Tumor-repopulating cells evade ferroptosis via PCK2-dependent phospholipid remodeling.

Whether stem-cell-like cancer cells avert ferroptosis to mediate therapy resistance remains unclear. In this study, using a soft fibrin gel culture system, we found that tumor-repopulating cells (TRCs) with stem-cell-like cancer cell characteristics resist chemotherapy and radiotherapy by decreasing ferroptosis sensitivity. Mechanistically, through quantitative mass spectrometry and lipidomic analysis, we determined that mitochondria metabolic kinase PCK2 phosphorylates and activates ACSL4 to drive ferroptosis-associated phospholipid remodeling. TRCs downregulate the PCK2 expression to confer themselves on a structural ferroptosis-resistant state. Notably, in addition to confirming the role of PCK2-pACSL4(T679) in multiple preclinical models, we discovered that higher PCK2 and pACSL4(T679) levels are correlated with better response to chemotherapy and radiotherapy as well as lower distant metastasis in nasopharyngeal carcinoma cohorts.

Fusion of airborne multimodal point clouds for vegetation parameter correction extraction in burned areas.

Most experimental studies use unimodal data for processing, the RGB image point cloud cannot separate the shrub and tree layers according to the visible vegetation index, and the airborne laser point cloud is difficult to distinguish between the ground and grass ranges, to address the above problems, a multi-band information image fusing the LiDAR point cloud and the RGB image point cloud is constructed. In this study, data collected from UAV platforms, including RGB image point clouds and laser point clouds, were used to construct a fine canopy height model (using laser point cloud data) and high-definition digital orthophotos (using image point cloud data), and the orthophotos were fused with a canopy height model (CHM) by selecting the Difference Enhancement Vegetation Index (DEVI) and Normalised Green-Blue Discrepancy Index (NGBDI) after comparing the accuracy of different indices. Morphological reconstruction of CHM + DEVI/NGBDI fusion image, remove unreasonable values; construct training samples, using classification regression tree algorithm, segmentation of the range of the burned areas and adaptive extraction of vegetation as trees, shrubs and grasslands, tree areas as foreground markers using the local maximum algorithm to detect the tree apexes, the non-tree areas are assigned to be the background markers, and the Watershed Transform is performed to obtain the segmentation contour; the original laser point cloud is divided into chunks according to the segmented single-tree contour, and the highest point is traversed to search for the highest point, and corrected for the height of the single-tree elevations one by one. Accuracy analysis of the vegetation information extracted by the method with the measured data showed that the improved method increased the overall recall rate by 4.1%, the overall precision rate by 3.7%, the overall accuracy F1 score by 3.9%, and the tree height accuracy by 8.8%, 1.4%, 1.7%, 6.4%, 1.8%, and 0.3%, respectively, in the six sampling plots. The effectiveness of the improved method is verified, while the higher the degree of vegetation mixing in the region the better the extraction effect of the improved algorithm.

Quasi-bound states in the continuum in a metal nanograting metasurface for a high figure-of-merit refractive index sensor.

In this work, we investigate the bound states in the continuum (BICs) in a gold nanograting metal-insulator-metal metasurface structure at oblique angles of incidence. The nanograting metasurface consists of a gold nanograting patterned on a silicon dioxide dielectric film deposited on a thick gold film supported by a substrate. With rigorous full-wave finite difference time domain simulations, two bound states in the continuum are revealed upon transverse magnetic wave angular incidence. One BIC is formed by the interference between the surface plasmon polariton mode of the gold nanograting and the FP cavity mode. Another BIC mode is formed by the interference between the metal-dielectric hybrid structure guided mode resonance mode and the FP cavity mode. While true BIC modes cannot be observed, quasi-BIC modes are investigated at angles of incidence slightly off from the corresponding true BIC angles. It is shown that quasi-BIC modes can suppress radiation loss, resulting in narrow resonance spectral linewidths and high quality-factors. The quasi-BIC mode associated with the surface plasmon polariton mode is investigated for refractive index sensing. As a result, a high sensitivity refractive index sensor with a large figure-of-merit of 364 has been obtained.

Prognostic impact of SF3B1 mutation and multilineage dysplasia in myelodysplastic syndromes with ring sideroblasts: a Mayo Clinic study of 170 informative cases.

The revised 4th edition of the World Health Organization (WHO4R) classification lists myelodysplastic syndromes with ring sideroblasts (MDS-RS) as a separate entity with single lineage (MDS-RS-SLD) or multilineage (MDS-RS-MLD) dysplasia. The more recent International Consensus Classification (ICC) distinguishes between MDS with SF3B1 mutation (MDS-SF3B1) and MDS-RS without SF3B1 mutation; the latter is instead included under the category of MDS not otherwise specified. The current study includes 170 Mayo Clinic patients with WHO4R-defined MDS-RS, including MDS-RS-SLD (N=83) and MDS-RSMLD (N=87); a subset of 145 patients were also evaluable for the presence of SF3B1 and other mutations, including 126 with (87%) and 19 (13%) without SF3B1 mutation. Median overall survival for all 170 patients was 6.6 years with 5- and 10-year survival rates of 59% and 25%, respectively. A significant difference in overall survival was apparent between MDS-RS-MLD and MDS-RS-SLD (P<0.01) but not between MDS-RS with and without SF3B1 mutation (P=0.36). Multivariable analysis confirmed the independent prognostic contribution of MLD (hazard ratio=1.8, 95% confidence interval: 1.1-2.8; P=0.01) and also identified age (P<0.01), transfusion need at diagnosis (P<0.01), and abnormal karyotype (P<0.01), as additional risk factors; the impact from SF3B1 or other mutations was not significant. Leukemia-free survival was independently affected by abnormal karyotype (P<0.01), RUNX1 (P=0.02) and IDH1 (P=0.01) mutations, but not by MLD or SF3B1 mutation. Exclusion of patients not meeting ICC-criteria for MDS-SF3B1 did not change the observations on overall survival. MLD-based, as opposed to SF3B1 mutation-based, disease classification for MDS-RS might be prognostically more relevant.

Genetic landscape and clinical outcomes of patients with BCOR mutated myeloid neoplasms.

The BCL6-corepressor (BCOR) is a tumor-suppressor gene located on the short arm of chromosome X. Data are limited regarding factors predicting survival in BCOR-mutated (mBCOR) acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). We evaluated 138 patients with mBCOR myeloid disorders, of which 36 (26.1%) had AML and 63 (45.6%) had MDS. Sixty-six (47.8%) patients had a normal karyotype while 18 (13%) patients had complex karyotype. BCOR-mutated MDS/AML were highly associated with RUNX1 and U2AF1 co-mutations. In contrast, TP53 mutation was infrequently seen with mBCOR MDS. Patients with an isolated BCOR mutation had similar survival compared to those with high-risk co-mutations by European LeukemiaNet (ELN) 2022 criteria (median OS 1.16 vs. 1.27 years, P=0.46). Complex karyotype adversely impacted survival among mBCOR AML/MDS (HR 4.12, P<0.001), while allogeneic stem cell transplant (alloSCT) improved survival (HR 0.38, P=0.04). However, RUNX1 co-mutation was associated with an increased risk of post-alloSCT relapse (HR 88.0, P=0.02), whereas melphalan-based conditioning was associated with a decreased relapse risk (HR 0.02, P=0.01). We conclude that mBCOR is a high-risk feature across MDS/AML, and that alloSCT improves survival in this population.

MMP12 is a Potential Predictive and Prognostic Biomarker of Various Cancers Including Lung Adenocarcinoma.

OBJECTIVE: This study sought to explore the clinical value of matrix metalloproteinases 12 (MMP12) in multiple cancers, including lung adenocarcinoma (LUAD). METHODS: Using >10,000 samples, this retrospective study demonstrated the first pan-cancer analysis of MMP12. The expression of MMP12 between cancer groups and their control groups was analyzed using Wilcoxon rank-sum tests. The clinical significance of MMP12 expression in multiple cancers was assessed using receiver operating characteristic curves, Kaplan-Meier curves, and univariate Cox analysis. A further LUAD-related analysis based on 4565 multi-center and in-house samples was performed to verify the findings regarding MMP12 in pan-cancer analysis partly. RESULTS: MMP12 mRNA is highly expressed in 13 cancers compared to their controls, and the MMP12 protein level is elevated in some of these cancers (e.g., colon adenocarcinoma) (P < .05). MMP12 expression makes it feasible to distinguish 21 cancer tissues from normal tissues (AUC = 0.86). A high MMP12 expression is a prognosis risk factor in eight cancers, such as adrenocortical carcinoma (hazard ratio >1, P < .05). The elevated MMP12 expression is also a prognosis protective factor in breast-invasive carcinoma and colon adenocarcinoma (hazard ratio <1, P < .05). Some pan-cancer findings regarding MMP12 are verified in LUAD-MMP12 expression is upregulated in LUAD at both the mRNA and protein levels (P < .05), has the potential to distinguish LUAD with considerable accuracy (AUC = .91), and plays a risk prognosis factor for patients with the disease (P < .05). CONCLUSIONS: MMP12 is highly expressed in most cancers and may serve as a novel biomarker for the prediction and prognosis of numerous cancers.

α-Ketoglutarate alleviates osteoarthritis by inhibiting ferroptosis via the ETV4/SLC7A11/GPX4 signaling pathway.

Osteoarthritis (OA) is the most common degenerative joint disorder that causes disability in aged individuals, caused by functional and structural alterations of the knee joint. To investigate whether metabolic drivers might be harnessed to promote cartilage repair, a liquid chromatography-mass spectrometry (LC-MS) untargeted metabolomics approach was carried out to screen serum biomarkers in osteoarthritic rats. Based on the correlation analyses, α-ketoglutarate (α-KG) has been demonstrated to have antioxidant and anti-inflammatory properties in various diseases. These properties make α-KG a prime candidate for further investigation of OA. Experimental results indicate that α-KG significantly inhibited H2O2-induced cartilage cell matrix degradation and apoptosis, reduced levels of reactive oxygen species (ROS) and malondialdehyde (MDA), increased superoxide dismutase (SOD) and glutathione (GSH)/glutathione disulfide (GSSG) levels, and upregulated the expression of ETV4, SLC7A11 and GPX4. Further mechanistic studies observed that α-KG, like Ferrostatin-1 (Fer-1), effectively alleviated Erastin-induced apoptosis and ECM degradation. α-KG and Fer-1 upregulated ETV4, SLC7A11, and GPX4 at the mRNA and protein levels, decreased ferrous ion (Fe2+) accumulation, and preserved mitochondrial membrane potential (MMP) in ATDC5 cells. In vivo, α-KG treatment inhibited ferroptosis in OA rats by activating the ETV4/SLC7A11/GPX4 pathway. Thus, these findings indicate that α-KG inhibits ferroptosis via the ETV4/SLC7A11/GPX4 signaling pathway, thereby alleviating OA. These observations suggest that α-KG exhibits potential therapeutic properties for the treatment and prevention of OA, thereby having potential clinical applications in the future.

Clinical significance and potential pathogenesis of VCAN in adult non-cystic fibrosis bronchiectasis: a retrospective study.

BACKGROUND: The pathogenesis of adult non-cystic fibrosis (CF) bronchiectasis is complex, and the relevant molecular mechanism remains ambiguous. Versican (VCAN) is a key factor in inflammation through interactions with adhesion molecules. This study constructs a stable panoramic map of mRNA, reveals the possible pathogenesis of bronchiectasis, and provides new ideas and methods for bronchiectasis. METHODS: Peripheral blood and tissue gene expression data from patients with bronchiectasis and normal control were selected by bioinformatics analysis. The expression of VCAN in peripheral blood and bronchial tissues of bronchiectasis were obtained by transcriptome sequencing. The protein expression levels of VCAN in serums were verified by the enzyme-linked immunosorbent assay (ELISA). The mRNA expression levels of VCAN in co-culture of Pseudomonas aeruginosa and bronchial epithelial cells were verified by real-time quantitative polymerase chain reaction (RT-qPCR). In addition, the biological function of VCAN was detected by the transwell assay. RESULTS: The expression of VCAN was upregulated in the bronchiectasis group by sequencing analysis (P < 0.001). The expression of VCAN in the bronchial epithelial cell line BEAS-2B was increased in P. aeruginosa (P.a), which was co-cultured with BEAS-2B cells (P < 0.05). The concentration of VCAN protein in the serum of patients with bronchiectasis was higher than that in the normal control group (P < 0.05). Transwell experiments showed that exogenous VCAN protein induced the migration of neutrophils (P < 0.0001). CONCLUSIONS: Our findings indicate that VCAN may be involved in the development of bronchiectasis by increasing the migration of neutrophils and play an important role in bronchial pathogenesis.

Association of phthalate exposure with type 2 diabetes and the mediating effect of oxidative stress: A case-control and computational toxicology study.

Phthalic acid esters (PAEs) are widely used as plasticizers and have been suggested to engender adverse effects on glucose metabolism. However, epidemiological data regarding the PAE mixture on type 2 diabetes (T2DM), as well as the mediating role of oxidative stress are scarce. This case-control study enrolled 206 T2DM cases and 206 matched controls in Guangdong Province, southern China. The concentrations of eleven phthalate metabolites (mPAEs) and the oxidative stress biomarker 8-hydroxy-2'-deoxyguanosine (8-OHdG) in urine were determined. Additionally, biomarkers of T2DM in paired serum were measured to assess glycemic status and levels of insulin resistance. Significantly positive associations were observed for mono-(2-ethylhexyl) phthalate (MEHP) and Mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) with T2DM (P < 0.001). Restricted cubic spline modeling revealed a non-linear dose-response relationship between MEHHP and T2DM (Pnon-linear = 0.001). The Bayesian kernel machine regression and quantile g-computation analyses demonstrated a significant positive joint effect of PAE exposure on T2DM risk, with MEHHP being the most significant contributor. The mediation analysis revealed marginal evidence that oxidative stress mediated the association between the mPAEs mixture and T2DM, while 8-OHdG respectively mediated 26.88 % and 12.24 % of MEHP and MEHHP on T2DM risk individually (Pmediation < 0.05). Di(2-ethylhexyl) phthalate (DEHP, the parent compound for MEHP and MEHHP) was used to further examine the potential molecular mechanisms by in silico analysis. Oxidative stress may be crucial in the link between DEHP and T2DM, particularly in the reactive oxygen species metabolic process and glucose import/metabolism. Molecular simulation docking experiments further demonstrated the core role of Peroxisome Proliferator Activated Receptor alpha (PPARα) among the DEHP-induced T2DM. These findings suggest that PAE exposure can alter oxidative stress via PPARα, thereby increasing T2DM risk.

Short-term effects of ambient nitrogen dioxide on medical emergency calls for epileptic seizures: A time-series study.

Short-term exposure to air pollution has previously been studied in relation to certain neurological disorders, but there is still a lack of convincing data linking air pollution to epileptic seizures. The study's goal was to investigate how exposure to ambient nitrogen dioxide (NO2) affected the number of patients seeking assistance at the Wuhan Emergency Medical Center due to epileptic seizures. We gathered data on medical emergency calls (MECs), daily ambient air pollution concentrations (SO2, NO2, PM2.5, PM10, CO, and O3), and meteorological variables in Wuhan, China, spanning from January 1, 2017, to November 30, 2019. To investigate the potential influence of ambient nitrogen dioxide on MECs for epileptic seizures, we carried out a time-series investigation using the general additive model (GAM). Additionally, analyses stratified by season, age, and gender were performed. A total of 8989 records of MECs for epileptic seizures were enrolled in our study during the period. Statistical analysis indicates that a rise of 10 µg/m3 in NO2 concentration is linked to a 0.17% increase in daily MECs for epileptic seizures (95% confidence interval [CI]: 0.02%, 0.32%). Furthermore, people aged 14-59 years were more susceptible(2.25%, P < 0.05). The short-term effects of NO2 exposure on daily MECs for epileptic seizures were stronger in warm seasons than in cool seasons (0.55% vs. -0.10%, P < 0.0001). Our findings suggests that short-term exposure to ambient NO2 was positively correlated with daily MECs for epileptic seizures in Wuhan, China. Additionally, we observed that these associations were stronger in patients aged above 14 but under 60 years and the warmer seasons (from April to September).

Efficacy and safety of ibrexafungerp in the treatment of vulvovaginal candidiasis: A meta-analysis of randomized controlled trials.

Background: This study aims to evaluate the efficacy and safety associated with ibrexafungerp in the treatment of vulvovaginal candidiasis infection patients. Methods: We conducted a comprehensive search of the PubMed, Embase, Cochrane Library, and Clinical Trials databases up to December 25, 2022. The primary outcomes were clinical cure rate and mycological eradication rate, whereas the secondary outcomes were the risk of an adverse events. Results: In total of four studies encompassing 880 patients diagnosed with vulvovaginal candidiasis (VVC) were included in the analysis. The findings demonstrated that ibrexafungerp exhibited superior clinical cure ratio (RR = 1.33 [1.07, 1.66]), mycological eradication rate (RR = 1.72 [1.00, 2.95]), and overall success ratio (RR = 1.64 [0.92, 2.92]) when compared to the fluconazole/placebo in the treatment of VVC. Furthermore, patients treated with ibrexafungerp demonstrated significantly higher clinical cure rates, mycological eradication, and overall success ratio compared to those receiving other treatments for vulvovaginal candidiasis caused by C. albicans. When ibrexafungerp was compared to fluconazole/placebo, the duration of any treatment-related treatment-emergent adverse events (TEAE), nausea, and diarrhea during therapy was significantly longer. Conclusion: In summary, the use of ibrexafungerp was linked to superior clinical cure ratio, and mycological eradication when compared to fluconazole/placebo.

GPCR-mediated regulation of beige adipocyte formation: Implications for obesity and metabolic health.

Obesity and its associated complications pose a significant burden on health. The non-shivering thermogenesis (NST) and metabolic capacity properties of brown adipose tissue (BAT), which are distinct from those of white adipose tissue (WAT), in combating obesity and its related metabolic diseases has been well documented. However, beige adipose tissue, the third and relatively novel type of adipose tissue, which emerges in extensive presence of WAT and shares similar favorable metabolic properties with BAT, has garnered considerable attention in recent years. In this review, we focused on the role of G protein-coupled receptors (GPCRs), the largest receptor family and the most successful class of drug targets in humans, in the induction of beige adipocytes. More importantly, we highlight researchers' clinical treatment attempts to ameliorate obesity and other related metabolic diseases through the formation and activation of beige adipose tissue. In summary, this review provides valuable insights into the formation of beige adipose tissue and the involvement of GPCRs, based on the latest advancements in scientific research.

Elexacaftor-tezacaftor-ivacaftor for cystic fibrosis with Phe508del mutation: Evidence from randomized controlled trials.

Objective: This study aimed to conduct a systematic review and meta-analysis of randomized controlled trials to evaluate the effects of elexacaftor-tezacaftor-ivacaftor (ELX-TEZ-IVA) on patients with cystic fibrosis (CF). Methods: A systematic search was performed in PubMed, Embase, and the Cochrane Library from inception to August 1, 2022. Meta-analysis was conducted using Review Manager 5.3 software. Results: Six studies comprising seven reports involving a total of 1125 CF patients were included. The meta-analyses indicated that ELX-TEZ-IVA significantly improved the percentage predicted forced expiratory volume in 1 s (ppFEV1) by 10.29% (95% confidence interval (CI) (6.44, 14.14), p < 0.00001) and the CF questionnaire-revised respiratory domain (CFQ-R RD) by 14.59 points (95% CI (9.25, 19.94), p < 0.00001) compared to placebo, ivacaftor (IVA), or tezacaftor-ivacaftor (TEZ-IVA). In addition, the ELX-TEZ-IVA group showed significantly lower sweat chloride concentrations by 40.30 mmol/L (95% CI (-49.85, -30.74), p < 0.00001). However, the incidence of adverse events in the ELX-TEZ-IVA group was slightly higher than that in the placebo, IVA, or TEZ-IVA groups. Conclusion: ELX-TEZ-IVA demonstrated efficacy in improving ppFEV1, CFQ-R RD, and sweat chloride concentrations in patients with CF. However, caution should be exercised regarding the incidence of AEs, particularly mild and moderate ones.

Enhanced emulsification performance and interfacial properties of Janus-like rapeseed cruciferin through asymmetric acylation modification.

Plant protein emulsifiers, particularly rapeseed protein isolate with its superior amino acid composition and predominantly globular protein, have captured significant interest in the food industry. Nonetheless, the application of these proteins has been stymied by their lackluster emulsification properties. Addressing this challenge, our study implements an innovative asymmetric acylation technique to modify the surface of rapeseed cruciferin (RC), morphing it into a structure resembling Janus nanoparticles. This alteration amplifies the emulsification prowess of RC by a remarkable 2.7 times compared to its natural form, and 1.43 times over its conventionally acylated counterpart. The asymmetrically acylated RC, marked by a distinctive three-phase contact angle of 90.4°, manifests an outstanding amphiphilic character. Moreover, it surpasses both the natural and conventionally acylated RC in terms of diffusion, penetration, and rearrangement rates, as well as protein concentration at the oil-water interface. Compared to commonly used emulsifiers in the food industry, such as lecithin and soy protein, the asymmetrically acylated RC stands out, stabilizing emulsions with the tiniest particle size and effectively staving off emulsion stratification over a longer duration. This study underscores that asymmetric acylation serves as a reliable methodology for producing efficient plant protein emulsifiers, considerably amplifying their utility in the food industry.

Phylogenomic analysis and molecular identification of true fruit flies.

The family Tephritidae in the order Diptera, known as true fruit flies, are agriculturally important insect pests. However, the phylogenetic relationships of true fruit flies, remain controversial. Moreover, rapid identification of important invasive true fruit flies is essential for plant quarantine but is still challenging. To this end, we sequenced the genome of 16 true fruit fly species at coverage of 47-228×. Together with the previously reported genomes of nine species, we reconstructed phylogenetic trees of the Tephritidae using benchmarking universal single-copy ortholog (BUSCO), ultraconserved element (UCE) and anchored hybrid enrichment (AHE) gene sets, respectively. The resulting trees of 50% taxon-occupancy dataset for each marker type were generally congruent at 88% nodes for both concatenation and coalescent analyses. At the subfamily level, both Dacinae and Trypetinae are monophyletic. At the species level, Bactrocera dorsalis is more closely related to Bactrocera latifrons than Bactrocera tryoni. This is inconsistent with previous conclusions based on mitochondrial genes but consistent with recent studies based on nuclear data. By analyzing these genome data, we screened ten pairs of species-specific primers for molecular identification of ten invasive fruit flies, which PCR validated. In summary, our work provides draft genome data of 16 true fruit fly species, addressing the long-standing taxonomic controversies and providing species-specific primers for molecular identification of invasive fruit flies.

Histogram analysis based on intravoxel incoherent motion diffusion-weighted imaging for determining the perineural invasion status of rectal cancer.

Background: Unfortunately, the morphologic magnetic resonance imaging (MRI) is unable to determine perineural invasion (PNI) status. This study applied histogram analysis of intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI) in the assessment of PNI status of rectal cancer (RC). Methods: The retrospective analysis enrolled 175 patients with RC confirmed by postoperative pathology in The First Affiliated Hospital of Shandong First Medical University from January 2019 to December 2021. All patients underwent preoperative rectal MRI. Whole-tumor volume histogram features from IVIM-DWI were extracted using open-source software. Univariate analysis and multivariate logistic regression analysis were used to compare the differences in histogram parameters and clinical features between the PNI-positive group and PNI-negative group. Receiver operating characteristic curve analysis was used to evaluate the diagnostic performance, while the Delong test was used to compare the area under the curve of the models. Results: The interobserver agreement of the histogram features derived from DWI, including apparent diffusion coefficient (ADC), true diffusion coefficient (D), pseudo-diffusion coefficient (D*), perfusion fraction (f), water molecular diffusion heterogeneity index (α), and distributed diffusion coefficient (DDC) were good to excellent. A total of eight histogram features including DWI_maximum, DWI_skewness, D_kurtosis, D_minimum, D_skewness, D*_energy, D*_skewness, and f_minimum were significantly different between the PNI-positive and PNI-negative groups in the univariate analysis (P<0.05); among the clinicoradiologic factors, percentage of rectal wall circumference invasion (PCI) was significantly different between the two groups (P<0.05). Multivariate analysis demonstrated that the values of D*_energy, D*_skewness, and f_minimum differed significantly between the PNI-positive patients and PNI-negative patients (P<0.05), with the independent risk factors being D*_skewness [odds ratio (OR) =1.157; 95% confidence interval (CI): 1.050-1.276; P=0.003] and PCI (OR =11.108, 95% CI: 1.767-69.838; P=0.0002). The area under the curve of the model combining the three histogram features and PCI to assess PNI status in RC was 0.807 (95% CI: 0.741-0.863). The results of the Delong test showed that the combined model was significantly different from each single-parameter model (P<0.05). Conclusions: The combined model constructed on the basis of IVIM-DWI histogram features may help to assess the status of RC PNI.

Identification, structural characterization, and molecular dynamic simulation of ACE inhibitory peptides in whey hydrolysates from Chinese Rushan cheese by-product.

To realize the high-value utilization of Rushan cheese by-product, Rushan cheese whey was used as a raw material to prepare angiotensin-Ⅰ-converting enzyme inhibitory peptides (ACEIPs). After enzymatic hydrolysisn and ultrafiltration, the sequences of peptides were identified by liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS). Two novel ACE inhibitory peptides Phe-Asp-Arg-Pro-Phe-Leu (FDRPFL) and Lys-Trp-Glu-Lys-Pro-Phe (KWEKPF) were identified. Additionally, both of the peptides exhibited good water-solubility and no toxicity according to in-silico prediction. Fourier transform infrared spectroscopy results show that both FDRPFL and KWEKPF were enriched in ß-turn and ß-sheet structures. Lineweaver-Burk plots revealed that FDRPFL and KWEKPF exhibited non-competitive and mixed inhibition patterns, respectively. Molecular docking and MD simulation showed that hydrogen bonds and ionic bonds forces allowed FDRPFL and KWEKPF to form stable and compact complexes with ACE. In conclusion, enzymatic hydrolysis of Rushan cheese by-products yields bioactive peptides, increases the added value of whey and reduces environmental pollution.

Construction and validation of a RARRES3-based prognostic signature related to the specific immune microenvironment of pancreatic cancer.

Background: Tumor immune microenvironment (TiME) is prognostically instructive in Pancreatic adenocarcinoma (PAAD). However, the potential value of TiME-related genes in the individualized immunotherapy of PAAD has not been clarified. Methods: Correlation between Immune-Related Genes (IRGs) and immune-related transcription factors (TFs) was performed to prove the immune correlation of selected genes. Immune-related molecular subtypes were identified by consensus clustering. The TiME-score, an immune microenvironment-related prognostic signature for PAAD, was constructed using minimum absolute contraction and selection operator regression (Lasso-Cox). The International Cancer Genome Consortium (ICGC) dataset validated the reliability of TiME-score as external validation. Single-cell samples from GSE197177 confirmed microenvironment differences of TiME-score hub genes between tumor and its paracancer tissues. Then, RARRES3, a hub gene in TiME-score, was further analyzed about its upstream TP53 mutation and the specific immune landscape of itself in transcriptome and Single-cell level. Eventually, TiME-score were validated in different therapeutic cohorts of PAAD mice models. Results: A 14-genes PAAD immune-related risk signature, TiME-score, was constructed based on IRGs. The differences of TiME-score hub genes in single-cell samples of PAAD cancer tissues and adjacent tissues were consistent with the transcriptome. Single-cell samples of cancer tissues showed more pronounced immune cell infiltration. The upstream mutation factor TP53 of RARRES3 was significantly enriched in immune-related biological processes. High RARRES3 expression was correlated with a worse prognosis and high macrophages M1 infiltration. Additionally, the immunohistochemistry of hub genes AGT, DEFB1, GH1, IL20RB, and TRAF3 in different treatment cohorts of mice PAAD models were consistent with the predicted results. The combination of immunotherapy, chemotherapy and targeted therapy has shown significantly better therapeutic effects than single drug therapy in PAAD. Conclusion: TiME-score, as a prognostic signature related to PAAD-specific immune microenvironment constructed based on RARRES3, has predictive value for prognosis and the potential to guide individualized immunotherapy for PAAD patients.