced by the reduction of cardiac histopathological changes as well as the attenuation of apoptosis. RSV-induced cardioprotection was linked to a significant increase in antioxidant activity and mitochondrial transmembrane potential, as well as a reduction in oxidative damage. Additionally, RSV inhibited the production of pro-inflammatory cytokines such as interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α). Furthermore, the expression of toll-like receptor 4 (TLR4), nuclear factor kappa-B p65 (NF-κB p65), and notch 1 protein were inhibited by RSV, indicating that inhibiting the Notch/NF-κB pathway played a critical role in RSV-triggered heart protection in aging mice. Moreover, further data on intestinal function demonstrated that RSV significantly increased short-chain fatty acids (SCFAs) in intestinal contents and reduced the pH value in the feces of aging mice. RSV alleviated aging-induced cardiac dysfunction through the suppression of oxidative stress and inflammation via the Notch/NF-κB pathway in heart tissue. Furthermore, this therapeutic effect was found to be associated with its protective roles in the intestine.

Linagliptin's impact on lymphatic barrier and lymphangiogenesis in oral cancer with high glucose.

OBJECTIVES: Uncertainties remain regarding the effect of elevated glucose levels on lymphatic metastasis of cancer cells. Our study elucidated the mechanisms linking high glucose to lymphangiogenesis and lymphatic barrier-related factors and investigated the protective role of linagliptin against lymphatic barrier dysfunction. MATERIALS AND METHODS: A CAL-27-LEC co-culture system was established. Sodium fluorescein permeability assay observed lymphatic endothelial cell permeability. Western blotting and RT-qPCR detected protein and mRNA expression under different conditions, respectively. CCK-8, scratch wound healing, and transwell assays revealed cell migration and proliferation. Tube formation experiment tested capacity for endothelial tube formation. Immunohistochemical staining analyzed tissue sections from 43 oral cancer individuals with/without diabetes. RESULTS: In high-glucose co-culture system, we observed increased lymphatic barrier permeability and decreased expression of ZO-1 and occludin, two tight-junction proteins; conversely, the expression of PAR2, a high permeability-related protein, was increased. Following linagliptin treatment, the expression levels of VEGF-C, VEGFR-3, and PAR2 decreased, while those of ZO-1 and occludin increased. Considerably higher levels of LYVE-1 expression in individuals with diabetes than in those without diabetes. CONCLUSIONS: By ameliorating the high glucose-induced disruption of the lymphatic endothelial barrier, linagliptin may reduce lymphangiogenesis and exhibit an inhibitory effect on lymphatic metastasis in oral cancer patients with diabetes.

Engineering mesoporous bioactive glasses for emerging stimuli-responsive drug delivery and theranostic applications.

Mesoporous bioactive glasses (MBGs), which belong to the category of modern porous nanomaterials, have garnered significant attention due to their impressive biological activities, appealing physicochemical properties, and desirable morphological features. They hold immense potential for utilization in diverse fields, including adsorption, separation, catalysis, bioengineering, and medicine. Despite possessing interior porous structures, excellent morphological characteristics, and superior biocompatibility, primitive MBGs face challenges related to weak encapsulation efficiency, drug loading, and mechanical strength when applied in biomedical fields. It is important to note that the advantageous attributes of MBGs can be effectively preserved by incorporating supramolecular assemblies, miscellaneous metal species, and their conjugates into the material surfaces or intrinsic mesoporous networks. The innovative advancements in these modified colloidal inorganic nanocarriers inspire researchers to explore novel applications, such as stimuli-responsive drug delivery, with exceptional in-vivo performances. In view of the above, we outline the fabrication process of calcium-silicon-phosphorus based MBGs, followed by discussions on their significant progress in various engineered strategies involving surface functionalization, nanostructures, and network modification. Furthermore, we emphasize the recent advancements in the textural and physicochemical properties of MBGs, along with their theranostic potentials in multiple cancerous and non-cancerous diseases. Lastly, we recapitulate compelling viewpoints, with specific considerations given from bench to bedside.

Mesenchymal Stem Cell-Derived Mitochondria Enhance Extracellular Matrix-Derived Grafts for the Repair of Nerve Defect.

Peripheral nerve injuries (PNI) can lead to mitochondrial dysfunction and energy depletion within the affected microenvironment. The objective is to investigate the potential of transplanting mitochondria to reshape the neural regeneration microenvironment. High-purity functional mitochondria with an intact structure are extracted from human umbilical cord-derived mesenchymal stem cells (hUCMSCs) using the Dounce homogenization combined with ultracentrifugation. Results show that when hUCMSC-derived mitochondria (hUCMSC-Mitos) are cocultured with Schwann cells (SCs), they promote the proliferation, migration, and respiratory capacity of SCs. Acellular nerve allografts (ANAs) have shown promise in nerve regeneration, however, their therapeutic effect is not satisfactory enough. The incorporation of hUCMSC-Mitos within ANAs has the potential to remodel the regenerative microenvironment. This approach demonstrates satisfactory outcomes in terms of tissue regeneration and functional recovery. Particularly, the use of metabolomics and bioenergetic profiling is used for the first time to analyze the energy metabolism microenvironment after PNI. This remodeling occurs through the enhancement of the tricarboxylic acid cycle and the regulation of associated metabolites, resulting in increased energy synthesis. Overall, the hUCMSC-Mito-loaded ANAs exhibit high functionality to promote nerve regeneration, providing a novel regenerative strategy based on improving energy metabolism for neural repair.

The stool syndecan2 methylation test is more robust than blood tests for methylated septin9, CEA, CA19-9 and CA724: a diagnostic test for the early detection of colorectal neoplasms.

Background: Methylated syndecan2 (mSDC2) in stool samples has been found to be associated with colorectal cancer (CRC) and precancerous lesions. However, the available data are limited, and no previous studies have compared the analysis of mSDC2 with other diagnostic tests. Thus, we aimed to evaluate the clinical performance of a stool mSDC2 test and compare its performance with that of blood-based tests for methylated septin9 (mSEPT9), carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9) and carbohydrate antigen 724 (CA724) in detecting colorectal neoplasms. Methods: The gold standard diagnostic technique that was used was colonoscopy combined with a pathological analysis of biopsied tissue. Stool DNA was extracted from 1,002 stool samples (445 from CRCs, 115 from adenomas, and 442 from controls) and then bisulfite-converted, followed by real-time quantitative methylation-specific polymerase chain reaction. Blood mSEPT9 levels were quantified by the Epi proColon 2.0 assay, and serum CEA, CA19-9 and CA724 levels were measured by electrochemiluminescence. The main indexes used during the evaluation were sensitivity, specificity and the area under the receiver operating characteristic curve (AUC). Results: Stool mSDC2 detected 69.7% of CRCs, which was significantly higher than 53.8% by plasma mSEPT9, 37.2% by CEA, 13.1% by CA19-9 and 17.5% by CA724; for adenoma, the detection rates were 31.3%, 11.1%, 2.3% and 11.9%, respectively. The AUC of mSDC2 in detecting CRC was 0.83, compared to 0.72, 0.75, 0.63 and 0.54 for mSEPT9, CEA, CA19-9 and CA724, respectively. mSDC2 identified patients with stage I-III CRC with a sensitivity of 71.6%, which was significantly higher than that of mSEPT9, CEA, CA19-9 and CA724 (54.2%, 35.5%, 11.9%, and 15.0%, respectively); for stage IV CRC, the sensitivities of mSDC2, mSEPT9, CEA, CA19-9 and CA724 were 75.9%, 82.6%, 79.3%, 36.0% and 56.5%, respectively. SDC2 and CEA had a significantly higher sensitivity for distal CRC than for proximal CRC. Conclusions: The stool SDC2 methylation test had a better performance in detecting nonmetastatic CRC and adenoma than evaluations of mSEPT9, CEA, CA19-9 and CA724 in blood. Our findings could be used to modify approaches for CRC prevention and early detection.

Plasma metabolomic characterization of premature ovarian insufficiency.

BACKGROUND: Premature ovarian insufficiency (POI) patients are predisposed to metabolic disturbances, including in lipid metabolism and glucose metabolism, and metabolic disorders appear to be a prerequisite of the typical long-term complications of POI, such as cardiovascular diseases or osteoporosis. However, the metabolic changes underlying the development of POI and its subsequent complications are incompletely understood, and there are few studies characterizing the disturbed metabolome in POI patients. The aim of this study was to characterize the plasma metabolome in POI by using ultrahigh-performance liquid chromatography-mass spectrometry (UHPLC-MS/MS) metabolomics and to evaluate whether these disturbances identified in the plasma metabolome relate to ovarian reserve and have diagnostic value in POI. METHODS: This observational study recruited 30 POI patients and 30 age- and body mass index (BMI)-matched controls in the Center for Reproductive Medicine, Department of Gynecology and Obstetrics, Nanfang Hospital, Southern Medical University, from January 2018 to October 2020. Fasting venous blood was collected at 9:00 am on days 2-4 of the menstrual cycle and centrifuged for analysis. An untargeted quantitative metabolomic analysis was performed using UHPLC-MS/MS. RESULTS: Our study identified 48 upregulated and 21 downregulated positive metabolites, and 13 upregulated and 48 downregulated negative metabolites in the plasma of POI patients. The differentially regulated metabolites were involved in pathways such as caffeine metabolism and ubiquinone and other terpenoid-quinone biosynthesis. Six metabolites with an AUC value > 0.8, including arachidonoyl amide, 3-hydroxy-3-methylbutanoic acid, dihexyl nonanedioate, 18-HETE, cystine, and PG (16:0/18:1), were correlated with ovarian reserve and thus have the potential to be diagnostic biomarkers of POI. CONCLUSION: This UHPLC-MS/MS untargeted metabolomics study revealed differentially expressed metabolites in the plasma of patients with POI. The differential metabolites may not only be involved in the aetiology of POI but also contribute to its major complications. These findings offer a panoramic view of the plasma metabolite changes caused by POI, which may provide useful diagnostic and therapeutic clues for POI disease.

Utilizing chemotherapy-induced tumor RNA nanoparticles to improve cancer chemoimmunotherapy.

Chemotherapy has become a popular combination strategy to improve the response rate of immunotherapy since certain chemotherapeutic drugs kill tumor cells by an immunogenic cell death (ICD) pathway, which activates antitumor immune responses. Unfortunately, the synergistic effect of chemoimmunotherapy can be impaired due to the toxicities of chemotherapeutic agent-induced lymphatic depletion and immunosuppression. In this study, we present an approach to improve immunotherapy by using tumor RNA nanoparticles (RNA-NPs) where RNA is directly extracted from chemotherapy-treated cancer cells and then condensed by protamine via electrostatic interactions to form complexes. Such RNA-NPs can be effectively taken up by dendritic cells (DCs) in the draining lymph nodes after subcutaneous injection. Compared with noninduced tumor RNA nanoparticles (N-RNA-NPs), chemotherapy-induced tumor RNA nanoparticles (C-RNA-NPs) can significantly promote DC maturation and stimulate a stronger immune response against established CT-26 colon carcinoma. Besides, C-RNA-NPs can improve the efficacy of immune checkpoint blockade (ICB) therapy by facilitating the infiltration of intratumoral T cells and increasing the ratio of CD8+ T cells to regulatory T cells (Tregs). More importantly, the synergistic effect of chemoimmunotherapy is also enhanced by treatment with C-RNA-NPs. STATEMENT OF SIGNIFICANCE: Although immune checkpoint blockade therapy has been demonstrated to be effective in some advanced cancers, the low response rate has significantly limited its clinical application. To address this issue, a new strategy for improving cancer immunotherapy using chemotherapy-induced tumor RNA nanoparticles (C-RNA-NPs) is developed in this work. The proposed C-RNA-NPs could be captured by dendritic cells, which were then stimulated to the maturation status to initiate an anticancer immune response. Furthermore, the response rate to immunotherapy was significantly increased by promoting intratumoral T-cell infiltration and elevating the intratumoral ratio of CD8+ T cells to regulatory T cells after treatment with C-RNA-NPs. Therefore, C-RNA-NPs have the potential to improve cancer immunotherapy.

Young Patients With Colorectal Cancer Have Higher Early Mortality but Better Long-Term Survival.

INTRODUCTION: To define the prognosis of colorectal cancer (CRC) in young patients and to compare their postoperative treatment with that of older patients. METHODS: This multicenter study enrolled 5,457 patients with primary CRC who underwent surgical resection. The overall survival (OS), clinicopathologic characteristics, and postoperative treatment of 253 young patients aged 18-44 years and 5,204 older patients aged 44-80 years were analyzed. RESULTS: The OS rate was 77.1% for young and 74.2% for older patients (P = 0.348). Landmark analysis showed a significant difference in survival between young and older patients, with 63.8% of deaths among young patients being within 25 months of surgery compared with 42.4% among older patients (P = 0.002). Among those who survived more than 25 months, young patients had significantly better survival than older patients (P = 0.009). Multivariable analysis of young patients revealed that the tumor location, perineural invasion, and stage were associated with poor survival within 25 months; after this period, stage was the only prognostic marker. Young patients were more likely to receive chemotherapy, particularly multiagent regimens. For young patients, no significant difference in OS was found based on the chemotherapy regimen, regardless of disease stage (II, III, or IV, all P > 0.05). In addition, unlike in older patients, no difference in OS was found in young patients regardless of the drug regimen administered (all P > 0.05). DISCUSSION: Young-onset CRC may have a unique disease biology that warrants further research and therapy development.

The prognostic and clinical value of p53 upregulated modulator of apoptosis expression in solid tumors: a meta-analysis and TCGA data review.

BACKGROUND: Previous studies have reported the prognostic value of p53 upregulated modulator of apoptosis (PUMA) in numerous human tumors, but the conclusions have not been consistent. Therefore, this meta-analysis and the Cancer Genome Atlas (TCGA) data analysis were performed to estimate the prognostic significance of PUMA in solid tumors. RESEARCH DESIGN AND METHODS: A search was conducted in PubMed, Embase, Web of Science, Cochrane Library and CNKI up to 21 July 2022. In total, 10 studies with 2,207 patients were included. We extracted the overall survival (OS) and disease-free survival (DFS) data. The hazard ratios (HRs) and 95% confidence intervals (95% CI) were adopted for evaluating the association. RESULTS: Decreased PUMA expression was significantly associated with worse OS (HR = 0.54, 95% CI = 0.38-0.78) and worse DFS (HR = 0.54, 95% CI = 0.42-0.70). Subgroup analysis showed that the prognostic role of PUMA for OS was most significant in the digestive system (HR = 0.52, 95% CI = 0.38-0.69). Furthermore, the expression of PUMA was not affected by tumor differentiation or clinical stage, and TCGA dataset analysis confirmed these results. CONCLUSIONS: We proved that expression of PUMA may serve as an independent prognostic factor for patients with solid tumors.

m6A modification-mediated lncRNA TP53TG1 inhibits gastric cancer progression by regulating CIP2A stability.

Long noncoding RNAs (lncRNAs) are associated with various types of cancer. However, the precise roles of many lncRNAs in tumor progression remain unclear. In this study, we found that the expression of the lncRNA TP53TG1 was downregulated in gastric cancer (GC) and it functioned as a tumor suppressor. In addition, low TP53TG1 expression was significantly associated with poor survival in patients with GC. TP53TG1 inhibited the proliferation, metastasis, and cell cycle progression of GC cells, while it promoted their apoptosis. m6A modification sites are highly abundant on TP53TG1, and demethylase ALKBH5 reduces TP53TG1 stability and downregulates its expression. TP53TG1 interacts with cancerous inhibitor of protein phosphatase 2A (CIP2A) and triggers its ubiquitination-mediated degradation, resulting in the inhibition of the PI3K/AKT pathway. These results suggest that TP53TG1 plays an important role in inhibiting the progression of GC and provides a crucial target for GC treatment.

Circulating Methylated SEPT9 DNA Analyses to Predict Recurrence Risk and Adjuvant Chemotherapy Benefit in Stage II to III Colorectal Cancer.

BACKGROUND We aimed to evaluate the ability of circulating cell-free methylated SETP9 DNA (mSEPT9) to identify recurrence and to determine its clinical utility in adjuvant chemotherapy (ACT) regimen decisions. MATERIAL AND METHODS This study enrolled 426 patients with stage II-III CRC who received radical resection between January 8, 2018, and November 30, 2020. The median follow-up duration was 15.8 months (range, 8.1-43.4 months). The primary endpoint was recurrence-free survival (RFS). A propensity score matching model was used to minimize potential confounding covariates and to confirm our findings. RESULTS In stage II-III CRC patients, postoperative (within 1 month after surgery) mSEPT9 positivity was significantly correlated with worse RFS (HR=6.21, P<0.001), and it remained the strongest independent predictor in multivariate Cox regression analysis (HR=5.83, P<0.001), which was significantly superior to CEA, CA19-9, and CA242. During disease surveillance, mSEPT9 positivity preceded radiographic recurrence by a median of 5.0 months. The postoperative mSEPT9-positive patients benefited more from CAPEOX compared to FOLFOX (HR=3.97, P=0.017), while for mSEPT9-negative patients, CAPEOX and FOLFOX resulted in similar RFS (HR=1.70, P=0.322). Furthermore, 3 months of CAPEOX was more effective than 3 and 6 months of FOLFOX (HR=4.40, P=0.065; HR=1.56, P=0.073, respectively). CONCLUSIONS Our results revealed that mSEPT9 detection after radical resection could identify minimal residual disease (MRD) and could predict a high risk of recurrence in patients with stage II-III CRC. Furthermore, we show pioneering work that mSEPT9 detection could be used to guide the selection of an adjuvant chemotherapy regimen to improve RFS.

Patient stratification based on urea cycle metabolism for exploration of combination immunotherapy in colon cancer.

BACKGROUND: Owing to the low ratio of patients benefitting from immunotherapy, patient stratification becomes necessary. An accurate patient stratification contributes to therapy for different tumor types. Therefore, this study aimed to subdivide colon cancer patients for improved combination immunotherapy. METHODS: We characterized the patients based on urea cycle metabolism, performed a consensus clustering analysis and constructed a risk model in the cancer genome atlas cohort. Colon cancer patients were further categorized into two tags: clusters, and risk groups, for the exploration of combination immunotherapy. In addition to external validation in the Gene Expression Omnibus datasets, several images of immunohistochemistry were used for further validation. RESULTS: Patient characterization based on urea cycle metabolism was related to immune infiltration. An analysis of consensus clustering and immune infiltration generated a cluster distribution and identified patients in cluster 1 with high immune infiltration levels as hot tumors for immunotherapy. A risk model of seven genes was constructed to subdivide the patients into low- and high-risk groups. Validation was performed using a cohort of 731 colon cancer patients. Patients in cluster 1 had a higher immunophenoscore (IPS) in immune checkpoint inhibitor therapy, and those other risk groups displayed varying sensitivities to potential combination immunotherapeutic agents. Finally, we subdivided the colon cancer patients into four groups to explore combination immunotherapy. Immunohistochemistry analysis showed that protein expression of two genes were upregulated while that of other two genes were downregulated or undetected in cancerous colon tissues. CONCLUSION: Using subdivision to combine chemotherapy with immunotherapy would not only change the dilemma of immunotherapy in not hot tumors, but also promote the proposition of more rational personalized therapy strategies in future.

Nickel-Catalyzed Decarbonylative Thioetherification of Carboxylic Acids with Thiols.

A nickel-catalyzed decarbonylative thioetherification of carboxylic acids with thiols was developed. Under the reaction conditions, benzoic acids, cinnamic acids, and benzyl carboxylic acids coupled with various thiols including both aromatic and aliphatic ones produce the corresponding thioethers in up to 99% yields. Moreover, this reaction was applicable to the modification of bioactive molecules such as 3-methylflavone-8-carboxylic acid, probenecid, and flufenamic acid, and the synthesis of acaricide chlorbenside. These results well demonstrated the potential synthetic value of this new reaction in organic synthesis.

Advances of functional nanomaterials for magnetic resonance imaging and biomedical engineering applications.

Functional nanomaterials have been widely used in biomedical fields due to their good biocompatibility, excellent physicochemical properties, easy surface modification, and easy regulation of size and morphology. Functional nanomaterials for magnetic resonance imaging (MRI) can target specific sites in vivo and more easily detect disease-related specific biomarkers at the molecular and cellular levels than traditional contrast agents, achieving a broad application prospect in MRI. This review focuses on the basic principles of MRI, the classification, synthesis and surface modification methods of contrast agents, and their clinical applications to provide guidance for designing novel contrast agents and optimizing the contrast effect. Furthermore, the latest biomedical advances of functional nanomaterials in medical diagnosis and disease detection, disease treatment, the combination of diagnosis and treatment (theranostics), multi-model imaging and nanozyme are also summarized and discussed. Finally, the bright application prospects of functional nanomaterials in biomedicine are emphasized and the urgent need to achieve significant breakthroughs in the industrial transformation and the clinical translation is proposed. This article is categorized under: Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Diagnostic Tools > Diagnostic Nanodevices Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.

Effect of gelatin content and oral processing ability on vitamin C release in gummy jelly.

In order to investigate the factors affecting the release of vitamin C (VC) in gummy jelly during oral processing, four levels of gelatin (3%, 6%, 9% and 12%) were selected and a bionic chewing robot was employed in chewing experiments. Textural profile analysis showed the hardness of gummy jelly increased from 91.7 N to 198.8 N when the gelatin content was raised from 3 to 12%. Single factor chewing experiment showed that the release of VC was positively correlated with chewing frequency (Fchew) and chewing strain (STchew), while negatively correlated with gelatin content, chewing speed (SPchew) and volume of saliva (Vsaliva). Orthogonal chewing experiment showed that the priority of the factors affected the release of VC was following: STchew > Fchew > SPchew > Vsaliva. Multivariate linear regression analysis proposed a model to predict the amount of VC released and the goodness-of-fit of the model was 95.7%. The amount of VC released was the highest under the combination of Fchew 12 times, STchew 100%, Vsaliva 2 ml and SPchew 40 times/min. The optimal amount of gelatin addition was 6%. This study provided an effective reference for the formula design and chewing mode optimization of gummy jelly.

PMN-MDSCs accumulation induced by CXCL1 promotes CD8+ T cells exhaustion in gastric cancer.

Myeloid-derived suppressor cells (MDSCs) accumulation in multiple tumor is associated with immune checkpoint inhibitors (ICIs) resistance. However, mechanisms of MDSCs in ICIs resistance of gastric cancer (GC) have not been thoroughly explored. In this study, we found that the PMN-MDSCs frequency rather than the M-MDSCs frequency was correlated with the survival of GC patients and CXCL1 induced PMN-MDSCs accumulation in GC. S100A8/A9 heterodimer, a hallmark of MDSCs, upregulated the CXCL1 expression in GC cells through the TLR4/p38 MAPK/NF-κB pathway. Notably, PMN-MDSCs exerted immunosuppressive effect through S100A8/A9. Mechanically, S100A8/A9 led to CD8+ T cells exhaustion including inhibiting CD8+ T cells glycolysis, proliferation and TNF-α and IFN-γ production, which was dependent on TLR4/AKT/mTOR pathway. In tumor-bearing mice, the CXCR2 antagonist SB225002 decreased PMN-MDSCs accumulation, increased CD8+ T cells infiltration in GC and further enhanced anti-tumor efficacy of anti-PD-1. Taken together, our study identified that CXCL1 induced PMN-MDSCs accumulation in GC, and unveiled how PMN-MDSCs promoted CD8+ T cells exhaustion, which may provide a potential therapeutic strategy for GC.

Clinicopathological and prognostic value of SIRT6 in patients with solid tumors: a meta-analysis and TCGA data review.

PURPOSES: In addition to its role in cellular progression and cancer, SIRT6, a member of nicotinamide adenine dinucleotide (NAD+)-dependent class III deacylase sirtuin family, serves a variety of roles in the body's immune system. In this study, we sought to determine the relationship between the expression of SIRT6 and the clinicopathological outcomes of patients with solid tumours by conducting a meta-analysis of the available data. METHODS: The databases PubMed and ISI Web of Science were searched for relevant literature, and the results were presented here. Using Stata16.0, a meta-analysis was conducted to determine the impact of SIRT6 on clinicopathological characteristics and prognosis in malignancy patients. The results were published in the journal Cancer Research. The dataset from the Cancer Genome Atlas (TCGA) was used to investigate the prognostic significance of SIRT6 in various types of tumors. RESULTS: The inclusion and exclusion criteria were met by 15 studies. In patients with solid tumours, reduced SIRT6 expression was found to be related with improved overall survival (OS) (HR = 0.66, 95% CI = 0.45-0.97, P < 0.001) as well as improved disease-free survival (DFS) (HR = 0.48, 95% CI = 0.26-0.91, P < 0.001). Low SIRT6 expression was found to be associated with a better OS in breast cancer (HR = 0.49, 95% CI = 0.27-0.89, P = 0.179), but was found to be associated with a worse OS in gastrointestinal cancer (gastric cancer and colon cancer) (HR = 1.83, 95% CI = 1.20-2.79, P = 0.939) after subgroup analysis. In terms of clinicopathological characteristics, SIRT6 expression was found to be linked with distant metastasis (OR = 2.98, 95% CI = 1.59-5.57, P = 0.694). When the data from the TCGA dataset was compared to normal tissue, it was discovered that SIRT6 expression was significantly different in 11 different types of cancers. Meanwhile, reduced SIRT6 expression was shown to be associated with improved OS (P < 0.05), which was consistent with the findings of the meta-analysis. Aside from that, the expression of SIRT6 was found to be associated with both gender and clinical stage. CONCLUSION: The overall data of the present meta-analysis indicated that low expression of SIRT6 may predict a favorable survival for patients with solid tumors.

Necroptosis-Related lncRNAs: Predicting Prognosis and the Distinction between the Cold and Hot Tumors in Gastric Cancer.

BACKGROUND: In the face of poor prognosis and immunotherapy failure of gastric cancer (GC), this project tried to find new potential biomarkers for predicting prognosis and precision medication to ameliorate the situation. METHODS: To form synthetic matrices, we retrieved stomach adenocarcinoma transcriptome data from Genotype-Tissue Expression Project (GTEx) and The Cancer Genome Atlas (TCGA). Necroptosis-related prognostic lncRNA was identified by coexpression analysis and univariate Cox regression. Then we performed the least absolute shrinkage and selection operator (LASSO) to construct the necroptosis-related lncRNA model. Next, the Kaplan-Meier analysis, time-dependent receiver operating characteristics (ROC), univariate Cox (uni-Cox) regression, multivariate Cox (multi-Cox) regression, nomogram, and calibration curves were made to verify and evaluate the model. Gene set enrichment analyses (GSEA), principal component analysis (PCA), immune analysis, and prediction of the half-maximal inhibitory concentration (IC50) in risk groups were also analyzed. For further discussing immunotherapy between the cold and hot tumors, we divided the entire set into two clusters based on necroptosis-related lncRNAs. RESULTS: We constructed a model with 16 necroptosis-related lncRNAs. In the model, we found the calibration plots showed a good concordance with the prognosis prediction. The area's 1-, 2-, and 3-year OS under the ROC curve (AUC) were 0.726, 0.763, and 0.770, respectively. Risk groups could be a guide of systemic treatment because of significantly different IC50 between risk groups. Above all, clusters could help distinguish between the cold and hot tumors effectively and contribute to precise mediation. Cluster 2 was identified as the hot tumor and more susceptible to immunotherapeutic drugs. CONCLUSION: The results of this project supported that necroptosis-related lncRNAs could predict prognosis and help make a distinction between the cold and hot tumors for improving individual therapy in GC.