Efficacy of intestinal microorganisms on immunotherapy of non-small cell lung cancer.

While the 5-year survival rate of patients with advanced non-small cell lung cancer (NSCLC) has seen some improvement, the majority of NSCLC patients fail to respond to immunotherapy with immune checkpoint inhibitors (ICIs). It is critical to identify effective biomarkers that can enhance the efficacy of immunotherapy. The clinical data in the current study were collected from NSCLC patients treated with ICIs, and two groups were classified according to treatment effect: good group with consistent efficacy, poor group with only progressiveness. Differences in intestinal microbiota between the two groups were analyzed using 16s rRNA sequencing. Beta diversity analysis indicated differences between the two groups that were available for differentiation. Comparison of the number of common or unique operational taxonomic units (OTUs) among different groups suggested that there were 53 unique OTUs in the good group and 51 unique OTUs in the poor group. At the phylum level, there was a difference between the two groups for several bacterial groups with the highest abundance values, among which Firmicutes, Actinobacteria and Fusobacteria were more abundant in the good group. Members of the genera Bifidobacterium and Lactobacillus were abundant in the good group, while the abundance of Bacteroides was low. Biomarkers in the poor group included Bacteroides, Bacteroidetes, Bacteroidia, Bacteroidales, Bacteroidaceae and Veillonellaceae. The intestinal microbiota composition affected the immunotherapy process for NSCLC, which might offer more rational instructions for the clinical application of ICIs in NSCLC patients.

XTP8 Promotes Ovarian Cancer Progression by Activating AKT/AMPK/mTOR Pathway to Regulate EMT.

Ovarian cancer (OC) ranks as the fifth leading cause of cancer-related death in women. The main contributors to the poor prognosis of ovarian cancer are the high rates of recurrence and metastasis. Studies have indicated a crucial role for hepatitis B virus X Ag-Transactivated Protein 8 (XTP8), a protein containing the DEP domain, in various cellular processes, including cell growth, movement, and differentiation, across several types of cancers. However, the role of XTP8 in ovarian cancer remains unclear. We observed elevated expression of XTP8 in ovarian cancer. Silencing XTP8 inhibited cell proliferation, promoted apoptosis, and yielded contrasting results in cells overexpressing XTP8. Furthermore, XTP8 facilitated ovarian cancer invasion and migration, triggering epithelial-mesenchymal transition (EMT). Mechanistically, XTP8 silencing led to reduced phosphorylation levels of AKT, increased p-AMPK levels, and decreased p-mTOR levels, while XTP8 overexpression exerted the opposite effects. Additionally, the activation of p-AMPK rescued the promoting effect of XTP8 on EMT in ovarian cancer cell lines, indicating that XTP8 acts as an oncogene by modulating the AKT/AMPK/mTOR pathway. Through transcriptome sequencing to identify downstream targets of XTP8, we found that XTP8 influences the expression of Caldesmon (CALD1) at both transcriptional and translational levels. CALD1 can be considered a downstream target of XTP8. The collaborative action of XTP8 and CALD1 activates the AKT/AMPK/mTOR pathway, regulating EMT to promote ovarian cancer progression. Inhibiting this signaling axis might represent a potential therapeutic target for ovarian cancer.

[Treatment of cervical ossification of posterior longitudinal ligament with titanium alloy trabecular bone three-dimensional printed artificial vertebral body].

Objective: To evaluate the effectiveness of using titanium alloy trabecular bone three-dimensional (3D) printed artificial vertebral body in treating cervical ossification of the posterior longitudinal ligament (OPLL). Methods: A retrospective analysis was conducted on clinical data from 45 patients with cervical OPLL admitted between September 2019 and August 2021 and meeting the selection criteria. All patients underwent anterior cervical corpectomy and decompression, interbody bone graft fusion, and titanium plate internal fixation. During operation, 21 patients in the study group received titanium alloy trabecular bone 3D printed artificial vertebral bodies, while 24 patients in the control group received titanium cages. There was no significant difference in baseline data such as gender, age, disease duration, affected segments, or preoperative pain visual analogue scale (VAS) score, Japanese Orthopaedic Association (JOA) score, Neck Disability Index (NDI), vertebral height, and C 2-7Cobb angle ( P>0.05). Operation time, intraoperative blood loss, and occurrence of complications were recorded for both groups. Preoperatively and at 3 and 12 months postoperatively, the functionality and symptom relief were assessed using JOA scores, VAS scores, and NDI evaluations. The vertebral height and C 2-7 Cobb angle were detected by imaging examinations and the implant subsidence and intervertebral fusion were observed. Results: The operation time and incidence of complications were significantly lower in the study group than in the control group ( P<0.05), while the difference in intraoperative blood loss between the two groups was not significant ( P>0.05). All patients were followed up 12-18 months, with the follow-up time of (14.28±4.34) months in the study group and (15.23±3.54) months in the control group, showing no significant difference ( t=0.809, P=0.423). The JOA score, VAS score, and NDI of the two groups improved after operation, and further improved at 12 months compared to 3 months, with significant differences ( P<0.05). At each time point, the study group exhibited significantly higher JOA scores and improvement rate compared to the control group ( P<0.05); but there was no significantly difference in VAS score and NDI between the two groups ( P>0.05). Imaging re-examination showed that the vertebral height and C 2-7Cobb angle of the two groups significantly increased at 3 and 12 months after operation ( P<0.05), and there was no significant difference between 3 and 12 months after operation ( P>0.05). At each time point, the vertebral height and C 2-7Cobb angle of the study group were significantly higher than those of the control group ( P<0.05), and the implant subsidence rate was significantly lower than that of the control group ( P<0.05). However, there was no significant difference in intervertebral fusion rate between the two groups ( P>0.05). Conclusion: Compared to traditional titanium cages, the use of titanium alloy trabecular bone 3D-printed artificial vertebral bodies for treating cervical OPLL results in shorter operative time, fewer postoperative complications, and lower implant subsidence rates, making it superior in vertebral reconstruction.

Unraveling ETC complex I function in ferroptosis reveals a potential ferroptosis-inducing therapeutic strategy for LKB1-deficient cancers.

The role of the mitochondrial electron transport chain (ETC) in regulating ferroptosis is not fully elucidated. Here, we reveal that pharmacological inhibition of the ETC complex I reduces ubiquinol levels while decreasing ATP levels and activating AMP-activated protein kinase (AMPK), the two effects known for their roles in promoting and suppressing ferroptosis, respectively. Consequently, the impact of complex I inhibitors on ferroptosis induced by glutathione peroxidase 4 (GPX4) inhibition is limited. The pharmacological inhibition of complex I in LKB1-AMPK-inactivated cells, or genetic ablation of complex I (which does not trigger apparent AMPK activation), abrogates the AMPK-mediated ferroptosis-suppressive effect and sensitizes cancer cells to GPX4-inactivation-induced ferroptosis. Furthermore, complex I inhibition synergizes with radiotherapy (RT) to selectively suppress the growth of LKB1-deficient tumors by inducing ferroptosis in mouse models. Our data demonstrate a multifaceted role of complex I in regulating ferroptosis and propose a ferroptosis-inducing therapeutic strategy for LKB1-deficient cancers.

Identification and Visualization of Polystyrene Microplastics/Nanoplastics in Flavored Yogurt by Raman Imaging.

The contamination of food by microplastics has garnered widespread attention, particularly concerning the health risks associated with small-sized microplastics. However, detecting these smaller microplastics in food poses challenges attributed to the complexity of food matrices and instrumental and method limitations. Here, we employed Raman imaging for visualization and identification of polystyrene particles synthesized in polymerization reactions, ranging from 400 to 2600 nm. We successfully developed a quantitative model of particle size and concentration for polystyrene, exhibiting excellent fit (R2 of 0.9946). We established procedures for spiked flavored yogurt using synthesized polystyrene, providing fresh insights into microplastic extraction efficiency. Recovery rates calculated from models validated the method's feasibility. In practical applications, the assessment of the size, type, shape, and quantity of microplastics in unspiked flavored yogurt was conducted. The most common polymers found were polystyrene, polypropylene, and polyethylene, with the smallest polystyrene sizes ranging from 1 to 10 µm. Additionally, we conducted exposure assessments of microplastics in branded flavored yogurt. This study established a foundation for developing a universal method to quantify microplastics in food, covering synthesis of standards, method development, validation, and application.

Chemical profiling of Zhi-Ke-Bao pills and its potential mechanism against cough by ultra-high performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry and network pharmacology.

Zhi-Ke-Bao pills (ZKB), a traditional Chinese medicine preparation composed of 13 herbs, is generally used to treat cough caused by external wind cold, phlegm, etc in clinical applications, and it plays a core role in relieving cough caused by COVID-19 and influenza in China. Till now, the understanding of its chemical constituents was dramatically limited due to its chemical complexity, restricting its clinical application or development. In this work, a developed ultra-high performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry (UPLC-Q/TOF MS) method, a targeted and non-targeted strategy and network pharmacology were used to comprehensively characterize the chemical compositions in ZKB and predict its mechanism against cough. A total of 164 compounds (148 targeted compounds and 16 non-targeted ones) were identified or tentatively characterized in ZKB, including 65 flavonoids, 25 alkaloids, 19 organic acids, 41 saponins, 9 coumarins, 2 phenylpropanoids, 2 anthraquinones, and 1 other types. Among them, 37 compounds were unambiguously identified by comparison to reference standards. Meanwhile, the fragmentation behaviors of five main chemical structure types were also summarized. 309 targets and two core signaling pathways of ZKB against cough were predicted by network pharmacology, including MAPK and PI3K-Akt signaling pathways. It was the first time to characterize the chemical compounds of ZKB and reveal its potential mechanism against cough, providing the material basis for further quality control or pharmacodynamic evaluation of ZKB.

Integral sliding mode control and stability for Markov jump systems with structured perturbations and time-varying delay driven by fractional Brownian motion.

The issues of stability and sliding mode control (SMC) for time-varying delay Markov jump systems (MJSs) with structured perturbations constrained by fractional Brownian motion (fBm) are explored. First, constructing a novel Lyapunov-Krasovskii functional (LKF) with exponential terms that contain the double-integral term, the pth moment exponential stability conditions are derived by utilizing the generalized fractional Itoˆ formula and conditional mathematical expectation. Subsequently, by designing the innovative integral sliding mode surface (SMS) associated with time-varying delay and the SMC law, the state trajectories of the dynamic systems can reach the designed SMS within a finite time. Ultimately, the numerical experiment is executed to confirm and ensure the accuracy and reliability of the obtained results.

Choroidal Layer Analysis in OCT images via Ambiguous Boundary-aware Attention.

Optical Coherence Tomography (OCT) is a commonly used retina imaging technique, and it is capable of revealing the morphology of the choroid. However, the segmentation and quantitative analysis of the sublayers and vessels in choroid are rarely explored, primarily due to the indistinct boundaries of choroidal sublayers, and imbalanced distribution of vessels observed in OCT imagery. In this paper, we propose a novel two-stage architecture called Choroidal Layer Analysis network (CLA), that may be considered the first attempt in this research community for joint segmentation of choroidal sublayers and choroidal vessels in OCT images. CLA employs the encoder-decoder network with the residual U-shape module as the backbone. In order to empower the ability of the segmentation model to identify the inconspicuous boundaries of choroidal sublayers, we introduce an Ambiguous Boundary Attention block (ABA) into the bottleneck of the encoder-decoder network in the first stage. For more accurate segmentation of large choroidal vessels with ambiguous contours and imbalanced spatial distribution, the second stage introduces an active contour-based loss to refine the contours of choroidal vessels simultaneously with precise identification of each vessel via contextual modeling. To train, test and validate the proposed model, we conducted a choroidal segmentation dataset containing 800 OCT images, with their sublayers and large choroidal vessels manually annotated. Experimental results demonstrate the superiority of the proposed approach compared with other state-of-the-art segmentation networks in large margins. It is worth noting that we also reconstructed the large choroidal vessels in three-dimensional (3D) based on the segmentation results, and multiple 3D morphological parameters were calculated. The statistical analysis of these parameters demonstrates significant differences between the healthy control and high myopia group, and this further confirms the proposed work may facilitate subsequent disease understanding and clinical decision-making.

Designing cellulose nanofibrils/carbon dots intelligent label with colorimetric and fluorescent dual responsiveness for real-time monitoring of food freshness.

This study utilized 1,2,4-triaminobenzene dihydrochloride and NaOH as precursors to prepare the pH optical sensor based on carbon dots (CDs). By incorporating CDs into pineapple peel cellulose nanofibrils (CNF) matrix, an intelligent label (CNF/CDs label) with colorimetric and fluorescent dual responsiveness was created for real-time monitoring of food freshness. The CNF/CDs labels exhibited remarkable sensitivity and recognizability towards pH changes from 1 to 12. They also demonstrated excellent reversibility during acid-alkali cycling. Moreover, these labels exhibited exceptional responsiveness to the alkaline and acidic gas environments formed by ammonium hydroxide and acetic acid solutions, respectively. These responses were visually distinguishable through visible color changes and ultraviolet (UV) fluorescence alterations. Encouragingly, the developed labels were successfully applied to monitor the freshness of prawns and fruits, enabling timely assessment of food freshness levels. The dual-mode response of color and fluorescence provided double assurance for the accuracy of the results.

Ambient air pollution, lifestyle, and genetic predisposition on all-cause and cause-specific mortality: A prospective cohort study.

BACKGROUND: Although it is widely acknowledged that long-term exposure to ambient air pollution is closely related to the risk of mortality, there were inconsistencies in terms of cause-specific mortality and it is still unknown whether lifestyle and genetic susceptibility could modify the association. METHODS: This population-based prospective cohort study involved 461,112 participants from the UK Biobank. The land-use regression model was used to estimate the concentrations of particulate matter (PM2.5, PMcoarse, PM10), and nitrogen oxides (NO2 and NOx). The association between air pollution and mortality was evaluated using Cox proportional hazard models. Furthermore, a lifestyle score incorporated with smoking status, physical activity, alcohol consumption, and diet behaviors, and polygenic risk score using 12 genetic variants, were developed to assess the modifying effect of air pollution on mortality outcomes. RESULTS: During a median follow-up of 14.0 years, 33,903 deaths were recorded, including 17,083 (2835; 14,248), 6970, 2429, and 1287 deaths due to cancer (lung cancer, non-lung cancer), cardiovascular disease (CVD), respiratory and digestive disease, respectively. Each interquartile range (IQR) increase in PM2.5, NO2 and NOx was associated with 7 %, 6 % and 5 % higher risk of all-cause mortality, respectively. Specifically, for cause-specific mortality, each IQR increase in PM2.5, NO2 and NOx was also linked to mortality due to cancer (lung cancer and non-lung cancer), CVD, respiratory and digestive disease. Furthermore, additive and multiplicative interactions were identified between high ambient air pollution and unhealthy lifestyle on mortality. In addition, associations between air pollution and mortality were modified by lifestyle behaviors. CONCLUSION: Long-term exposure to air pollutants increased the risk of all-cause and cause-specific mortality, which was modified by lifestyle behaviors. In addition, we also revealed a synergistically detrimental effect between air pollution and an unhealthy lifestyle, suggesting the significance of joint air pollution management and adherence to a healthy lifestyle on public health.

Pan-cancer analysis of LRRC59 with a focus on prognostic and immunological roles in hepatocellular carcinoma.

BACKGROUND: LRRC59 is a leucine-rich repeats-containing protein located in the endoplasmic reticulum (ER), it serves as a prognostic marker in several cancers. However, there has been no systematic analysis of its role in the tumor immune microenvironment, nor its predictive value of prognosis and immunotherapy response in different cancers. METHODS: A comprehensive pan-cancer analysis of LRRC59 was conducted from various databases to elucidate the associations between its expression and the prognosis of cancer, genetic alterations, tumor metabolism, and tumor immunity. Additionally, further functional assays were performed in hepatocellular carcinoma (HCC) to study its biological role in regulating cell proliferation, migration, apoptosis, cell cycle arrest, and sensitivity to immunotherapy. RESULTS: The pan-cancer analysis reveals a significant upregulation of LRRC59 in pan-cancer, and its overexpression is correlated with unfavorable prognosis in cancer patients. LRRC59 is negatively correlated with immune cell infiltration, tumor purity estimation, and immune checkpoint genes. Finally, the validation in HCC demonstrates LRRC59 is significantly overexpressed in cancer tissue and cell lines, and its knockdown inhibits cell proliferation and migration, promotes cell apoptosis, induces cell cycle arrest, and enhances the sensitivity to immunotherapy in HCC cells. CONCLUSIONS: LRRC59 emerges as a novel potential prognostic biomarker across malignancies, offering promise for anti-cancer drugs and immunotherapy.

Characteristics and prognostic impact of cancer cachexia defined by the Asian Working Group for Cachexia consensus in patients with curable gastric cancer.

BACKGROUND: Cachexia is prevalent in cancer patients. The conventional diagnostic criteria for cachexia are often based on Western evidence, lacking consensus for Asian populations. This study aims to compare Asian Working Group for Cachexia (AWGC) criteria with Fearon's criteria, assessing their differences in population characteristics and prognostic impact. METHODS: The clinical data of patients who underwent radical gastrectomy between 2013 and 2019 were prospectively collected. Cachexia diagnosis involves the utilization of either AWGC criteria and the previous international consensus proposed by Fearon et al. A scoring model is established based on the optional criteria according to the AWGC criteria. Univariate and multivariate logistic and Cox regression analysis were conducted to determine the independent effect factors for postoperative complications and overall survival. RESULTS: In a total of 1330 patients, 461 met AWGC cachexia criteria and 311 met Fearon's criteria. Excluding 262 overlapping cases, those diagnosed solely with AWGC-cachexia had higher age and lower BMI, albumin, hemoglobin, and handgrip strength compared to those by Fearon's criteria alone. AWGC-cachexia independently increased the risk of postoperative complications, whereas Fearon's criteria did not. Patients with AWGC-cachexia also exhibited shorter overall survival than Fearon's criteria. The AWGC-based cachexia grading system effectively stratifies the risks of postoperative complications and mortality. CONCLUSIONS: The AWGC criteria is more effective in diagnosing cancer cachexia in the Asian population and provide better prognostic indicators.

Structure Identification of Ganoderma lucidum Spore Polysaccharides and Their Antitumor Activity In Vivo.

Ganoderma lucidum spore powder, valued for its nutritional and medicinal properties, contains polysaccharides crucial for its efficacy. However, the complex structural nature of these polysaccharides necessitates further investigation to fully realize their potential. This study aimed to investigate the effects of acid heat treatment on Ganoderma lucidum spore polysaccharides (GLSPs) to enhance their properties and application in antitumor activity. The GLSP was obtained via acid heat treatment, concentration, and centrifugal separation. This process led to a notable reduction in polysaccharide molecular weight, increasing water solubility and bioavailability. Analytical techniques including NMR spectroscopy and methylation analysis revealed a polysaccharide composition comprising four distinct monosaccharides, with molecular weights of 3291 Da (Mw) and 3216 Da (Mn). Six different linkage modes were identified, with a molar ratio of 1:5:2:3:4:3. In vivo experiments demonstrated the GLSP's significant inhibitory effect on the growth of four tumor models (sarcoma S180, Lewis lung cancer, liver cancer H22, and colon cancer C26) in mice, with no observed toxicity. These findings suggest the GLSP's potential as an antitumor therapeutic agent for clinical use.

Targeting PRKDC activates the efficacy of antitumor immunity while sensitizing to chemotherapy and targeted therapy in liver hepatocellular carcinoma.

BACKGROUND: Liver hepatocellular carcinoma (LIHC) ranks among the malignancies with the highest mortality rates, primarily due to chemoresistance culminating in treatment failure. Despite its impact, predictive models addressing disease progression, tumor microenvironment, and drug sensitivity remain elusive for LIHC patients. Recognizing the significant influence of various programmed cell death (PCD) modes on tumor evolution, this study investigates PCD genes to elucidate their implications on the prognosis and immune landscape of LIHC. METHODS: To develop the classification and model, we employed a total of 17 genes associated with PCD patterns. To collect data, we acquired gene expression profiles, somatic mutation information, copy number variation data, and corresponding clinical data from the TCGA database, specifically from LIHC patients. Moreover, we obtained spatial transcriptome data and additional bulk datasets from the Gene Expression Omnibus (GEO) database to conduct further analysis. Various experiments were conducted to validate the role of the PCD gene PRKDC in proliferation, migration, invasion, EMT, cell cycle, therapeutic sensitivity, and antitumor immunity. RESULTS: A novel LIHC classification based on these genes divided patients into two clusters, C1 and C2. The C2 cluster exhibited characteristics indicative of poor prognosis and an immune-activated microenvironment. This group showed greater response potential to immune checkpoint inhibitors, displaying higher levels of certain immune signatures and receptors. A programmed cell death index (PCDI) was constructed using 17 selected PCD genes. This index could effectively predict patient prognosis, with higher PCDI indicating poorer survival rates and a more pro-tumor microenvironment. Immune landscapes revealed varying interactions with PCDI, suggesting therapeutic targets and insights into treatment resistance. Moreover, experiments results suggested that PRKDC can augment the invasive nature and growth of malignant cells and it can serve as a potential target for therapy, offering hope for ameliorating the prognosis of LIHC patients. CONCLUSIONS: The study uncovers the insights of programmed cell death in the prognosis and potential therapeutic interventions. And we found that PRKDC can serve as a target for enhancing the efficacy of antitumor immunity while sensitizing chemotherapy and targeted therapy in liver hepatocellular carcinoma.

Primary lung cancer in children and adolescents.

PURPOSE: Primary lung cancer is extremely rare in children and adolescents. The aim of this study is to clarify clinical features and outcomes of primary lung cancer in children and adolescents. METHODS: Young patients (aged ≤ 20 years) diagnosed as primary lung cancer between 2012 and 2023 were retrospective reviewed. According to radiological appearance of the nodules, they were divided into solid nodule (SN) group and ground glass opacity (GGO) group. RESULTS: A total of 74 patients were identified, with a median age at diagnosis of 18 years old (range: 11-20), including 7 patients in SN group and 67 patients in GGO group. In the GGO group, none of the nodules enlarged or changed during an average surveillance period of 10.8 months before surgery, except one. Wedge resection was the most common procedure (82.1%), followed by segmentectomy (16.4%) and lobectomy (1.5%). Histopathological analysis revealed that 64.2% of GGO nodules were adenocarcinoma in situ and minimally invasive adenocarcinomas, while the remaining 35.8% were invasive adenocarcinomas. Mutational analysis was performed in nine patients, with mutations identified in all cases. After a mean follow-up period of 1.73 ± 1.62 years, two patients in the SN group died due to multiple distant metastases, while all patients in the GGO group survived without recurrence. The overall survival (100%) of the GGO group was significantly higher than SN group (66.7%). CONCLUSIONS: Primary lung cancer in children and adolescents are rare and histopathological heterogeneous. Persistent GGO nodules may indicate early-stage lung adenocarcinoma in children and adolescents.

Cold plasma for enhancing covalent conjugation of ovalbumin-gallic acid and its functional properties.

The utilization of cold plasma (CP) treatment to promote covalent conjugation of ovalbumin (OVA) and gallic acid (GA), as well as its functionality, were investigated. Results demonstrated that CP significantly enhanced the covalent grafting of OVA and GA. The maximum conjugation of GA, 24.33 ± 2.24 mg/g, was achieved following 45 s of CP treatment. Covalent conjugation between GA and OVA were confirmed through analyses of total sulfhydryl (-SH) group, Fourier transform infrared (FTIR) spectroscopy, and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). Unfolding of the OVA molecule occurred upon conjugation with GA, as evidenced by multiple spectroscopy analyses. Additionally, conjugation with GA resulted in significant improvements in the antioxidant activity and emulsifying properties of OVA. This study demonstrated that CP is a robust and sustainable technique for promoting the covalent conjugate of polyphenols and proteins, offering a novel approach to enhance the functional properties of proteins.

A survival nomogram model for patients with resectable non-small cell lung cancer and lymph node metastasis (N1 or N2) based on the Surveillance, Epidemiology, and End Results Database and single-center data.

Background: The ability to predict survival in patients with lymph node metastasis has long been elusive. After surgery, the basis for decision-making on the combination treatment of patients is not clear. The purpose of this study was thus to build a survival nomogram model to effectively predict the overall survival (OS) of patients with non-small cell lung cancer (NSCLC) and lymph node metastasis. The number of dissected lymph nodes (NDLN), number of positive lymph nodes (NPLN), lymph node ratio (LNR), and log odds of positive lymph nodes (LODDS) were included in this study to determine the risk factors in patients with advanced NSCLC. Methods: The data of 5,132 patients with NSCLC and lymph node metastasis (N1 or N2) were extracted from the Surveillance, Epidemiology, and End Results (SEER) database according to inclusion and exclusion criteria and used as the training cohort. We enrolled 117 patients from the First Affiliated Hospital, Zhejiang University School of Medicine as the external validation cohort. Receiver operating characteristic (ROC) analyses were performed to determine the best cutoff values for predicting the prognosis of patients with NSCLC. Based on the risk factors affecting prognosis, a nomogram was constructed using univariate and multivariate Cox proportional hazard regression models. The discrimination ability of the nomogram was evaluated with the concordance index (C-index) and calibration curves. For the independent risk factors, survival curves were drawn using Kaplan-Meier analysis. Results: ROC curve analysis showed that the optimal NPLN cut-off value was 4, LNR was 0.26, and LODDS was -0.25, respectively. However, LNR was nonsignificant in multivariate analysis, with a P value of 0.274. The novel survival nomogram model included seven independent risk factors, among which were NPLN, LODDS, and chemotherapy. Model 4, which included N stage, NPLN, and LODDS, had a higher likelihood ratio (LR) and C-index than did the other models. The C-index was 0.648 [95% confidence interval (CI): 0.636-0.659] in the training cohort and 0.807 (95% CI: 0.751-0.863) in the external validation cohort, showing good prognostic accuracy and discrimination ability. According to the median risk score, the patients in the training cohort and external validation cohort were divided into high-risk and low-risk groups, between which significant differences in OS were found. In the training cohort, age, sex, T stage, N stage, NPLN, LODDS, and chemotherapy were significantly associated with OS (P<0.001). In the external validation cohort, T stage, NPLN, LODDS, and chemotherapy were found to be correlated with OS. Conclusions: The NPLN and LODDS nomogram is an accurate survival prediction tool for patients with N1 or N2 NSCLC. Patients with lymph node metastasis can benefit from chemotherapy, but no evidence shows that radiotherapy is necessary for patients with resectable NSCLC.

TDF and TAF inhibit liver cancer cell migration, invasion via p7TP3.

Tenofovir disoproxil fumarate (TDF) seems to prevent hepatocellular carcinoma (HCC) in patients with chronic hepatitis B virus (HBV). However, the mechanism is still little known. This study aimed to investigate the the roles and mechanisms of TDF, tenofovir alafenamide fumarate (TAF), and entecavir (ETV) on the malignant characteristics of liver cancer cells. Using the wound-healing assays, transwell assays, matrigel transwell assays, and cell counting kit-8 (CCK-8) assays, it was possible to identify that TDF/TAF, inhibited migration, invasion, and proliferation of HepG2 cells and Huh7 cells. To investigate the mechanisms, we performed TOP/FOP-Flash system, Western blot, and RT-qPCR assays of liver cancer cells cultured with TDF/TAF and found a lower activity of Wnt/ß-catenin signaling pathway compared with control cells. Finally, Hepatitis C virus p7 trans-regulated protein 3 (p7TP3), a tumor suppressor in liver cancers, was significantly increased in HepG2 cells and Huh7 cells that treated with TDF/TAF. However, entecavir (ETV)-treated liver cancer cells showed no significant difference in the malignant characteristics of liver cancer cells, activity of Wnt/ß-catenin signaling pathway, and expression of p7TP3, compared with the control groups. To conclude, TDF/TAF maybe novel promising therapeutic strategy for liver cancers, including HCC and hepatoblastoma, via Wnt/ß-catenin signaling pathway, by up-regulating expression of the tumor suppressor, p7TP3.

Single-cell RNA-seq reveals T cell exhaustion and immune response landscape in osteosarcoma.

Background: T cell exhaustion in the tumor microenvironment has been demonstrated as a substantial contributor to tumor immunosuppression and progression. However, the correlation between T cell exhaustion and osteosarcoma (OS) remains unclear. Methods: In our present study, single-cell RNA-seq data for OS from the GEO database was analysed to identify CD8+ T cells and discern CD8+ T cell subsets objectively. Subgroup differentiation trajectory was then used to pinpoint genes altered in response to T cell exhaustion. Subsequently, six machine learning algorithms were applied to develop a prognostic model linked with T cell exhaustion. This model was subsequently validated in the TARGETs and Meta cohorts. Finally, we examined disparities in immune cell infiltration, immune checkpoints, immune-related pathways, and the efficacy of immunotherapy between high and low TEX score groups. Results: The findings unveiled differential exhaustion in CD8+ T cells within the OS microenvironment. Three genes related to T cell exhaustion (RAD23A, SAC3D1, PSIP1) were identified and employed to formulate a T cell exhaustion model. This model exhibited robust predictive capabilities for OS prognosis, with patients in the low TEX score group demonstrating a more favorable prognosis, increased immune cell infiltration, and heightened responsiveness to treatment compared to those in the high TEX score group. Conclusion: In summary, our research elucidates the role of T cell exhaustion in the immunotherapy and progression of OS, the prognostic model constructed based on T cell exhaustion-related genes holds promise as a potential method for prognostication in the management and treatment of OS patients.

Target-Guided Diffusion Models for Unpaired Cross-modality Medical Image Translation.

In a clinical setting, the acquisition of certain medical image modality is often unavailable due to various considerations such as cost, radiation, etc. Therefore, unpaired cross-modality translation techniques, which involve training on the unpaired data and synthesizing the target modality with the guidance of the acquired source modality, are of great interest. Previous methods for synthesizing target medical images are to establish one-shot mapping through generative adversarial networks (GANs). As promising alternatives to GANs, diffusion models have recently received wide interests in generative tasks. In this paper, we propose a target-guided diffusion model (TGDM) for unpaired cross-modality medical image translation. For training, to encourage our diffusion model to learn more visual concepts, we adopted a perception prioritized weight scheme (P2W) to the training objectives. For sampling, a pre-trained classifier is adopted in the reverse process to relieve modality-specific remnants from source data. Experiments on both brain MRI-CT and prostate MRI-US datasets demonstrate that the proposed method achieves a visually realistic result that mimics a vivid anatomical section of the target organ. In addition, we have also conducted a subjective assessment based on the synthesized samples to further validate the clinical value of TGDM.