Protective effect of Tetrandrine on optic nerve by inhibiting glial activation through NF-κB pathway.

Introduction: This study aimed to explore the effect and molecular mechanism of Tetrandrine (Tet) onlipopolysaccharide (LPS)-induceduveitis andoptic nerve injury in vivo and in vitro. Methods: Uveitis was induced by LPS injected into the hindlimb foot pad of Wistar rats and was intervened by retroeyeball injection of Tet (100 nM, 1 µM or 10 µM).The anterior segment inflammation was observed by slit lamp. Tunelassay was used to detect the survival state of ganglion cells and nuclear layers of inner and outer. The detection of characteristic markers in different activation states of glial cells were performed by qualitative and quantitative test of immunofluorescence and western blotting. Also, western blotting was used to detect the expression of inflammatory factors in retina and the activation of nuclear factor kappa B (NF-κB) signal pathway. Meanwhile, routine blood test and function of liver and renal were performed. Results: The ciliary hyperemia was obvious, and the iris vessels were dilated and tortuous in rats with LPS-induced uveitis. Tet-pretreated obviously elieved these symptoms. In addition, the dilation and hyperemia in Tet group were alleviated compared with LPS group, and the inflammatory scores in Tetgroup were significantly lower than those of LPS group. TUNEL Staining showed that the number ofretinal ganglion cell (RGCs) in Tetgroup was slightly less than that in normal group, but significantly more than that in LPS group, and the cells arranged orderly. Besides, the number of apoptotic cells was significantly less than that in LPS group. Tet reduced LPS-activated gliocyte in a dose-dependent manner. Tumour necrosis factor alpha (TNF-α), interleukin (IL)-1ß, interferon gamma (γ-IFN) and IL-2 in retina were increased by LPS but decreased significantly viaTet-pretreatment. Moreover, LPS activate NF-κB signal pathway, while Tet efficiently inhibited this effect.Furthermore, injection of Tet did not damage theroutineblood, liver and kidney. Conclusions: Retrobulbar injection of Tet significantly alleviatedLPS-induced uveitisand optic nerve injuryof rats by activating gliocyte and NF-κB signaling pathway.

The predictive value of peripheral blood CD4 cells ATP concentration for immune-related adverse events in advanced non-small cell lung cancer patients.

OBJECTIVE: Lung cancer with the highest incidence and mortality in the world. Immune checkpoint inhibitors (ICIs), can bring long-term survival benefits to patients, but also can bring immune-related adverse events (irAEs) in some patients during therapy. Therefore, the aim of this study was to investigate the predictive effect of peripheral blood WBC, NLR, sATPCD4 and nATPCD4 on irAEs in advanced non-small cell lung cancer (NSCLC). METHODS: Clinical data of 112 patients with advanced NSCLC who were treated with PD -1/PD -L1 inhibitor in the Fifth Affiliated Hospital of Guangzhou Medical University from December 15, 2019 to April 30, 2023 were retrospectively analyzed. These patients were divided into the irAEs group (n = 27) and non-irAEs group (n = 85). The clinical data of the two groups were compared. Receiver operating characteristic (ROC) curves were drawn to determine the threshold value of baseline peripheral blood parameters to predict the occurrence of irAEs. Multivariate logistic regression analysis was used to explore the relationship between peripheral blood markers and the incidence of irAEs. RESULTS: The patient characteristics have no significant difference between irAEs and non-irAEs group. But the baseline peripheral blood WBC, sATPCD4 and nATPCD4 of patients in the irAEs group were higher than those in the non-irAEs group (p < 0.05), and the NLR in irAEs group was similar to in the non-irAEs group (p = 0.639).Univariate analysis showed that high WBC, sATPCD4 and nATPCD4 may the risk factors for the occurrence of irAEs (p < 0.05). Multivariate logistic regression analysis showed that high sATPCD4 and nATPCD4 were independent risk factors for the occurrence of irAEs (p < 0.05). The best critical values of WBC, sATPCD4 and nATPCD4 before treatment for predicting the occurrence of irAEs were 8.165 × 109cells/L (AUC = 0.705) ,484.5 ng/mL (AUC = 0.777), and 156 ng/mL (AUC = 0.840), respectively. CONCLUSIONS: sATPCD4 and nATPCD4 were independent risk factors for the occurrence of irAEs in advanced NSCLC patients. This discovery provides a new method to predict the occurrence of irAEs in patients. Based on the prediction results, corresponding treatment measures can be taken to reduce the incidence of adverse events.

NOTCH3 promotes docetaxel resistance of prostate cancer cells through regulating TUBB3 and MAPK signaling pathway.

Docetaxel is the preferred chemotherapeutic agent in patients with castrate-resistant prostate cancer (CRPC). However, patients eventually develop docetaxel resistance and in the absence of effective treatment options. Consequently, it is essential to investigate the mechanisms generating docetaxel resistance and develop novel alternative therapeutic targets. RNA sequencing was undertaken on docetaxel-sensitive and docetaxel-resistant prostate cancer (PCa) cells. Subsequently, chemoresistance, cancer stemness, and lipid metabolism were investigated. To obtain insight into the precise activities and action mechanisms of NOTCH3 in docetaxel-resistant PCa, immunoprecipitation, mass spectrometry, ChIP, luciferase reporter assay, cell metabolism, and animal experiments were performed. Through RNA sequencing analysis, we found that NOTCH3 expression was markedly higher in docetaxel-resistant cells relative to parental cells, and that this trend was continued in docetaxel-resistant PCa tissues. Experiments in vitro and in vivo revealed that NOTCH3 enhanced stemness, lipid metabolism, and docetaxel resistance in PCa. Mechanistically, NOTCH3 is bound to TUBB3 and activates the MAPK signaling pathway. Moreover, NOTCH3 was directly regulated by MEF2A in docetaxel-resistant cells. Notably, targeting NOTCH3 and the MEF2A/TUBB3 signaling axis was related to docetaxel chemoresistance in PCa. Overall, these results demonstrated that NOTCH3 fostered stemness, lipid metabolism, and docetaxel resistance in PCa via the TUBB3 and MAPK signaling pathways. Therefore, NOTCH3 may be employed as a prognostic biomarker in PCa patients. NOTCH3 could be a therapeutic target for PCa patients, particularly those who have developed docetaxel resistance.

BLCA prognostic model creation and validation based on immune gene-metabolic gene combination.

BACKGROUND: Bladder cancer (BLCA) is a prevalent urinary system malignancy. Understanding the interplay of immunological and metabolic genes in BLCA is crucial for prognosis and treatment. METHODS: Immune/metabolism genes were extracted, their expression profiles analyzed. NMF clustering found prognostic genes. Immunocyte infiltration and tumor microenvironment were examined. Risk prognostic signature using Cox/LASSO methods was developed. Immunological Microenvironment and functional enrichment analysis explored. Immunotherapy response and somatic mutations evaluated. RT-qPCR validated gene expression. RESULTS: We investigated these genes in 614 BLCA samples, identifying relevant prognostic genes. We developed a predictive feature and signature comprising 7 genes (POLE2, AHNAK, SHMT2, NR2F1, TFRC, OAS1, CHKB). This immune and metabolism-related gene (IMRG) signature showed superior predictive performance across multiple datasets and was independent of clinical indicators. Immunotherapy response and immune cell infiltration correlated with the risk score. Functional enrichment analysis revealed distinct biological pathways between low- and high-risk groups. The signature demonstrated higher prediction accuracy than other signatures. qRT-PCR confirmed differential gene expression and immunotherapy response. CONCLUSIONS: The model in our work is a novel assessment tool to measure immunotherapy's effectiveness and anticipate BLCA patients' prognosis, offering new avenues for immunological biomarkers and targeted treatments.

Advances in diagnosis and prediction for aggression of pure solid T1 lung cancer.

A growing number of early-stage lung cancers presenting as malignant pulmonary nodules have been diagnosed because of the increased adoption of low-dose spiral computed tomography. But pure solid T1 lung cancer with ≤3 cm in the greatest dimension is not always at an early stage, despite its small size. This type of cancer can be highly aggressive and is associated with pathological involvement, metastasis, postoperative relapse, and even death. However, it is easily misdiagnosed or delay diagnosed in clinics and thus poses a serious threat to human health. The percentage of nodal or extrathoracic metastases has been reported to be >20% in T1 lung cancer. As such, understanding and identifying the aggressive characteristics of pure solid T1 lung cancer is crucial for prevention, diagnosis, and therapeutic strategies, and beneficial to improving the prognosis. With the widespread of lung cancer screening, these highly invasive pure solid T1 lung cancer will become the main advanced lung cancer in future. However, there is limited information regarding precision medicine on how to identify these "early-stage" aggressive lung cancers. To provide clinicians with new insights into early recognition and intervention of the highly invasive pure solid T1 lung cancer, this review summarizes its clinical characteristics, imaging, pathology, gene alterations, immune microenvironment, multi-omics, and current techniques for diagnosis and prediction.

Aedes albopictus salivary adenosine deaminase is an immunomodulatory factor facilitating dengue virus replication.

The Asian tiger mosquito, Aedes albopictus, is an important vector for the transmission of arboviruses such as dengue virus (DENV). Adenosine deaminase (ADA) is a well-characterized metabolic enzyme involved in facilitating blood feeding and (or) arbovirus transmission in some hematophagous insect species. We previously reported the immunologic function of ADA by investigating its effect on mast cell activation and the interaction with mast cell tryptase and chymase. The 2-D gel electrophoresis and mass spectrometry analysis in the current study revealed that ADA is present and upregulated following mosquito blood feeding, as confirmed by qRT-PCR and western blot. In addition, the recombinant ADA efficiently converted adenosine to inosine. Challenging the Raw264.7 and THP-1 cells with recombinant ADA resulted in the upregulation of IL-1ß, IL-6, TNF-α, CCL2, IFN-ß, and ISG15. The current study further identified recombinant ADA as a positive regulator in NF-κB signaling targeting TAK1. It was also found that recombinant Ae. albopictus ADA facilitates the replication of DENV-2. Compared with cells infected by DENV-2 alone, the co-incubation of recombinant ADA with DENV-2 substantially increased IL-1ß, IL-6, TNF-α, and CCL2 gene transcripts in Raw264.7 and THP-1 cells. However, the expression of IFN-ß and ISG15 were markedly downregulated in Raw264.7 cells but upregulated in THP-1 cells. These findings suggest that the immunomodulatory protein, Ae. albopictus ADA is involved in mosquito blood feeding and may modulate DENV transmission via macrophage or monocyte-driven immune response.

Effect of early oral carbohydrate intake after elective Cesarean delivery on maternal body temperature and satisfaction: a randomized controlled trial.

PURPOSE: Although the Enhanced Recovery After Cesarean Delivery (ERAC) consensus statement provides recommendations for early postoperative drinking and eating, evidence from high-quality clinical research directly addressing parturients is sparse. Our objective was to assess if early oral carbohydrate intake after elective Cesarean delivery improves maternal recovery. METHODS: In this randomized controlled trial, we enrolled parturients undergoing elective Cesarean delivery under spinal anesthesia with tympanic membrane temperatures ≤ 36.5 °C immediately upon arrival at the postanesthesia care unit. Parturients were randomized to either 100 mL of oral complex carbohydrate intake (group CC) or 10 mL of water (group C). The primary outcome was maternal tympanic membrane temperature. Other outcomes included maternal thermal comfort score, degree of shivering, satisfaction, degree of thirst and hunger, and gastric emptying assessed by ultrasonography. RESULTS: We included 90 participants in the final analysis. The mean (standard deviation [SD]) maternal body temperature at 120 min after ingestion was 36.7 (0.3) °C in group CC and 36.6 (0.3) °C in group C (difference in means, 0.14 °C; 95% confidence interval, 0.02 to 0.26; P = 0.02). Furthermore, using repeated measure models, the linear trends of temperature changes over time between groups CC and C were significantly different (P = 0.04). The thermal comfort scores at 120 min after ingestion were higher in group CC than in group C (P = 0.02), and the linear trends of shivering score changes over time between groups CC and C also were different (P = 0.003). The mean (SD) visual analogue scale scores for maternal satisfaction were 84 (13) mm in group CC and 47 (20) mm in group C (P < 0.001). Nevertheless, at 90 and 120 min after ingestion, there were no differences between the two groups in the number of participants with a gastric antrum cross-sectional area > 10.3 cm2. CONCLUSIONS: Early oral carbohydrate intake after Cesarean delivery helped to restore maternal body temperature postoperatively and improve maternal satisfaction. Nevertheless, the clinical importance of these finding is unclear, given that most of the differences were small. In addition, there was no delay in maternal gastric emptying after consumption of a complex carbohydrate beverage in the early post-Cesarean period. STUDY REGISTRATION: www.chictr.org.cn (ChiCTR2000031085); first submitted 13 November 2022.

RéSUMé: OBJECTIF: Bien que la déclaration de consensus sur la Récupération améliorée après un accouchement par césarienne (ERAC/RAAC) fournisse des recommandations pour l'ingestion postopératoire précoce de liquides et d'aliments, les données probantes issues de recherches cliniques de haute qualité portant directement sur les personnes parturientes sont rares. Notre objectif était d'évaluer si l'ingestion précoce de glucides par voie orale après une césarienne programmée améliorait la récupération maternelle. MéTHODE: Dans cette étude randomisée contrôlée, nous avons recruté des personnes parturientes bénéficiant d'une césarienne programmée sous rachianesthésie avec une température tympanique ≤ 36,5 °C immédiatement après leur arrivée en salle de réveil. Les personnes parturientes ont été randomisées à recevoir soit 100 mL de glucides complexes par voie orale (groupe GC) ou 10 mL d'eau (groupe C). Le critère d'évaluation principal était la température tympanique maternelle. Les autres critères d'évaluation comprenaient, chez la mère, le score de confort thermique, le degré de frissons, la satisfaction, le degré de soif et de faim, et la vidange gastrique évaluée par échographie. RéSULTATS: Nous avons inclus 90 personnes dans l'analyse finale. La température corporelle maternelle moyenne (écart type [ET]) à 120 minutes après l'ingestion était de 36,7 (0,3) °C dans le groupe GC et de 36,6 (0,3) °C dans le groupe C (différence dans les moyennes, 0,14 °C; intervalle de confiance à 95 %, 0,02 à 0,26; P = 0,02). De plus, à l'aide de modèles à mesures répétées, les tendances linéaires des changements de température au fil du temps entre les groupes GC et C étaient significativement différentes (P = 0,04). Les scores de confort thermique à 120 minutes après l'ingestion étaient plus élevés dans le groupe GC que dans le groupe C (P = 0,02), et les tendances linéaires des changements de score de frissons au fil du temps entre les groupes GC et C étaient également différentes (P = 0,003). Les scores moyens (ET) de l'échelle visuelle analogique concernant la satisfaction maternelle étaient de 84 (13) mm dans le groupe GC et de 47 (20) mm dans le groupe C (P < 0,001). Néanmoins, à 90 et 120 minutes après l'ingestion, il n'y avait aucune différence entre les deux groupes dans le nombre de personnes présentant une section transversale de l'antre gastrique > 10,3 cm2. CONCLUSION: L'ingestion précoce de glucides par voie orale après un accouchement par césarienne a aidé à rétablir la température corporelle maternelle postopératoire et à améliorer la satisfaction maternelle. Néanmoins, l'importance clinique de ces résultats n'est pas claire, étant donné que la plupart des différences étaient faibles. De plus, il n'y avait pas de retard dans la vidange gastrique maternelle après la consommation d'une boisson glucidique complexe au début de la période post-césarienne. ENREGISTREMENT DE L'éTUDE: www.chictr.org.cn (ChiCTR2000031085); soumis pour la première fois le 13 novembre 2022.

Bevacizumab plus erlotinib versus erlotinib alone for advanced EGFR-mutant non-small cell lung cancer: a meta-analysis of randomized clinical trials.

OBJECTIVE: Previous studies showed that the combination of bevacizumab and erlotinib (combination therapy) significantly prolonged progression-free survival (PFS) but no overall survival (OS) compared to erlotinib alone (monotherapy) for advanced EGFR-mutant non-small cell lung cancer (NSCLC). Two phase III randomized controlled trials (RCTs) had reported the OS results in 2021. This meta-analysis aimed to include the results of the two RCTs to make a decision. MATERIALS AND METHODS: We systematically searched relevant databases for RCTs on the use of bevacizumab plus erlotinib in advanced EGFR-mutant NSCLC. The main outcomes of interest were PFS, OS, and the reported hazard ratio (HR). Fixed-effect model was used to estimate pooled HR. RESULTS: Total 5 RCTs with 935 patients were eligible for this meta-analysis. All studies reached their primary study endpoints including PFS and OS. Compared to monotherapy, combination therapy remarkably prolonged PFS (HR = 0.60, 95% confidence interval CI 0.51-0.70; p < 0.00001); however, OS was similar between the two groups (HR = 0.90, 95% CI 0.76-1.08; p = 0.26). Subgroup analysis demonstrated that in deletion within exon 19 (19del) mutation subgroup, the combination therapy could only prolong PFS (HR = 0.60, 95% CI 0.47-0.76; p < 0.0001) but not OS (HR = 1.00, 95% CI 0.73-1.37; p = 1.00), and also in leucine-to-arginine substitution in exon 21 (L858R) mutation subgroup (HR = 0.59, p < 0.0001 and HR = 0.80, p = 0.18, respectively). For patients with brain metastasis at baseline, the combination therapy achieved a significant better PFS than the monotherapy (HR = 0.60, 95% CI 0.39-0.90; p = 0.01), and a better OS with the difference marginally significant (HR = 0.69, 95% CI 0.46-1.02; p = 0.06). CONCLUSIONS: Combination of bevacizumab and erlotinib can prolong progression-free survival but not overall survival compared to erlotinib alone in advanced EGFR-mutant non-small cell lung cancer patients. The combination therapy not only can prolong progression-free survival but also has a tendency to prolong overall survival for patients with brain metastasis at baseline.

Deep learning predicts malignancy and metastasis of solid pulmonary nodules from CT scans.

In the clinic, it is difficult to distinguish the malignancy and aggressiveness of solid pulmonary nodules (PNs). Incorrect assessments may lead to delayed diagnosis and an increased risk of complications. We developed and validated a deep learning-based model for the prediction of malignancy as well as local or distant metastasis in solid PNs based on CT images of primary lesions during initial diagnosis. In this study, we reviewed the data from multiple patients with solid PNs at our institution from 1 January 2019 to 30 April 2022. The patients were divided into three groups: benign, Ia-stage lung cancer, and T1-stage lung cancer with metastasis. Each cohort was further split into training and testing groups. The deep learning system predicted the malignancy and metastasis status of solid PNs based on CT images, and then we compared the malignancy prediction results among four different levels of clinicians. Experiments confirmed that human-computer collaboration can further enhance diagnostic accuracy. We made a held-out testing set of 134 cases, with 689 cases in total. Our convolutional neural network model reached an area under the ROC (AUC) of 80.37% for malignancy prediction and an AUC of 86.44% for metastasis prediction. In observer studies involving four clinicians, the proposed deep learning method outperformed a junior respiratory clinician and a 5-year respiratory clinician by considerable margins; it was on par with a senior respiratory clinician and was only slightly inferior to a senior radiologist. Our human-computer collaboration experiment showed that by simply adding binary human diagnosis into model prediction probabilities, model AUC scores improved to 81.80-88.70% when combined with three out of four clinicians. In summary, the deep learning method can accurately diagnose the malignancy of solid PNs, improve its performance when collaborating with human experts, predict local or distant metastasis in patients with T1-stage lung cancer, and facilitate the application of precision medicine.

ScRNA-seq revealed an immunosuppression state and tumor microenvironment heterogeneity related to lymph node metastasis in prostate cancer.

BACKGROUND: Metastasis is a crucial aspect of disease progression leading to death in patients with prostate cancer (PCa). However, its mechanism remains unclear. We aimed to explore the mechanism of lymph node metastasis (LNM) by analyzing the heterogeneity of tumor microenvironment (TME) in PCa using scRNA-seq. METHODS: A total of 32,766 cells were obtained from four PCa tissue samples for scRNA-seq, annotated, and grouped. InferCNV, GSVA, DEG functional enrichment analysis, trajectory analysis, intercellular network evaluation, and transcription factor analysis were carried out for each cell subgroup. Furthermore, validation experiments targeting luminal cell subgroups and CXCR4 + fibroblast subgroup were performed. RESULTS: The results showed that only EEF2 + and FOLH1 + luminal subgroups were present in LNM, and they appeared at the initial stage of luminal cell differentiation, which were comfirmed by verification experiments. The MYC pathway was enriched in the EEF2 + and FOLH1 + luminal subgroups, and MYC was associated with PCa LNM. Moreover, MYC did not only promote the progression of PCa, but also led to immunosuppression in TME by regulating PDL1 and CD47. The proportion of CD8 + T cells in TME and among NK cells and monocytes was lower in LNM than in the primary lesion, while the opposite was true for Th and Treg cells. Furthermore, these immune cells in TME underwent transcriptional reprogramming, including CD8 + T subgroups of CCR7 + and IL7R+, as well as M2-like monocyte subgroups expressing tumor-associated signature genes, like CCR7, SGKI, and RPL31. Furthermore, STEAP4+, ADGRF5 + and CXCR4+, and SRGNC + fibroblast subgroups were closely related to tumor progression, tumor metabolism, and immunosuppression, indicating their contributions in PCa metastasis. Meanwhile, The presence of CXCR4 + Fibroblasts in PCa was confirmed by polychromatic immunofluorescence. CONCLUSIONS: The significant heterogeneity of luminal, immune, and interstitial cells in PCa LNM may not only directly contribute to tumor progression, but also indirectly result in TME immunosuppression, which may be the cause of metastasis in PCa and in which MYC played an role.

PPRX-1701, a nanoparticle formulation of 6'-bromoindirubin acetoxime, improves delivery and shows efficacy in preclinical GBM models.

Derivatives of the Chinese traditional medicine indirubin have shown potential for the treatment of cancer through a range of mechanisms. This study investigates the impact of 6'-bromoindirubin-3'-acetoxime (BiA) on immunosuppressive mechanisms in glioblastoma (GBM) and evaluates the efficacy of a BiA nanoparticle formulation, PPRX-1701, in immunocompetent mouse GBM models. Transcriptomic studies reveal that BiA downregulates immune-related genes, including indoleamine 2,3-dioxygenase 1 (IDO1), a critical enzyme in the tryptophan-kynurenine-aryl hydrocarbon receptor (Trp-Kyn-AhR) immunosuppressive pathway in tumor cells. BiA blocks interferon-γ (IFNγ)-induced IDO1 protein expression in vitro and enhances T cell-mediated tumor cell killing in GBM stem-like cell co-culture models. PPRX-1701 reaches intracranial murine GBM and significantly improves survival in immunocompetent GBM models in vivo. Our results indicate that BiA improves survival in murine GBM models via effects on important immunotherapeutic targets in GBM and that it can be delivered efficiently via PPRX-1701, a nanoparticle injectable formulation of BiA.

Volumetric analysis of effectiveness of embolization for preventing type II endoleaks following endovascular aortic aneurysm repair.

OBJECTIVE: The presence of endoleak was associated with the failure of endovascular aortic aneurysm repair (EVAR) treatment. The key to eliminating type II endoleak has shifted from reintervention to prevention. This study aimed to evaluate the effectiveness and safety of applying fibrin sealant to prevent type II endoleak in conjunction with EVAR. METHODS: All patients with abdominal aortic aneurysm who underwent EVAR from June 2019 to July 2021 were reviewed. Patients were grouped as Group A: standard EVAR with preemptive embolization and Group B: standard EVAR alone. The primary endpoint was the incidence of type II endoleak. The secondary endpoints were aneurysm sac regression, the inferior mesenteric artery patency, the numbers of patent lumbar arteries, and all-cause mortality. RESULTS: A total of 104 patients were included in Group A, and 116 were included in Group B. Technical success rate was 100%. The overall incidence of type II endoleak in Group A was significantly lower than that in Group B (4.8% vs 19.0%). The mean time of freedom from type II endoleak was 22.71 months for Group A (95% confidence interval, 21.59-23.83 months) and 19.89 months for Group B (95% confidence interval, 18.08-21.70 months). The Kaplan-Meier estimate of freedom from type II endoleak showed a significantly longer duration of freedom from type II endoleak in Group A (81.0% vs 95.2%). Group A showed a continuous sac regression tendency. In Group B, the sac volume decreased within 12 months but increased by 3.07 cm3 at 24 months. No complications were noted in both groups. CONCLUSIONS: Nonselective preemptive embolization with porcine fibrin sealant during EVAR was safe and effective in preventing type II endoleak in the short and mid-term. Preemptive embolization can lead to a significantly higher sac regression rate. Larger patient populations and longer follow-ups with randomized control designed trials are expected to verify the long-term effectiveness and safety of preemptive embolization in preventing type II endoleak.

Investigation of the adsorption-desorption behavior of antibiotics by polybutylene succinate and polypropylene aged in different water conditions.

Microplastics (MPs) are widely present in aqueous environments and aged by natural components of complex water environments, such as salinity (SI) and dissolved organic matter (DOM). However, the effects of multicondition aging on the physicochemical properties and environmental behavior of MPs have not been completely investigated. In this study, the degradable MP polybutylene succinate (PBS) was used to investigate the environmental behavior of sulfamethoxazole (SMZ) and was compared with polypropylene (PP). The results showed that the single-factor conditions of DOM and SI, particularly DOM, promoted the aging process of MPs more significantly, especially for PBS. The degrees of MP aging under multiple conditions were lower than those under single-factor conditions. Compared with PP, PBS had greater specific surface area, crystallinity, and hydrophilicity and thus a stronger SMZ adsorption capacity. The adsorption behavior of MPs fitted well with the pseudo-second-order kinetic and Freundlich isotherm models, indicating multilayer adsorption. Compared with PP, PBS showed relatively a higher adsorption capacity, for example, for MPs aged under DOM conditions, the adsorption of SMZ by PBS was up to 5.74 mg/g, whereas that for PP was only 3.41 mg/g. The desorption experiments showed that the desorption amount of SMZ on MPs in the simulated intestinal fluid was greater than that in Milli-Q water. In addition, both the original PBS and the aged PBS had stronger desorption capacities than that of PP. The desorption quantity of PBS was 1.23-1.84 times greater than PP, whereas the desorption rates were not significantly different. This experiment provides a theoretical basis for assessing the ecological risks of degradable MPs in complex water conditions.

Discovery of Notch Pathway-Related Genes for Predicting Prognosis and Tumor Microenvironment Status in Bladder Cancer.

Background: Notch signaling is a key regulator of immune cell differentiation and linked to autoimmune diseases, tumorigenesis and tumor-induced immunomodulation. An abnormally activated Notch signaling pathway contributes to almost all of the key features of cancer, including tumor angiogenesis, stemness, and epithelial-mesenchymal transition. Consequently, we investigated Notch pathway-related genes for developing prognostic marker and assessing immune status in bladder cancer. Methods: The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were utilized to analyze RNA-seq data for bladder cancer. Cluster subtypes were identified using the NMF algorithm. In order to establish a prognostic risk signature, the least absolute shrinkage and selection operator (Lasso) and Cox regression analysis was utilized. GSEA was carried out to investigate the molecular mechanisms. Immune cell infiltration levels in bladder cancer were calculated using the CIBERSORT algorithm. External clinical tissue samples were used to validate the expression levels of signature genes. Results: Based on the NMF algorithm, bladder cancer samples were divided into two cluster subtypes and displayed different survival outcome and immune microenvironment. A six-gene risk signature (DTX3L, CNTN1, ENO1, GATA3, MAGEA1, and SORBS2) was independent for prognosis and showed good stability. The infiltration of immune cells and clinical variables were significantly different among the risk groups of patients. Response to immunotherapy also differed between different risk groups. Furthermore, the mRNA expression levels of the signature genes were verified in tissue samples by qRT-PCR. Conclusion: We established a 6-gene signature associated with Notch pathway in bladder cancer to effectively predict prognosis and reflect immune microenvironment status.

The Prognostic Signature and Therapeutic Value of Phagocytic Regulatory Factors in Prostate Adenocarcinoma (PRAD).

There is growing evidence that phagocytosis regulatory factors (PRFs) play important roles in tumor progression, and therefore, identifying and characterizing these factors is crucial for understanding the mechanisms of cellular phagocytosis in tumorigenesis. Our research aimed to comprehensively characterize PRFs in prostate adenocarcinoma (PRAD) and to screen and determine important PRFs in PRAD which may help to inform tumor prognostic and therapeutic signatures based on these key PRFs. Here, we first systematically described the expression of PRFs in PRAD and evaluated their expression patterns and their prognostic value. We then analyzed prognostic phagocytic factors by Cox and Lasso analysis and constructed a phagocytic factor-mediated risk score. We then divided the samples into two groups with significant differences in overall survival (OS) based on the risk score. Then, we performed correlation analysis between the risk score and clinical features, immune infiltration levels, immune characteristics, immune checkpoint expression, IC50 of several classical sensitive drugs, and immunotherapy efficacy. Finally, the Human Protein Atlas (HPA) database was used to determine the protein expression of 18 PRF characteristic genes. The aforementioned results confirmed that multilayer alterations of PRFs were associated with the prognosis of patients with PRAD and the degree of macrophage infiltration. These findings may provide us with potential new therapies for PRAD.

Patient-reported adherence to physical exercises of patients with ankylosing spondylitis.

INTRODUCTION: Studies on adherence to exercise therapy of patients with ankylosing spondylitis (AS) are rare, and the criteria for adherence to exercise are inconsistent. This study aimed to quantify patient-reported adherence to exercise therapy of Chinese outpatients with AS and investigate the factors related to poor adherence. METHODS: The subjects' sociodemographic, disease-related, radiographic, and laboratory parameters were collected. Patients' adherence to exercise therapy was assessed using the Exercise Attitude Questionnaire (EAQ) with a 4-point Likert scale. All cases were grouped as good adherence and poor adherence using a cutoff score of 60, according to a previous study. Univariate analysis was conducted to assess the intergroup differences. Then, we built a multivariate logistic regression model to identify possible significant factors related to poor adherence to exercise therapy. RESULTS: A total of 185 outpatients completed the questionnaire. The mean EAQ score was 49.4 (IQR, 40.7-59.3) and 146 patients (78.9%) were considered to have poor adherence, and 39 patients (21.1%) were considered to have good adherence. The rates of current nonsteroidal anti-inflammatory drugs (NSAIDs), conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), and tumor necrosis factor-α inhibitor (TNF-i) use were significantly higher in the poor adherence group (p=0.001, p=0.027, p=0.018, respectively). Our multivariate logistic regression model revealed that the only significant associated factor was current use of NSAIDs (OR=3.517; p=0.016; 95% CI, 1.259-9.827). CONCLUSIONS: Outpatients with AS had an unacceptable level of adherence to exercise therapy, and current use of NSAIDs was a significantly associated factor. Key Points • Outpatients with AS had an unacceptable level of adherence to exercise therapy. • Current use of NSAIDs exerted a negative impact on patients' adherence to exercise therapy.

Association of Serum Magnesium with Insulin Resistance and Type 2 Diabetes among Adults in China.

Magnesium is an essential mineral for the human body and a cofactor or activator for more than 300 enzymatic reactions, including blood glucose control and insulin release. Diabetes is a well-known global burden of disease with increasing global prevalence. In China, the prevalence of diabetes in adults is higher than the global average. Evidence shows that magnesium is a predictor of insulin resistance and diabetes. However, the majority of studies focus on dietary magnesium instead of serum magnesium concentration. We study the correlation of serum magnesium levels with insulin resistance and Type 2 diabetes. In this prospective cohort study, we included 5044 participants aged 18 years and older without insulin resistance (IR) and diabetes at the baseline from China Health and Nutrition Survey (CHNS). A fasting blood sample was taken for the measurement of both types of magnesium, fasting blood glucose, hemoglobin A1c (HbA1c), and fasting insulin. The homeostatic model (HOMA-IR) was calculated. Demographic characteristics of participants, and risk factors such as intensity of physical activities, smoking status, drinking habit, and anthropometric information were recorded. IR was defined as HOMA-IR ≥ 2.5, and Type 2 diabetes mellitus was defined as fasting plasma glucose ≥ 7.0 mmol/L or HbA1c ≥ 6.5%, or a self-reported diagnosis or treatment of diabetes. A total of 1331 incident insulin resistance events and 429 incident diabetic events were recorded during an average follow-up of 5.8 years. The serum magnesium concentration was categorized into quintiles. After adjusting for relevant covariates, the third quintile of serum magnesium (0.89−0.93 mmol/L) was correlated with 29% lower risk of incident insulin resistance (hazard ratio = 0.71, 95% CI 0.58, 0.86) and with a lower risk of Type 2 diabetes. Multivariable-adjusted hazard ratios (95% confidence intervals) for insulin resistance were compared with the lowest quintile of serum magnesium (<0.85). We found similar results when evaluating serum magnesium as a continuous measure. Restricted cubic spline (RCS) curves showed a nonlinear dose−response correlation in both serum magnesium levels and insulin resistance, and in serum magnesium levels and Type 2 diabetes. Lower serum magnesium concentration was associated with a higher risk of insulin resistance and diabetes.

Identifying the Potential Role and Prognostic Value of the Platelet-Derived Growth Factor Pathway in Kidney Renal Clear Cell Carcinoma.

The platelet-derived growth factor (PDGF) pathway is important in angiogenesis, which can accelerate the formation of vessels in tumor tissues and promote the progression of malignant tumors. To clarify the role of PDGF in the occurrence of renal cell carcinoma and targeted drug resistance, we explored the pathway in kidney renal clear cell carcinoma (KIRC) through bioinformatics analysis with the aim of supporting comprehensive and individualized therapy. First, we found 40 genes related to the PDGF pathway through gene set enrichment analysis and then obtained their expressions and clinical data in 32 different cancers from The Cancer Genome Atlas (TCGA). Mutations in these genes (including copy number and single-nucleotide variation) and mRNA expression were also detected. Next, we conducted a hazard ratio analysis to determine whether the PDGF pathway genes were risk or protective factors in tumors. Although PDGF-related genes acted as traditional oncogenes and were closely related to tumor angiogenesis in many cancers, our results indicated that most genes had a protective role in KIRC. We further analyzed the methylation modification of PDGF pathway genes and found that they were prevalent in 32 different cancers. Furthermore, 539 KIRC samples obtained from TCGA were divided into three clusters based on the mRNA expression of PDGF genes, including normal, inactive, and active PDGF gene expressions. The results from survival curve analysis indicated that the active PDGF cluster of patients had the best survival rate. Using the three clusters, we studied the correlation between the PDGF pathway and 12 common targeted drugs, as well as classical oncogenes and infiltrating immune cells. A prognostic risk model was constructed based on the PDGF score using LASSO-Cox regression analysis to analyze the value of the model in predicting the prognosis of patients with KIRC. Finally, 11 genes were selected for LASSO regression analysis, and the results demonstrated the high predictive value of this risk model and its close relationship with the pathological characteristics of KIRC (metastasis, size, grade, stage, etc.). In addition, we found that the risk score was an independent risk factor correlated with overall survival through univariate and multivariate analyses and a nomogram was built to assess patient prognosis. In conclusion, the occurrence and development of KIRC may be associated with an abnormally activated PDGF pathway, which may be a potential drug target in the treatment of KIRC.

Does Postoperative Anxiety/Depression Impair the Long-Term Functional Outcomes of Laparoscopic Ventral Rectopexy for Obstructed Defecation?

Purpose: This study aimed to investigate the relationship between postoperative anxiety/depression and functional outcomes of laparoscopic ventral rectopexy (LVR) for obstructed defecation (OD). Methods: Patients who received LVR for OD between March 2014 and July 2020 were enrolled. Patient demographics were recorded before surgery. The validated Cleveland Clinic Constipation Score (CCCS) and Patient Assessment of Constipation Quality of Life (PAC-QoL) were evaluated to assess functional outcomes and QoL, respectively. The self-rating anxiety scale and self-rating depression scale were used to measure anxiety and depression, respectively. Results: Twenty-five patients were recruited. Significant improvement was found at last available follow-up (LAFU) in CCCS (P = .001), and three PAC-QoL subsets, physical discomfort (P = .003), satisfaction (P = .014), and worries/concerns (P = .033) during follow-up of 60 (11-84) months. In the patients with anxiety/depression (n = 11), significant improvement was found at LAFU in CCCS (P = .024) and the PAC-QoL subset, psychosocial discomfort (P = .038). In the patients without anxiety/depression (n = 14), improvement was found in CCCS (P = .009) and the PAC-QoL subset, physical discomfort (P = .018). Conclusion: The long-term functional outcomes of LVR for OD in patients with overt pelvic structural abnormalities are not undermined by postoperative anxiety/depression.