Predictive value of delta-radiomic features for prognosis of advanced non-small cell lung cancer patients undergoing immune checkpoint inhibitor therapy.

Background: No robust predictive biomarkers exist to identify non-small cell lung cancer (NSCLC) patients likely to benefit from immune checkpoint inhibitor (ICI) therapies. The aim of this study was to explore the role of delta-radiomics features in predicting the clinical outcomes of patients with advanced NSCLC who received ICI therapy. Methods: Data of 179 patients with advanced NSCLC (stages IIIB-IV) from two institutions (Database 1 =133; Database 2 =46) were retrospectively analyzed. Patients in the Database 1 were randomly assigned into training and validation dataset, with a ratio of 8:2. Patients in Database 2 were allocated into testing dataset. Features were selected from computed tomography (CT) images before and 6-8 weeks after ICI therapy. For each lesion, a total of 1,037 radiomic features were extracted. Lowly reliable [intraclass correlation coefficient (ICC) <0.8] and redundant (r>0.8) features were excluded. The delta-radiomics features were defined as the relative net change of radiomics features between two time points. Prognostic models for progression-free survival (PFS) and overall survival (OS) were established using the multivariate Cox regression based on selected delta-radiomics features. A clinical model and a pre-treatment radiomics model were established as well. Results: The median PFS (after therapy) was 7.0 [interquartile range (IQR): 3.4, 9.1] (range, 1.4-13.2) months. To predict PFS, the model established based on the five most contributing delta-radiomics features yielded Harrell's concordance index (C-index) values of 0.708, 0.688, and 0.603 in the training, validation, and testing databases, respectively. The median survival time was 12 (IQR: 8.7, 15.8) (range, 2.9-23.3) months. To predict OS, a promising prognostic performance was confirmed with the corresponding C-index values of 0.810, 0.762, and 0.697 in the three datasets based on the seven most contributing delta-radiomics features, respectively. Furthermore, compared with clinical and pre-treatment radiomics models, the delta-radiomics model had the highest area under the curve (AUC) value and the best patients' stratification ability. Conclusions: The delta-radiomics model showed a good performance in predicting therapeutic outcomes in advanced NSCLC patients undergoing ICI therapy. It provides a higher predictive value than clinical and the pre-treatment radiomics models.

Aerobic exercise training engages the canonical wnt pathway to improve pulmonary function and inflammation in COPD.

BACKGROUND: We studied whether the exercise improves cigarette smoke (CS) induced chronic obstructive pulmonary disease (COPD) in mice through inhibition of inflammation mediated by Wnt/ß-catenin-peroxisome proliferator-activated receptor (PPAR) γ signaling. METHODS: Firstly, we observed the effect of exercise on pulmonary inflammation, lung function, and Wnt/ß-catenin-PPARγ. A total of 30 male C57BL/6J mice were divided into the control group (CG), smoke group (SG), low-intensity exercise group (LEG), moderate-intensity exercise group (MEG), and high-intensity exercise group (HEG). All the groups, except for CG, underwent whole-body progressive exposure to CS for 25 weeks. Then, we assessed the maximal exercise capacity of mice from the LEG, MEG, and HEG, and performed an 8-week treadmill exercise intervention. Then, we used LiCl (Wnt/ß-catenin agonist) and XAV939 (Wnt/ß-catenin antagonist) to investigate whether Wnt/ß-catenin-PPARγ pathway played a role in the improvement of COPD via exercise. Male C57BL/6J mice were randomly divided into six groups (n = 6 per group): CG, SG, LiCl group, LiCl and exercise group, XAV939 group, and XAV939 and exercise group. Mice except those in the CG were exposed to CS, and those in the exercise groups were subjected to moderate-intensity exercise training. All the mice were subjected to lung function test, lung histological assessment, and analysis of inflammatory markers in the bronchoalveolar lavage fluid, as well as detection of Wnt1, ß-catenin and PPARγ proteins in the lung tissue. RESULTS: Exercise of various intensities alleviated lung structural changes, pulmonary function and inflammation in COPD, with moderate-intensity exercise exhibiting significant and comprehensive effects on the alleviation of pulmonary inflammation and improvement of lung function. Low-, moderate-, and high-intensity exercise decreased ß-catenin levels and increased those of PPARγ significantly, and only moderate-intensity exercise reduced the level of Wnt1 protein. Moderate-intensity exercise relieved the inflammation aggravated by Wnt agonist. Wnt antagonist combined with moderate-intensity exercise increased the levels of PPARγ, which may explain the highest improvement of pulmonary function observed in this group. CONCLUSIONS: Exercise effectively decreases COPD pulmonary inflammation and improves pulmonary function. The beneficial role of exercise may be exerted through Wnt/ß-catenin-PPARγ pathway.

A validated model to predict spread through air space in lung adenocarcinoma.

Background: Spread through air space (STAS) is currently considered to be a significant predictor of a poor outcome of pulmonary adenocarcinoma. Preoperative prediction of STAS is of great importance for treatment planning. The aim of the present study was to establish a nomogram based on computed tomography (CT) features for predicting STAS in lung adenocarcinoma and to assess the prognosis of the patients with STAS. Methods: A retrospective cohort study was performed in Wuhan Union Hospital from December 2015 to March 2021. The sample was divided into training and testing cohorts. Clinicopathologic and radiologic variables were recorded. The independent risk factors for STAS were determined by stepwise regression and then incorporated into the nomogram. Receiver operating characteristic (ROC) curves and calibration curves analysed by the Hosmer-Lemeshow test were used to evaluate the performance of the model. Decision curve analysis (DCA) was conducted to determine the clinical value of the nomogram. The Kaplan-Meier method was used for survival analysis and the multivariable Cox proportional hazards regression model was used to identify independent predictors for recurrence-free survival (RFS) and overall survival (OS). Results: The sample included 244 patients who underwent surgical resection for primary lung adenocarcinoma. The training cohort included 199 patients (68 STAS-positive and 131 STAS-negative patients), and the testing cohort included 45 patients (15 STAS-positive and 30 STAS-negative patients). The preoperative CT features associated with STAS were shape, ground-glass opacity (GGO) ratio and spicules. The nomogram including these three factors had good discriminative power, and the areas under the ROC curve were 0.875 and 0.922 for the training and testing data sets, respectively, with well-fitted calibration curves. DCA showed that the nomogram was clinically useful. STAS-positive patients had significantly worse OS and RFS than STAS-negative patients (both P<0.01). OS and RFS at 5-year for STAS-positive patients were 63.1% and 59.5%, respectively. Multivariate analysis showed that age [hazard ratio (HR), 1.1; 95% confidence interval (CI): 1.035-1.169; P=0.002], diameter (HR, 1.06; 95% CI: 1.04-1.11; P=0.03) and surgical margin (HR, 32.8; 95% CI: 6.8-158.3; P<0.001) were independent risk factors for OS. Adjuvant therapy (HR, 7.345; 95% CI: 2.52-21.41; P<0.001), N stage (N2) (HR, 0.239; 95% CI: 0.069-0.828; P=0.02) and surgical margin (HR, 15.6; 95% CI: 5.9-41.1; P<0.001) were found to be independent risk factors for RFS. Conclusions: The outcome of STAS-positive patients was worse. The nomogram incorporating the identified CT features could be applied to facilitate individualized preoperative prediction of STAS and selection of rational therapy.

Revisiting airway epithelial dysfunction and mechanisms in chronic obstructive pulmonary disease: the role of mitochondrial damage.

Chronic exposure to environmental hazards causes airway epithelial dysfunction, primarily impaired physical barriers, immune dysfunction, and repair or regeneration. Impairment of airway epithelial function subsequently leads to exaggerated airway inflammation and remodeling, the main features of chronic obstructive pulmonary disease (COPD). Mitochondrial damage has been identified as one of the mechanisms of airway abnormalities in COPD, which is closely related to airway inflammation and airflow limitation. In this review, we evaluate updated evidence for airway epithelial mitochondrial damage in COPD and focus on the role of mitochondrial damage in airway epithelial dysfunction. In addition, the possible mechanism of airway epithelial dysfunction mediated by mitochondrial damage is discussed in detail, and recent strategies related to airway epithelial-targeted mitochondrial therapy are summarized. Results have shown that dysregulation of mitochondrial quality and oxidative stress may lead to airway epithelial dysfunction in COPD. This may result from mitochondrial damage as a central organelle mediating abnormalities in cellular metabolism. Mitochondrial damage mediates procellular senescence effects due to mitochondrial reactive oxygen species, which effectively exacerbate different types of programmed cell death, participate in lipid metabolism abnormalities, and ultimately promote airway epithelial dysfunction and trigger COPD airway abnormalities. These can be prevented by targeting mitochondrial damage factors and mitochondrial transfer. Thus, because mitochondrial damage is involved in COPD progression as a central factor of homeostatic imbalance in airway epithelial cells, it may be a novel target for therapeutic intervention to restore airway epithelial integrity and function in COPD.

MS/MS-based molecular networking discovery of sesquiterpenes from Carpesium abrotanoides L. with their cytotoxic and acetylcholinesterase inhibitory activity.

Employing an MS/MS-based molecular networking-guided strategy, three new eudesmane-type sesquiterpenes (1-3) and one undescribed pseudoguaianolide sesquiterpene (8), along with four known eudesmane-type sesquiterpene lactones (4-7) were extracted and purified from the herbs of Carpesium abrotanoides L. Structural elucidation encompassed comprehensive spectroscopic analysis, NMR calculations, DP4+ analysis, and ECD calculations. The cytotoxicity activity of all isolates was evaluated against two human hepatoma carcinoma cells (HepG2 and Hep3B) in vitro. It was demonstrated that compounds 2 and 4 showed moderate cytotoxic against HepG2 and Hep3B cells. Furthermore, all compounds were evaluated for their acetylcholinesterase (AChE) inhibitory activity. Particularly noteworthy is that, in comparison to the positive control, compound 1 demonstrated significant AChE inhibition with an inhibition rate of 77.86%. In addition, the inhibitory mechanism of compound 1 were investigated by in silico docking analyze and molecular dynamic simulation.

Active substance and mechanisms of Actinidia chinensis Planch for the treatment of breast cancer was explored based on network pharmacology and in silico study.

In this paper, our objective was to investigate the potential mechanisms of Actinidia chinensis Planch (ACP) for breast cancer treatment with the application of network pharmacology, molecular docking, and molecular dynamics. "Mihoutaogen" was used as a key word to query the Traditional Chinese Medicine Systems Pharmacology database for putative ingredients of ACP and its related targets. DrugBank, GeneCards, Online Mendelian Inheritance in Man, and therapeutic target databases were used to search for genes associated with "breast cancer." Using Cytoscape 3.9.0 we then constructed the protein-protein interaction and drug-ingredient-target-disease networks. An enrichment analysis of Kyoto encyclopedia of genes and genomes pathway and gene ontology were performed to exploration of the signaling pathways associated with ACP for breast cancer treatment. Discovery Studio software was applied to molecular docking. Finally, the ligand-receptor complex was subjected to a 50-ns molecular dynamics simulation using the Desmond_2020.4 tools. Six main active ingredients and 176 targets of ACP and 2243 targets of breast cancer were screened. There were 118 intersections of targets for both active ingredients and diseases. Tumor protein P53 (TP53), AKT serine/threonine kinase 1 (AKT1), estrogen receptor 1 (ESR1), Erb-B2 receptor tyrosine kinase 2 (ERBB2), epidermal growth factor receptor (EGFR), Jun Proto-Oncogene (JUN), and Heat Shock Protein 90 Alpha Family Class A Member 1 (HSP90AA1) selected as the most important genes were used for verification by molecular docking and molecular dynamics simulation. The primary active compounds of ACP against breast cancer were predicted preliminarily, and its mechanism was studied, thereby providing a theoretical basis for future clinical studies.

Music Nursing as Complementary Therapy Improves Anxiety, Fatigue, and Quality of Life in Children with Acute Leukaemia: A Retrospective Study.

OBJECTIVE: To explore the effects of music nursing as a complementary therapy on anxiety, fatigue, and quality of life in children with acute leukemia (AL). METHODS: This study included 150 children with AL admitted to our hospital from August 2021 to August 2023 and divided them into two groups based on treatment: the control (n = 76, received routine nursing) and observation (n = 74, received music nursing on the basis of routine nursing) groups. Comparison of groups was performed in terms of general information, anxiety, fatigue, and quality of life at admission (T0) and 1 month after admission (T1). RESULTS: No significant differences were observed in the general data between the two groups (P > 0.05). Anxiety, fatigue, and quality of life of the two groups also showed no significant differences at T0 (P > 0.05). The observation group showed significantly lower anxiety than the control group at T1 (P < 0.05). At T1, the observation group exhibited a lower fatigue degree compared with the control group (P < 0.05). At T1, the observation group attained higher scores on physiological and emotional dimensions of the quality of life compared with the control group, and the differences were statistically significant (P < 0.05). CONCLUSION: Music nursing for AL children, which has a certain clinical application value, can effectively reduce their anxiety and fatigue and improve their quality of life.

Effects of polymerization types on plastics ingestion and biodegradation by Zophobas atratus larvae, and successions of both gut bacterial and fungal microbiomes.

Recent studies demonstrated that plastic degradation in Zophobas atratus superworms is related to the gut microbiota. To determine whether the biodegradation and gut-microbiota were influenced by ingested plastic polymerization types, foams of polypropylene (PP), polyurethane (PU) and ethylene vinyl acetate (EVA) were selected as representatives of polyolefins, polyester and copolymers, and the sole feedstock for superworms for 45 d. Both growth and survival rates of superworms were influenced by the type of plastic diet. Although the total consumptions of EVA- and PP-fed groups were similar at 29.03 ± 0.93 and 28.89 ± 1.14 mg/g-larva, which were both significantly higher than that of PU-fed groups (21.63 ± 2.18 mg/g-larva), the final survival rates of the EVA-fed group of 36.67 ± 10.41% exhibited significantly lower than that of the PP- and PU-fed groups of 76.67 ± 2.89% and 75.00 ± 7.07%, respectively, and even the starvation group of 51.67 ± 10.93%. The Illumina MiSeq results revealed similarities in the dominant gut bacterial communities between PU- and EVA-fed groups, with an increase in relative abundance of Lactococcus, but significant differences from the PP-fed groups, which had two predominant genera of unclassified Enterobacteriaceae and Enterococcus. Compared to bran-fed groups, changes in gut fungal communities were similar across all plastics-fed groups, with an increase in the dominant abundance of Rhodotorula. The abundance of Rhodotorula increased in the order of polyolefin, polyester, and copolymer. In summary, plastic ingestion, larval growth, and changes in gut bacterial and fungal community of superworms were all influenced by foam diets of different polymerization types, and especially influences on the gut microbiomes were different from each other.

Effect of moxibustion on colonic low-grade inflammatory response in rats with diarrhea-predominant irritable bowel syndrome based on mast cell degranulation. / åŸºäºŽè‚¥å¤§ç»†èƒžè„±é¢—ç²’æŽ¢è®¨è‰¾ç¸å¯¹è ¹æ³»åž‹è‚ æ˜“æ¿€ç»¼åˆå¾å¤§é¼ ç»“è‚ ä½Žåº¦ç‚Žæ€§ååº”çš„å½±å“.

OBJECTIVES: To observe the effects of moxibustion on colonic mast cell degranulation and inflammatory factor expression in rats with diarrhea-predominant irritable bowel syndrome (IBS-D), and explore the potential mechanism of moxibustion in treating IBS-D. METHODS: Forty-five rat pups born from 5 healthy SPF-grade pregnant SD rats, with 8 rats were randomly selected as the normal group. The remaining 37 rats were intervened with maternal separation, acetic acid enema, and chronic restraint stress to establish the IBS-D model. The successfully modeled 32 rats were then randomly assigned to a model group, a ketotifen group, a moxibustion group, and a moxibustion-medication group, with 8 rats in each group. The rats in the ketotifen group were intervened with intragastric administration of ketotifen solution (10 mL/kg); the rats in the moxibustion group were intervened with suspended moxibustion on bilateral "Tianshu" (ST 25) and "Shangjuxu" (ST 37); the rats in the moxibustion-medication group were intervened with suspended moxibustion combined with intragastric administration of ketotifen solution. All interventions were administered once daily for 7 consecutive days. The diarrhea rate and minimum volume threshold of abdominal withdrawal reflex (AWR) were calculated before and after modeling, as well as after intervention. After intervention, colonic tissue morphology was observed using HE staining; colonic mucosal ultrastructure was examined by scanning electron microscopy; colonic mast cell ultrastructure was observed using transmission electron microscopy; mast cell degranulation was assessed by toluidine blue staining; serum and colonic levels of histamine, interleukin (IL)-1ß, IL-6, IL-1α, trypsin-like enzyme, and protease-activated receptor 2 (PAR-2) were measured by ELISA; the Western blot and real-time quantitative PCR were employed to evaluate the protein and mRNA expression of colonic IL-1ß, IL-6, IL-1α, trypsin-like enzyme, and PAR-2; the immunofluorescence was used to detect the positive expression of histamine, IL-1ß, IL-6, IL-1α, trypsin-like enzyme, and PAR-2 in the colonic tissue. RESULTS: Compared to the normal group, the rats in the model group exhibited extensive infiltration of inflammatory cells in colonic tissue, severe damage to the colonic mucosa, disordered arrangement of villi, reduced electron density, and a significant decrease in granule quantity within mast cells. The diarrhea rate and mast cell degranulation rate were increased (P<0.01), AWR minimum volume threshold was decreased (P<0.01); the serum and colonic levels of histamine, IL-1ß, IL-6, IL-1α, trypsin-like enzyme, and PAR-2 were elevated (P<0.01); the positive expression of histamine, as well as protein, mRNA and positive expression of IL-1ß, IL-6, IL-1α, trypsin-like enzyme, and PAR-2 in the colon were all elevated (P<0.01). Compared to the model group, the rats in the ketotifen group, the moxibustion group, and the moxibustion-medication group exhibited significantly reduced infiltration of inflammatory cells in colonic tissue, relatively intact colonic mucosa, orderly arranged villi, increased electron density, and an augmented number of mast cell granules; the diarrhea rate and mast cell degranulation rate were decreased (P<0.01), and AWR minimum volume threshold was increased (P<0.01); the serum and colonic levels of histamine, IL-1ß, IL-6, IL-1α, trypsin-like enzyme, and PAR-2 were reduced (P<0.01); the positive expression of histamine, as well as protein, mRNA and positive expression of IL-1ß, IL-6, IL-1α, trypsin-like enzyme, and PAR-2 in the colon were all decreased (P<0.01). Compared to the ketotifen group, the moxibustion group showed decreased serum levels of histamine, IL-6, and trypsin-like enzyme (P<0.01, P<0.05), as well as reduced colonic levels of IL-1ß and IL-6 (P<0.01, P<0.05); the protein expression of colonic IL-1ß, IL-1α, and PAR-2 was reduced (P<0.05), and the positive expression of colonic IL-1ß and trypsin-like enzyme was reduced (P<0.01, P<0.05). Compared to both the ketotifen group and the moxibustion group, the moxibustion-medication group exhibited decreased diarrhea rate and mast cell degranulation rate (P<0.01), an increased AWR minimum volume threshold (P<0.01), reduced serum and colonic levels of histamine, IL-1ß, IL-6, IL-1α, trypsin-like enzyme, and PAR-2 (P<0.01), decreased protein expression of colonic IL-1ß, trypsin-like enzyme, and PAR-2 (P<0.01, P<0.05), reduced mRNA and positive expression of colonic IL-1ß, IL-6, IL-1α, trypsin-like enzyme, and PAR-2 (P<0.01, P<0.05), and decreased positive expression of colonic histamine (P<0.01). CONCLUSIONS: Moxibustion on "Tianshu" (ST 25) and "Shangjuxu" (ST 37) might inhibit low-grade inflammatory reactions in the colon of IBS-D model rats. The mechanism may be related to the inhibition of histamine and trypsin-like enzyme secreted by mast cell, thereby reducing the expression of related inflammatory factors.

Targeting KDM4 family epigenetically triggers antitumour immunity via enhancing tumour-intrinsic innate sensing and immunogenicity.

Despite the remarkable clinical efficacy of cancer immunotherapy, considerable patients fail to benefit from it due to primary or acquired resistance. Tumours frequently hijack diverse epigenetic mechanisms to evade immune detection, thereby highlighting the potential for pharmacologically targeting epigenetic regulators to restore the impaired immunosurveillance and re-sensitise tumours to immunotherapy. Herein, we demonstrated that KDM4-targeting chemotherapeutic drug JIB-04, epigenetically triggered the tumour-intrinsic innate immune responses and immunogenic cell death (ICD), resulting in impressive antitumour effects. Specifically, JIB-04 induced H3K9 hypermethylation through specific inhibition of the KDM4 family (KDM4A-D), leading to impaired DNA repair signalling and subsequent DNA damage. As a result, JIB-04 not only activated the tumour-intrinsic cyclic GMP-AMP synthase (cGAS)-STING pathway via DNA-damage-induced cytosolic DNA accumulation, but also promoted ICD, releasing numerous damage-associated molecular patterns. Furthermore, JIB-04 induced adaptive resistance through the upregulation of programmed death-ligand 1 (PD-L1), which could be overcome with additional PD-L1 blockade. In human tumours, KDM4B expression was negatively correlated with clinical outcomes, type I interferon signatures, and responses to immunotherapy. In conclusion, our results demonstrate that targeting KDM4 family can activate tumour-intrinsic innate sensing and immunogenicity, and synergise with immunotherapy to improve antitumour outcomes.

Differences in ingestion and biodegradation of the melamine formaldehyde plastic by yellow mealworms Tenebrio molitor and superworms Zophobas atratus, and the prediction of functional gut microbes.

Plastics biodegradation by insect larvae is considered as a new strategy for plastic wastes treatment. To uncover the biodegradation of a more complex chemical polymer of melamine formaldehyde (MF) by insect larvae, two worm species of yellow mealworm Tenebrio molitor and superworm Zophobas atratus were fed on MF foam as sole diet for 45 days with sole bran diet as control. Although the MF foam consumption by yellow mealworms of 0.38 mg/d/g-larvae was almost 40% higher than that by superworms of 0.28 mg/d/g-larvae, a similar decrease of survival rates in both species were obtained at about 58%, indicating the adverse effects on their growth. Depolymerization and biodegradation of MF foam occurred in both larval guts, but was more extensive in yellow mealworms. MF foam sole diet influenced gut bacterial and fungal microbiomes of both larvae species, which were assessed by Illumina MiSeq on day 45. Compared to the bran-fed group, both gut bacterial and fungal communities significantly changed in MF-fed groups, but differed in the two larvae species. The results demonstrated a strong association between the distinctive gut microbiome and MF foam degradation, such as unclassified Enterobacteriaceae, Hyphopichia and Issatchenkia. However, sole MF foam diet negatively influenced worms, like lower survival rates and gut abnormalities. In summary, MF foam could be degraded by both yellow mealworms and superworms, albeit with adverse effects. Gut microbes were strongly associated to MF foam degradation, especially the gut fungi.

Ultrasonic-ethanol pretreatment assisted aqueous enzymatic extraction of hemp seed oil with low Δ9-THC.

In this study, ultrasonic-ethanol pretreatment combined with AEE was developed for oil extraction from hemp seeds. The oil yield reached a maximum of 23.32 % at 200 W ultrasonic power and 30 min ultrasonic time, at this point, the degradation rate of Δ9-THC was 83.11 %. By determining the composition of hemp seed before and after pretreatment, it was shown that ultrasonic-ethanol pretreatment reduced the protein content of the raw material. An enzyme mixture consisting of pectinase and hemicellulase (1/1/1, w/w/w) was experimentally determined to be used, and the AEE extraction conditions were optimized using the Plackett-Burman design and the Box-Behnken. The optimal conditions were determined to be pH 5, total enzyme activity of 37,800 U/g, liquid-solid ratio of 10.4 mL/g, enzyme digestion temperature of 32 °C, enzymatic time of 189 min, and oil recovery of 88.38 %. The results of confocal laser scanning microscopy (CLSM) and scanning electron microscopy (SEM) showed that the emulsion formed during ultrasonic ethanol pretreatment was not uniformly distributed, and the droplets appeared to be aggregated; and the irregular pores of hemp seed increased after pretreatment. The contents of Δ9-THC and CBN in the extracted oil samples were 9.58 mg/kg and 52.45 mg/kg, respectively. Compared with the oil extracted by Soxhlet extraction (SE), the oil extracted by this experimental method was of better quality and similar in fatty acid composition.

Delta-radiomics features for predicting the major pathological response to neoadjuvant chemoimmunotherapy in non-small cell lung cancer.

OBJECTIVES: To investigate if delta-radiomics features have the potential to predict the major pathological response (MPR) to neoadjuvant chemoimmunotherapy in non-small cell lung cancer (NSCLC) patients. METHODS: Two hundred six stage IIA-IIIB NSCLC patients from three institutions (Database1 = 164; Database2 = 21; Database3 = 21) who received neoadjuvant chemoimmunotherapy and surgery were included. Patients in Database1 were randomly assigned to the training dataset and test dataset, with a ratio of 0.7:0.3. Patients in Database2 and Database3 were used as two independent external validation datasets. Contrast-enhanced CT scans were obtained at baseline and before surgery. The delta-radiomics features were defined as the relative net change of radiomics features between baseline and preoperative. The delta-radiomics model and pre-treatment radiomics model were established. The performance of Immune-Related Response Evaluation Criteria in Solid Tumors (iRECIST) for predicting MPR was also evaluated. RESULTS: Half of the patients (106/206, 51.5%) showed MPR after neoadjuvant chemoimmunotherapy. For predicting MPR, the delta-radiomics model achieved a satisfying area under the curves (AUCs) values of 0.768, 0.732, 0.833, and 0.716 in the training, test, and two external validation databases, respectively, which showed a superior predictive performance than the pre-treatment radiomics model (0.644, 0.616, 0.475, and 0.608). Compared with iRECIST criteria (0.624, 0.572, 0.650, and 0.466), a mixed model that combines delta-radiomics features and iRECIST had higher AUC values for MPR prediction of 0.777, 0.761, 0.850, and 0.670 in four sets. CONCLUSION: The delta-radiomics model demonstrated superior diagnostic performance compared to pre-treatment radiomics model and iRECIST criteria in predicting MPR preoperatively in neoadjuvant chemoimmunotherapy for stage II-III NSCLC. CLINICAL RELEVANCE STATEMENT: Delta-radiomics features based on the relative net change of radiomics features between baseline and preoperative CT scans serve a vital support tool in accurately identifying responses to neoadjuvant chemoimmunotherapy, which can help physicians make more appropriate treatment decisions. KEY POINTS: • The performances of pre-treatment radiomics model and iRECIST model in predicting major pathological response of neoadjuvant chemoimmunotherapy were unsatisfactory. • The delta-radiomics features based on relative net change of radiomics features between baseline and preoperative CT scans may be used as a noninvasive biomarker for predicting major pathological response of neoadjuvant chemoimmunotherapy. • Combining delta-radiomics features and iRECIST can further improve the predictive performance of responses to neoadjuvant chemoimmunotherapy.

Caspase-9 inhibition triggers Hsp90-based chemotherapy-mediated tumor intrinsic innate sensing and enhances antitumor immunity.

BACKGROUND: Antineoplastic chemotherapies are dramatically efficient when they provoke immunogenic cell death (ICD), thus inducing an antitumor immune response and even tumor elimination. However, activated caspases, the hallmark of most cancer chemotherapeutic agents, render apoptosis immunologically silent. Whether they are dispensable for chemotherapy-induced cell death and the apoptotic clearance of cells in vivo is still elusive. METHODS: A rational cell-based anticancer drug library screening was performed to explore the immunogenic apoptosis pathway and therapeutic targets under apoptotic caspase inhibition. Based on this screening, the potential of caspase inhibition in enhancing chemotherapy-induced antitumor immunity and the mechanism of actions was investigated by various cells and mouse models. RESULTS: Heat shock protein 90 (Hsp90) inhibition activates caspases in tumor cells to produce abundant genomic and mitochondrial DNA fragments and results in cell apoptosis. Meanwhile, it hijacks Caspase-9 signaling to suppress intrinsic DNA sensing. Pharmacological blockade or genetic deletion of Caspase-9 causes tumor cells to secrete interferon (IFN)-ß via tumor intrinsic mitochondrial DNA/the second messenger cyclic GMP-AMP (cGAS) /stimulator of interferon genes (STING) pathway without impairing Hsp90 inhibition-induced cell death. Importantly, both Caspase-9 and Hsp90 inhibition triggers an ICD, leading to the release of numerous damage-associated molecular patterns such as high-mobility group box protein 1, ATP and type I IFNs in vitro and remarkable antitumor effects in vivo. Moreover, the combination treatment also induces adaptive resistance by upregulating programmed death-ligand 1 (PD-L1). Additional PD-L1 blockade can further overcome this acquired immune resistance and achieve complete tumor regression. CONCLUSIONS: Blockade of Caspase-9 signaling selectively provokes Hsp90-based chemotherapy-mediated tumor innate sensing, leading to CD8+ T cell-dependent tumor control. Our findings implicate that pharmacological modulation of caspase pathway increases the tumor-intrinsic innate sensing and immunogenicity of chemotherapy-induced apoptosis, and synergizes with immunotherapy to overcome adaptive resistance.

Association between leisure sedentary behaviour and uterine fibroids in non-menopausal women: a population-based study.

OBJECTIVE: Sedentary behaviour is associated with a variety of adverse health outcomes, including obesity, oestrogen metabolism and chronic inflammation, all of which are related to the pathogenesis of uterine fibroids (UFs). This study aimed to explore the relationship between leisure sedentary time (LST) and UFs. DESIGN: Cross-sectional. SETTING: We conducted a cross-sectional analysis of data from patients from the Yunnan region in the China Multi-Ethnic Cohort Study. PARTICIPANTS: A total of 6623 non-menopausal women aged 30-55 years old were recruited. Menstrual status was self-reported. Participants who lacked a unique national identity card, suffered from serious mental illness, did not have a clear diagnosis of UFs, or provided incomplete information were excluded. PRIMARY AND SECONDARY OUTCOME: UFs were diagnosed by abdominal B-ultrasound. Leisure sedentary behaviour was assessed by using a face-to-face questionnaire interview. Logistic regression and restricted cubic spline were employed to explore the relationship between LST and UFs. RESULTS: A total of 562 participants had UFs, with a prevalence rate of 8.5% (7.8%, 9.2%). Multivariate adjusted logistic regression analysis showed that the risk of UFs in women with LST≥6 hour/day was 2.008 times that in women with LST<2 hour/day (95% CI 1.230 to 3.279). The restricted cubic spline results showed that there was a linear dose‒response relationship between LST and UFs (p for non-linearity>0.05). According to the results of the stratified analysis for menstrual status and body mass index (BMI), there was a correlation between LST and the prevalence of UFs only in women with a BMI<24 kg/m2 or perimenopause. CONCLUSION: LST was independently associated with the prevalence of UFs, and a linear dose‒response relationship was observed. Our study provides evidence on the factors influencing UFs, and further research is needed to propose feasible measures for UFs prevention.

Anti-inflammatory effects of acupuncture in the treatment of chronic obstructive pulmonary disease.

Numerous randomised controlled trials have suggested the positive effects of acupuncture on chronic obstructive pulmonary disease (COPD). However, the underlying therapeutic mechanisms of acupuncture for COPD have not been clearly summarized yet. Inflammation is central to the development of COPD. In this review, we elucidate the effects and underlying mechanisms of acupuncture from an anti-inflammatory perspective based on animal studies. Cigarette smoke combined with lipopolysaccharide is often used to establish animal models of COPD. Electroacupuncture can be an effective intervention to improve inflammation in COPD, and Feishu (BL13) and Zusanli (ST36) can be used as basic acupoints in COPD animal models. Different acupuncture types can regulate different types of inflammatory cytokines; meanwhile, different acupuncture types and acupoint options have similar effects on modulating the level of inflammatory cytokines. In particular, acupuncture exerts anti-inflammatory effects by inhibiting the release of inflammatory cells, inflammasomes and inflammatory cytokines. The main underlying mechanism through which acupuncture improves inflammation in COPD is the modulation of relevant signalling pathways: nuclear factor-κB (NF-κB) (e.g., myeloid differentiation primary response 88/NF-κB, toll-like receptor-4/NF-κB, silent information regulator transcript-1/NF-κB), mitogen-activated protein kinase signalling pathways (extracellular signal-regulated kinase 1/2, p38 and c-Jun NH2-terminal kinase), cholinergic anti-inflammatory pathway, and dopamine D2 receptor pathway. The current synthesis will be beneficial for further research on the effect of acupuncture on COPD inflammation. Please cite this article as: Jiang LH, Li PJ, Wang YQ, Jiang ML, Han XY, Bao YD, Deng XL, Wu WB, Liu XD. Anti-inflammatory effects of acupuncture in the treatment of chronic obstructive pulmonary disease. J Integr Med. 2023; 21(6): 518-527.

A Combination of EGFR Inhibitors and AE-PDT Could Synergistically Suppress Breast Cancer Progression.

BACKGROUND: Breast cancer is the most frequently diagnosed malignancy and the leading cause of cancerrelated deaths in women. Activation of EGFR by EC-secreted EGFR ligands promotes breast cancer progression. Current treatments provide limited benefits in triple-negative breast cancer (TNBC). Photodynamic therapy (PDT) has been proven effective for the treatment of TNBC through the EGFR pathway, but the underlying mechanism is still unclear. PURPOSE: The purpose of this study was to determine the role of the EGFR pathway in the treatment of PDT on TNBC in a co-culture system. METHODS: MB-231 and HUVEC were co-cultured for experiments (HU-231). Cell viability and ROS production were detected after AE-PDT, a combination of EGFR inhibitors (AEE788)with PDT to test angiogenesis, apoptosis, and pyroptosis. WB detects expression of EGFR. EGFR, P-EGFR, VEGF, caspase-1, capase-3, and GSDMD . RESULTS: AE-PDT inhibited HU-231 cell proliferation and tumor angiogenesis, and induced cell apoptosis and pyroptosis by promoting ROS production. AEE788, an inhibitor of the EGFR, enhanced HU-231 cell killing after AE-PDT. CONCLUSION: Our study suggested that the combination of EGFR inhibitors and AE-PDT could synergistically suppress breast cancer progression, providing a new treatment strategy.

Tumor microenvironment-responsive DNA-based nanomedicine triggers innate sensing for enhanced immunotherapy.

Lack of proper innate sensing inside the tumor microenvironment could reduce both innate and adaptive immunity, which remains a critical cause of immunotherapy failure in various tumor treatments. Double-stranded DNA (dsDNA) has been evidenced to be a promising immunostimulatory agent to induce type I interferons (IFN-Is) production for innate immunity activation through the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway, yet the unsatisfactory delivery and susceptibility to nuclease degradation hindered its feasibility for further clinical applications. Herein, we report on the constructed tumor microenvironment-responsive DNA-based nanomedicine loaded by dendritic mesoporous organosilica nanoparticles (DMONs), which provide efficient delivery of dsDNA to induce intratumoral IFN-Is production for triggering innate sensing for enhanced anti-tumor immunotherapy. Extensive in vitro and in vivo evaluations have demonstrated the dramatic IFN-Is production induced by dsDNA@DMONs in both immune cells and tumor cells, which facilitates dendritic cells (DCs) maturation and T cells activation for eliciting the potent innate immune and adaptive immune responses. Desirable biosafety and marked therapeutic efficacy with a tumor growth inhibition (TGI) of 51.0% on the murine B16-F10 melanoma model were achieved by the single agent dsDNA@DMONs. Moreover, dsDNA@DMONs combined with anti-PD-L1 antibody further enhanced the anti-tumor efficacy and led to almost complete tumor regression. Therefore, this work highlighted the immunostimulatory DNA-based nanomedicine as a promising strategy for overcoming the resistance to immunotherapy, by promoting the IFN-Is production for innate immunity activation and remodeling the tumor microenvironment.

Coordination of hydraulic and leaf-level gas exchange traits during water-deficit acclimation in apple rootstocks.

Water deficit episodes impact apple (Malus domestica) productivity through challenging the trees' water status, the influence of extreme high temperature climate has become increasingly prominent in recent years. Rootstocks can bestow specific properties on the fruit trees such as the resistance to drought stress. However, the related hydraulic mechanisms in response to water deficit have not been fully understood. Herein, five rootstocks (SH6, GM256, M9, M26, and MM106) were examined under water limitation. The hydraulic conductance of root (Kroot), shoots (Kshoot), and stems (Kstem-shoot) in the five rootstocks reduced slightly during drought stress. Whereas the leaf water potential and photosynthesis of five rootstocks decreased dramatically when they were exposed to drought stress. Additionally, the Kshoot and Kstem-shoot were strongly correlated with the total plant leaf area. Aquaporins (AQPs) involved in the symplastic water transport pathway, the PIP2:1, TIP1:1, and TIP2:2 mRNA levels of all genotypic rootstocks showed significant regulation under drought stress. We examined the relationships among photosynthesis, apoplastic, and symplastic water movement pathways to achieve a comprehensive understanding of rootstocks' hydraulic strategy for improving drought adaptation. The PIP2:1 and TIP2:1 in leaves were more sensitive to root hydraulic conductance in response to drought stress. Furthermore, the coordinated relationship existed in leaf-specific conductance of shoot (Kl -shoot) and transpiration rate (Tr) under drought stress in the rootstocks. Overall, the drought resistance in the five dwarfing rootstocks is associated with the rapid re-establishment of water-related traits, and the effect of the canopy on the drought resistance in apple rootstocks merits much more attention.

Study on secondary metabolites of endophytic fungus Diaporthe sp. AC1 induced by tryptophan analogs.

Small molecule-induced fermentation of the endophytic fungus Diaporthe sp. AC1 originated from Artemisia argyi was executed to investigate its secondary metabolites. It was fermented in a culture medium containing 5-hydroxytryptophan (5-HTP), 1-methyl-L-tryptophan (1-MT), and tryptamine (TA), respectively. The antibacterial activities of crude extracts against pathogenic bacteria and pathogenic fungi were determined by using the Oxford cup method, while the cytotoxicity of crude extracts against cancer cells was determined by using the MTT method. The results showed that the secondary metabolites of Diaporthe sp. AC1 induced by 1-MT exhibited optimal antibacterial activity and tumor cytotoxicity. The induction conditions of 1-MT were optimized, and the antibacterial activities and tumor cytotoxicity of crude extracts under different induction conditions were investigated. As indicated, the optimal moment for 1-MT addition was before inoculation and its optimal concentration was 0.25 mM. Under these conditions, Diaporthe sp. AC1 was fermented and approximately 12 g of crude extracts was obtained. The crude extracts were then separated and purified to acquire nine monomer compounds, including three new compounds (1-3) and six known compounds (4-9). The antibacterial activities of the compounds against pathogenic bacteria and pathogenic fungi were investigated by using the microdilution method, while their cytotoxicity against cancer cells was analyzed by using the MTT method. The results demonstrated that Compound 1 exhibited moderate antibacterial activities against Verticillium dahlia, Fusarium graminearum, and Botrytis cinerea, as well as a low inhibitory activity against Listeria monocytogenes. Nevertheless, Compound 1 showed significant cytotoxicity against five cancer cells, with IC50 ranging from 12.26 to 52.52 µM. Compounds 2 and 3 exhibited negligible biological activity, while other compounds showed detectable inhibitory activities against pathogenic bacteria and cancer cells.