Mechanisms of Bushenyiqi decoction in the treatment of asthma: an investigation based on network pharmacology with experimental validation.

Background and purpose: The Bushenyiqi decoction (BYD), a contemporary prescription of traditional Chinese medicine (TCM), has been observed to significantly ameliorate asthma symptoms in patients based on clinical observations. Although multi-component and multi-target characteristics are important attributes of BYD treatment, its pharmacological effect on asthma and the underlying mechanism of action remain unclear. Method: Network pharmacology: the asthma-related genes were retrieved from the GeneCards and OMIM database. The active constituents of BYD and their corresponding target genes were collected from the TCMSP database. The underlying pathways associated with overlapping targets between BYD and asthma were identified through GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) enrichment analysis. Experimental validation: pulmonary function tests, enzyme-linked immunosorbent assay (ELISA), Hematoxylin and eosin (HE), periodic acid-Schiff (PAS), and Masson's trichrome stainings were conducted to validate the efficacy of BYD in ameliorating airway inflammation in allergic asthma mice. Western blot (WB) and molecular docking were performed to confirm the involvement of the underlying pathway in BYD treatment of asthma. Results: The results of animal experiments demonstrated that BYD may improve airway responsiveness and suppress airway inflammation in allergic asthma mice. The network pharmacological analysis revealed the involvement of 11 potentially key active components, 9 potential key targets, and the phosphatidylinositol3 kinase-RAC-α serine/threonine-protein kinase (PI3K/AKT) signaling pathway in the mechanism of action of BYD for asthma treatment. Our findings have confirmed that BYD effectively alleviated airway inflammation by targeting interleukin 6 (IL-6), epidermal growth factor receptor (EGFR), and hypoxia inducible factor 1 alpha (HIF1A), with quercetin, kaempferol, and luteolin performing as the pivotal active constituents. BYD may potentially reduce inflammatory cell infiltration in lung tissues by regulating the PI3K/AKT signaling pathway. Conclusion: In conclusion, the integration of network pharmacology and biological experiments has demonstrated that key constituents of BYD, such as quercetin, kaempferol, and luteolin, exhibit targeted effects on IL-6, EGFR, and HIF1A in combating asthma-related inflammation through inhibition of the PI3K/AKT signaling pathway. The findings of this investigation provide evidence supporting the effectiveness of TCM's "bushenyiqi" therapy in asthma management, as corroborated by contemporary medical technology.

A potent bioreducible ionizable lipid nanoparticle enables siRNA delivery for retinal neovascularization inhibition.

Small interfering RNA (siRNA) is emerging as a promising treatment for retinal neovascularization due to its specific inhibition of the expression of target genes. However, the clinical translation of siRNA drugs is hindered by the efficiency and safety of delivery vectors. Here, we describe the properties of a new bioreducible ionizable lipid nanoparticle (LNP) 2N12H, which is based on a rationally designed novel ionizable lipid called 2N12B. 2N12H exhibited degradation in response to the mimic cytoplasmic glutathione condition and ionization with a pKa value of 6.5, which remaining neutral at pH 7.4. At a nitrogen to phosphorus ratio of 5, 2N12H efficiently encapsulated and protected siRNA from degradation. Compared to the commercial vehicle Lipofectamine 2000, 2N12H demonstrated similar silencing efficiency and improved safety in the in vitro cell experiments. 2N12H/siVEGFA reduced the expression of VEGFA in retinal pigment epithelium cells and mouse retina, consequently suppressing cell migration and retinal neovascularization. In the mouse model, the therapeutic effect of 2N12H/siVEGFA was comparable to that of the clinical drug ranibizumab. Together, these results suggest the potential of this novel ionizable LNP to facilitate the development of nonviral ocular gene delivery systems.

IGSF10 inhibits the metastasis of lung adenocarcinoma via the Spi-B/Integrin-ß1 signaling pathway.

IGSF10, a protein that belongs to the immunoglobulin superfamily, is involved in regulating the early migration of neurons that produce gonadotropin-releasing hormone and performs a fundamental function in development. Our previous study confirmed that the mRNA expression level of IGSF10 may be a protective prognosis factor for lung adenocarcinoma (LUAD) patients. However, the specific mechanisms of IGSF10 are still unclear. In this research, it was shown that the protein level of IGSF10 was down-modulated in LUAD tissues and had a link to the clinical and pathological characteristics as well as the patient's prognosis in LUAD. Importantly, IGSF10 regulates the metastatic ability of LUAD cells in vitro and in vivo. It was proven in a mechanistic sense that IGSF10 inhibits the capacity of LUAD cells to metastasize through the Spi-B/Integrin-ß1 signaling pathway. These findings gave credence to the premise that IGSF10 performed a crucial function in LUAD.

Correlation Between Impaired Sensitivity to Thyroid Hormones and Serum Uric Acid in Female Patients with Obesity and After Laparoscopic Sleeve Gastrectomy.

OBJECTIVE: An alterable risk factor for hyperuricemia is obesity. Additionally, obese persons may have a moderate form of acquired resistance to thyroid hormones. Thyrotropin (TSH), thyroid hormones, and obesity all interact subtly. However, the connection between thyroid hormone sensitivity and hyperuricaemia in obese patients both before and after laparoscopic sleeve gastrectomy (LSG) has not yet been clarified. The objective of our study was to investigate the connection between impaired thyroid hormone sensitivity and elevated uric acid (UA) levels before and after LSG. METHODS: In total, 1,054 euthyroid patients with obesity (481 males, 573 females), 248 (143 females) of whom underwent subsequent LSG, were enrolled in this retrospective study. Anthropometric measurements and thyroid hormone and UA levels were taken before and 3 months after LSG. RESULTS: Female patients with obesity with impaired sensitivity to thyroid hormones had higher UA levels (P for trend < 0.01). The odds ratio of the fourth versus first quartile of TFQI, TSHI, and TT4RI were 4.285 [confidence interval (CI): 1.360-13.507], 3.700 [CI: 1.276-10.729], and 2.839 [CI: 1.014-7.948], respectively, with robust relationships with female hyperuricemia (all P < 0.05). However, there was only a positive correlation between the decline in UA levels and TFQI, TSHI, and TT4RI in females following LSG. CONCLUSION: Female hyperuricemia is correlated with higher thyroid hormone resistance index scores. Resistance to thyroid hormones was greatly improved by LSG. The decrease in UA levels after surgery is correlated with the improvement of thyroid hormone resistance after LSG.

Total paeony glycoside relieves neuroinflammation to exert antidepressant effect via the interplay between NLRP3 inflammasome, pyroptosis and autophagy.

BACKGROUND: Depression is a common mental illness characterised by abnormal and depressed emotions. Total paeony glycoside (TPG) is a naturally active saponin extracted from the traditional Chinese medicine Radix Paeoniae rubra. However, the antidepressant and neuroinflammatory effects of TPG have not been thoroughly studied. PURPOSE: To study the therapeutic potential of TGP in depression caused by neuronal injury and neuroinflammation and to explore the mechanism of TGP and the relationship between the NLRP3 inflammasome, pyroptosis, and autophagy. STUDY DESIGN: A chronic unpredictable mild stress (CUMS)-induced depression model and a cell model of corticosterone (CORT)-induced hippocampal neuron injury were established to evaluate the therapeutic effects of TPG. METHODS: The composition of TPG was analysed using high-performance liquid chromatography and mass spectrometry. The effects of TPG and fluoxetine on depression-like behaviour, neuronal injury, neuroinflammation, pyroptosis, and mitochondrial autophagy in the mice models were evaluated. RESULTS: TGP alleviated depression-like behaviours in mice and inhibited hippocampal neuronal apoptosis. The secretion of inflammatory cytokines was significantly reduced in CORT-induced hippocampal neuron cells and in the serum of a mouse model of CUMS-induced depression. In addition, TGP treatment reduced the levels of NLRP3 family pyrin structural domains, including NLRP3, pro-caspase-1, caspase-1, and IL-1ß, and the pyroptosis related proteins such as GSDMD-N. Importantly, TPG attenuated mitochondrial dysfunction, promoted the clearance of damaged mitochondria, and the activation of mitochondrial autophagy, which reduced ROS accumulation and NLRP3 inflammasome activation. An in-depth study observed that the regulatory effect of TPG on autophagy was attenuated by the autophagy inhibitor 3-methyladenine (3-MA) in vitro and in vivo. However, administration of the caspase-1 inhibitor Belnacasan (VX-765) successfully inhibited pyroptosis and showed a synergistic therapeutic effect with TPG. CONCLUSION: These results indicate that TPG can repair neuronal damage by activating autophagy, restoring mitochondrial function, and reducing inflammation-mediated pyroptosis, thereby playing an important role in the alleviation of neuroinflammation and depression. This study suggests new potential drugs and treatment strategies for neuroinflammation-related diseases and depression.

Non-pharmacological interventions for preventing emergence delirium in children under general anesthesia: A scoping review.

PROBLEM: The phenomenon of emergence delirium in pediatric patients undergoing general anesthesia has garnered increasing attention in the academic community. While formal non-pharmaceutical interventions have demonstrated efficacy in mitigating this phenomenon, the diversity of intervention types and their varying degrees of effectiveness necessitate further discussion. A scoping review was conducted to identify and explicate the categorization, content elements, and outcomes measures of non-pharmacological interventions utilized to forestall the onset of emergence delirium in children undergoing general anesthesia. ELIGIBILITY CRITERIA: This review was conducted in accordance with the Arksey and O'Malley's methodology framework and PRISMA-ScR. It encompassed experimental and quasi-experimental studies that involved any non-pharmacological interventions during the perioperative period to prevent emergence delirium in children aged 0 to 18 years undergoing general anesthesia for elective surgery. SAMPLE: Thirty-two articles met the inclusion criteria, of which 29 were randomized controlled trials. The total sample size of the population was 4633. RESULTS: The scoping review revealed 10 non-pharmacological interventions, that included distraction intervention, visual preconditioning, virtual reality, parental participation, maternal voice, light drinking, acupuncture, auditory stimulation, monochromic light and breathing training. Emergence delirium, preoperative anxiety, and postoperative pain were the primary outcomes, and four assessment instruments were employed to measure the extent and incidence of emergence delirium. CONCLUSION: Numerous non-pharmacological interventions have been employed to prevent emergence delirium. Nevertheless, the effectiveness of some interventions is not yet evident. IMPLICATIONS: The utilization of visual preconditioning and distraction interventions appears to be an emerging area of interest.

Farnesoid X receptor promotes non-small cell lung cancer metastasis by activating Jak2/STAT3 signaling via transactivation of IL-6ST and IL-6 genes.

Metastasis accounts for the majority of cases of cancer recurrence and death in patients with advanced non-small cell lung cancer (NSCLC). Farnesoid X Receptor (FXR) is a bile acid nuclear receptor that was recently found to be upregulated in NSCLC tissues. However, whether and how FXR regulates NSCLC metastasis remains unclear. In the present study, it was found that FXR promoted the migration, invasion, and angiogenic ability of NSCLC cells in vitro, and increased NSCLC metastasis in a mouse model in vivo. Mechanistic investigation demonstrated that FXR specifically bound to the promoters of IL-6ST and IL-6 genes to upregulate their transcription, thereby leading to activation of the Jak2/STAT3 signaling pathway, which facilitated tumor migration, invasion, and angiogenesis in NSCLC. Notably, Z-guggulsterone, a natural FXR inhibitor, significantly reduced FXRhigh NSCLC metastasis, and decreased the expression of FXR, IL-6, IL-6ST, and p-STAT3 in the mouse model. Clinical analysis verified that FXR was positively correlated with IL-6, IL-6ST and p-STAT3 expression in NSCLC patients, and was indicative of a poor prognosis. Collectively, these results highlight a novel FXR-induced IL-6/IL-6ST/Jak2/STAT3 axis in NSCLC metastasis, and a promising therapeutic means for treating FXRhigh metastatic NSCLC.

Ultrasound image-guided cancer gene therapy using iRGD dual-targeted magnetic cationic microbubbles.

The gene therapy attracted more and more attention for the tumor therapy. To obtain a safe gene therapy system, the new gene vectors beyond the virus were developed for a high gene therapy efficiency. The ultrasound mediated gene therapy was safer and the plasmid DNA could be delivered by the microbubbles and combined with the ultrasound to increase the gene transfection efficiency. In this work, the cationic microbubbles decorated with Cyclo(Cys-Arg-Gly-Asp-Lys-Gly-Pro-AspCys) (iRGD peptides) and magnetic Fe3O4 nanoparticles (MBiM) was designed for targeted ultrasound contrast imaging guided gene therapy of tumors. The ultrasound image intensity was dramatically enhanced at the tumor site that received MBiM with the magnet applied, compared to those administrated the non-targeted microbubbles (MBb) or the microbubbles with only one target material on the surface (MBM and MBbi). The pGPU6/GFP/Neo-shAKT2 was used as a sample gene, which down regulate the AKT2 protein expression for the cancer therapy. It illustrated that MBiM/AKT2 had the highest gene transfection efficiency in the studied microbubbles mediated by the ultrasound, leading to the AKT2 protein expression downregulation and the strongest tumor killing effect in vitro and in vivo. In summary, a novel and biocompatible gene delivery platform via MBiM with both the endogenous and external targeting effects for breast cancer theranostics was developed.

SUMOylation inhibitors activate anti-tumor immunity by reshaping the immune microenvironment in a preclinical model of hepatocellular carcinoma.

PURPOSE: High levels of heterogeneity and immunosuppression characterize the HCC immune microenvironment (TME). Unfortunately, the majority of hepatocellular carcinoma (HCC) patients do not benefit from immune checkpoint inhibitors (ICIs) therapy. New small molecule therapies for the treatment of HCC are the goal of our research. METHODS: SUMOylation inhibitors (TAK-981 and ML-792) were evaluated for the treatment of preclinical mouse HCC models (including subcutaneous and orthotopic HCC models). We profile immune cell subsets from tumor samples after SUMOylation inhibitors treatment using single-cell RNA sequencing (scRNA-seq), mass cytometry (CyTOF), flow cytometry, and multiple immunofluorescences (mIF). RESULTS: We discover that SUMOylation is higher in HCC patient samples compared to normal liver tissue. TAK-981 and ML-792 decrease SUMOylation at nanomolar levels in HCC cells and also successfully reduced the tumor burden. Analysis combining scRNA-seq and CyTOF demonstrate that treatment with SUMOylation inhibitors reduces the exhausted CD8+T (Tex) cells while enhancing the cytotoxic NK cells, M1 macrophages and cytotoxic T lymphocytes (CTL) in preclinical mouse HCC model. Furthermore, SUMOylation inhibitors have the potential to activate innate immune signals from CD8+T, NK and macrophages while promoting TNFα and IL-17 secretion. Most notably, SUMOylation inhibitors can directly alter the TME by adjusting the abundance of intestinal microbiota, thereby restoring anti-tumor immunity in HCC models. CONCLUSIONS: This preclinical study suggests that SUMO signaling inhibitors may be beneficial for the treatment of HCC.

A picture is worth a thousand words: Understanding the predictors of picture sharing in online consumer reviews.

Picture in online customer reviews conveys detailed product information to help potential customers make purchase decisions, which is an important form of digital data. Therefore, understanding the predictors of picture sharing in online customer reviews is crucial for retail businesses to achieve digital transformation strategies for competitive advantage, high quality service and sustainable performance. By analyzing 6211 online customer reviews of 16 products crawled from the famous online shopping site JD.com in China, this study tests the effects of reviewer rank (who), product type (what), time interval (when), review device (where), consumption satisfaction (why), and the level of involvement (how) on whether customers sharing picture and picture count in online customer reviews based on the 5W1H analysis framework. The results show that: (1) with or without picture and picture count both influence the helpfulness of online customer reviews; (2) product type, time interval, review device, consumption satisfaction and the level of involvement significantly affect whether consumers share picture; and (3) review device, consumption satisfaction and the level of involvement significantly affect picture count. The findings can help managers manage picture reviews to improve business performance.

Plant and animal positive-sense single-stranded RNA viruses encode small proteins important for viral infection in their negative-sense strand.

Positive-sense single-stranded RNA (+ssRNA) viruses, the most abundant viruses of eukaryotes in nature, require the synthesis of negative-sense RNA (-RNA) using their genomic (positive-sense) RNA (+RNA) as a template for replication. Based on current evidence, viral proteins are translated via viral +RNAs, whereas -RNA is considered to be a viral replication intermediate without coding capacity. Here, we report that plant and animal +ssRNA viruses contain small open reading frames (ORFs) in their -RNA (reverse ORFs [rORFs]). Using turnip mosaic virus (TuMV) as a model for plant +ssRNA viruses, we demonstrate that small proteins encoded by rORFs display specific subcellular localizations, and confirm the presence of rORF2 in infected cells through mass spectrometry analysis. The protein encoded by TuMV rORF2 forms punctuate granules that are localized in the perinuclear region and co-localized with viral replication complexes. The rORF2 protein can directly interact with the viral RNA-dependent RNA polymerase, and mutation of rORF2 completely abolishes virus infection, whereas ectopic expression of rORF2 rescues the mutant virus. Furthermore, we show that several rORFs in the -RNA of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have the ability to suppress type I interferon production and facilitate the infection of vesicular stomatitis virus. In addition, we provide evidence that TuMV might utilize internal ribosome entry sites to translate these small rORFs. Taken together, these findings indicate that the -RNA of +ssRNA viruses can also have the coding capacity and that small proteins encoded therein play critical roles in viral infection, revealing a viral proteome larger than previously thought.

Evaluation of right heart function changes in patients with pulmonary hypertension via two-dimensional speckle tracking imaging: a retrospective study.

Objective: To realize the changes in pulmonary hypertension (PH) patients' right ventricular function.Methods: A total number of 74 patients with PH were included, and the parameters of standard echocardiographic were measured as well as the strain of peak longitudinal of each segment during the systole of the right ventricle to calculate the global longitudinal strain (LS) during systole of the right ventricular free wall.Results: ① As pulmonary arterial pressure increased, the right ventricular area gradually increased, and the case group showed the decreased right ventricular fractional area change (RVFAC), tricuspid annular plane systolic excursion (TAPSE), and tricuspid annular peak systolic velocity (S') (p < 0.05). They, RVFAC, and TAPSE depicted significant differences that were statistical (p < 0.05) from the other groups. ② With increasing pulmonary arterial pressure, the right ventricular free wall's LS gradually reduced (p < 0.05).Conclusion: ① LS right ventricular free wall is useful in detecting changes in right ventricular systolic function early on with greater sensitivity than RVFAC, TAPSE, and S'. In addition, increased right ventricular pressure loading can result in a subsequent impairment of right ventricular myocardial mechanics. ② As right ventricular pressure loading increases, right ventricular strain decreases. ③ In mild PH, the right ventricular free wall's. LS is more sensitive than standard measures in spotting early alterations in myocardial mechanics.

An erythrocyte membrane-modified biomimetic synergistic nanosystem for cancer anti-vascular therapy and initial efficacy monitoring.

Tumor vascular disruption has become a promising strategy for cancer therapy in recent decades. Nanocomposites loaded with therapeutic materials and drugs are expected to improve the accuracy of anti-vascular therapy and minimize side effects. However, how to prolong blood circulation of therapeutic nanocomposites for enhanced accumulation in tumor vasculature and how to monitor the initial efficacy of anti-vascular therapy for early evaluation of prognosis remain unsolved. Herein, a biomimetic nanosystem consisting of erythrocyte membrane modified nanocomposites (CMNCs) is developed for cooperation to achieve anti-vascular cancer therapy and initial efficacy monitoring. By utilizing poly(lactic-co-glycolic acid) (PLGA) as the interface material, functional nanomaterials and drug molecules are successfully integrated into CMNCs. The long circulation and immune escape features of the erythrocyte membrane facilitate CMNCs loaded with photothermal agents and chemodrugs to be delivered to the tumor region for anti-vascular treatment. Furthermore, the vascular damage-induced haemorrhage and the following coagulation process is labelled by near infrared emissive CMNCs to indicate the initial therapeutic efficacy of the treatment. This work not only points to a biomimetic strategy for conquering the challenges in anti-vascular cancer therapy, but also provides insights into the biological responses of erythrocyte membrane modified nanocomposites to exploit their biomedical applications.

Radiomics model based on contrast-enhanced computed tomography to predict early recurrence in patients with hepatocellular carcinoma after radical resection.

BACKGROUND: Radical resection remains an effective strategy for patients with hepatocellular carcinoma (HCC). Unfortunately, the postoperative early recurrence (recurrence within 2 years) rate is still high. AIM: To develop a radiomics model based on preoperative contrast-enhanced computed tomography (CECT) to evaluate early recurrence in HCC patients with a single tumour. METHODS: We enrolled a total of 402 HCC patients from two centres who were diagnosed with a single tumour and underwent radical resection. First, the features from the portal venous and arterial phases of CECT were extracted based on the region of interest, and the early recurrence-related radiomics features were selected via the least absolute shrinkage and selection operator proportional hazards model (LASSO Cox) to determine radiomics scores for each patient. Then, the clinicopathologic data were combined to develop a model to predict early recurrence by Cox regression. Finally, we evaluated the prediction performance of this model by multiple methods. RESULTS: A total of 1915 radiomics features were extracted from CECT images, and 31 of them were used to determine the radiomics scores, which showed a significant difference between the early recurrence and nonearly recurrence groups. Univariate and multivariate Cox regression analyses showed that radiomics scores and serum alpha-fetoprotein were independent indicators, and they were used to develop a combined model to predict early recurrence. The area under the receiver operating characteristic curve values for the training and validation cohorts were 0.77 and 0.74, respectively, while the C-indices were 0.712 and 0.674, respectively. The calibration curves and decision curve analysis showed satisfactory accuracy and clinical utilities. Kaplan-Meier curves based on recurrence-free survival and overall survival showed significant differences. CONCLUSION: The preoperative radiomics model was shown to be effective for predicting early recurrence among HCC patients with a single tumour.

In Vivo Fate of CXCR2-Overexpressing Mesenchymal Stromal/Stem Cells in Pulmonary Diseases Monitored by Near-Infrared Region 2 Imaging.

Lung-associated diseases pose a huge threat to human society. Mesenchymal stromal/stem cells (MSCs) hold great promise in the treatment of pulmonary diseases through cell transdifferentiation, paracrine factors, immune regulation, EV secretion, and drug loading. However, intravenous injection of MSCs often resulted in limited lesion tropism and apparent off-target accumulation. The IL-8-CXCR1/2 chemokine axis has been shown to be involved in progression of diseases including lung cancer and acute lung injury (ALI). Herein, we took advantage of this chemokine axis to enhance the homing of MSCs to cancerous and inflammation lesions. The in vivo distribution of MSCs was further monitored real-time by near-infrared region 2 (NIR-II) imaging owing to its outstanding performance in deep tissue imaging. Specifically, a new high-brightness D-A-D NIR-II dye, LJ-858, was synthesized and coprecipitated with a poly(d,l-lactic acid) polymer to form LJ-858 nanoparticles (NPs) with a relative quantum yield of 14.978%. LJ-858 NPs can efficiently label MSCs, and the NIR-II signal can be stable for 14 days without compromising the cell viability. Subcutaneous tracking of labeled MSCs showed no significant decline of NIR-II intensity within 24 h. The enhanced tropism of CXCR2-overexpressing MSCs to A549 tumor cells and the inflamed lung tissue was demonstrated through transwell models. The in vivo and ex vivo NIR-II imaging results further validated the significantly enhanced lesion retention of MSCCXCR2 in the lung cancer and ALI models. Taken together, this work reported a robust strategy to enhance the pulmonary disease tropism by the IL-8-CXCR1/2 chemokine axis. In addition, in vivo distribution of MSCs was successfully visualized by NIR-II imaging, which provides more insights into optimizing protocols for MSC-based therapies in the future.

Identifying optimal first-line immune checkpoint inhibitors based regiments for advanced non-small cell lung cancer without oncogenic driver mutations: A systematic review and network meta-analysis.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have changed the treatment pattern of advanced and metastatic NSCLC. A series of ICI based therapies have emerged in the first-line treatment field, but the comparative efficacy was unclear. METHOD: We searched multiple databases and abstracts of major conference proceedings up to Apri1, 2022 for phase III randomised trials of advanced driver-gene wild type NSCLC patients receiving first-line therapy. Outcomes analyzed included progression free survival (PFS), overall survival (OS), and et al. RESULTS: Thirty-two double-blind RCTs were included, involving 18,656 patients assigned to 22 ICI-based first-line regimens. A series of ICI regiments (including ICI plus chemotherapy), ICI monotherapy, doublet ICIs, doublet ICIs plus chemotherapy) emerged, and showed significant PFS and OS benefit than chemotherapy and chemotherapy + bevacizumab (BEV) for advanced wild-type NSCLC. In comprehensive terms of PFS, chemoimmunotherapy (CIT) were significantly more effective than ICI monotherapy and doublet ICIs. In terms of OS for patients with non-squamous NSCLC, pembrolizumab containing CIT was associated with a median rank of the best regimens, and followed by Atezolizumab+BEV based CIT; while for OS in patients with squamous NSCLC, Cemiplimab and sintilimab based CIT were the most effective regimens. For more than 2 years follow-up, the atezolizumab, pembrolizumab, nivolumab and durvalumab containing ICI therapy all provide a durable long-term OS benefit over chemotherapy and BEV + chemotherapy. CONCLUSIONS: The findings of the present NMA represent the most comprehensive evidence, which might suggest or provide basis for first-line ICI therapy decision for advanced NSCLC patients without oncogenic driver mutations.

Immune checkpoint inhibitor-associated toxicity in advanced non-small cell lung cancer: An updated understanding of risk factors.

Immune checkpoint inhibitors (ICIs), such as programmed death-1 (PD-1), programmed death-ligand 1 (PD-L1), cytotoxic T lymphocyte antigen 4 (CTLA-4) antibodies, etc, have revolutionized cancer treatment strategies, including non-small cell lung cancer (NSCLC). While these immunotherapy agents have achieved durable clinical benefits in a subset of NSCLC patients, they bring in a variety of immune-related adverse events (irAEs), which involve cardiac, pulmonary, gastrointestinal, endocrine and dermatologic system damage, ranging from mild to life-threatening. Thus, there is an urgent need to better understand the occurrence of irAEs and predict patients who are susceptible to those toxicities. Herein, we provide a comprehensive review of what is updated about the clinical manifestations, mechanisms, predictive biomarkers and management of ICI-associated toxicity in NSCLC. In addition, this review also provides perspective directions for future research of NSCLC-related irAEs.

Effects of a Dulaglutide plus Calorie-Restricted Diet versus a Calorie-Restricted Diet on Visceral Fat and Metabolic Profiles in Women with Polycystic Ovary Syndrome: A Randomized Controlled Trial.

The effects of dulaglutide and a calorie-restricted diet (CRD) on visceral adipose tissue (VAT) and metabolic profiles in polycystic ovary syndrome (PCOS) have not been extensively investigated. In this study, we investigated whether dulaglutide combined with CRD could further reduce VAT and promote clinical benefits as compared with a CRD regimen alone in overweight or obese PCOS-affected women. Between May 2021 and May 2022, this single-center, randomized, controlled, open-label clinical trial was conducted. Overall, 243 participants with PCOS were screened, of which 68 overweight or obese individuals were randomly randomized to undergo dulaglutide combined with CRD treatment (n = 35) or CRD treatment alone (n = 33). The duration of intervention was set as the time taken to achieve a 7% weight loss goal from baseline body weight, which was restricted to 6 months. The primary endpoint was the difference in the change in VAT area reduction between the groups. The secondary endpoints contained changes in menstrual frequency, metabolic profiles, hormonal parameters, liver fat, and body composition. As compared with the CRD group, the dulaglutide + CRD group had a considerably shorter median time to achieve 7% weight loss. There was no significant between-group difference in area change of VAT reduction (-0.97 cm2, 95% confidence interval from -14.36 to 12.42, p = 0.884). As compared with CRD alone, dulaglutide + CRD had significant advantages in reducing glycated hemoglobin A1c and postprandial plasma glucose levels. The results of the analyses showed different changes in menstruation frequency, additional metabolic profiles, hormonal markers, liver fat, and body composition between the two groups did not differ significantly. Nausea, vomiting, constipation, and loss of appetite were the main adverse events of dulaglutide. These results emphasize the value of dietary intervention as the first line of treatment for PCOS-affected women, while glucagon-like peptide 1 receptor agonist therapy provides an efficient and typically well tolerated adjuvant therapy to aid in reaching weight targets based on dietary therapy in the population of overweight/obese PCOS-affected women.

A Novel "Inside-Out" Intraocular Nanomedicine Delivery Mode for Nanomaterials' Biological Effect Enhanced Choroidal Neovascularization Occlusion and Microenvironment Regulation.

Photodynamic therapy (PDT) is commonly used in choroidal neovascularization (CNV) treatment due to the superior light transmittance of the eye. However, PDT often leads to surrounding tissue damage and further microenvironmental deterioration, including exacerbated hypoxia, inflammation, and secondary neovascularization. In this work, Pt nanoparticles (NPs) and Au NPs decorated zeolitic imidazolate framework-8 nanoplatform is developed to load indocyanine green for precise PDT and microenvironment amelioration, which can penetrate the internal limiting membrane through Müller cells endocytosis and target to CNV by surface-grafted cyclo(Arg-Gly-Asp-d-Phe-Lys) after intravitreal injection. The excessive H2 O2 in the CNV microenvironment is catalyzed by catalase-like Pt NPs for hypoxia relief and enhanced PDT occlusion of neovascular. Meanwhile, Au NPs show significant anti-inflammatory and anti-angiogenesis properties in regulating macrophages and blocking vascular endothelial growth factor (VEGF). Compared with verteporfin treatment, the mRNA expressions of hypoxia-inducible factor-1α and VEGF in the nanoplatform group are downregulated by 90.2% and 81.7%, respectively. Therefore, the nanoplatform realizes a comprehensive CNV treatment effect based on the high drug loading capacity and biosafety. The CNV treatment mode developed in this work provides a valuable reference for treating other diseases with similar physiological barriers that limit drug delivery and similar microenvironment.

Kinetics, mechanism, and application of sodium persulfate activated by sodium hydroxide for removing 1,2-dichloroethane from groundwater.

1,2-Dichloroethane (1,2-DCA) is a common compound found in groundwater contaminated with organics. This compound is difficult to remove from groundwater and has the potential to inflict significant harm on human health and the environment. This study used sodium persulfate (Na2S2O8) activated by sodium hydroxide (NaOH) to remove 1,2-DCA from aqueous solutions. Density functional theory was employed to calculate the potential energy surface of the reactants, intermediates, transient states, and products to thoroughly analyze the degradation pathways. The computations were performed in combination with in situ remediation of a 1,2-DCA plume from a point source to verify the industrial applicability of the technology. The results showed the 1,2-DCA removal efficiency was impacted considerably by the Na2S2O8 dosage and the dosing sequence of Na2S2O8 and NaOH, with the mean removal ratio reaching 96.24%. A free radical reaction was the main pathway of 1,2-DCA degradation; superoxide radical (O2•-) existed stably and played a key role in the reaction, and the main transformation proceeded via a vinyl chloride intermediate. The maximum removal of 1,2-DCA reached 91.79% in the in situ remediation. The developed technology exhibits important advantages in enabling flexible control over chemical dosages, long durations of effective activity, and rapid full-cycle remediation.