Hydrogel-based platforms for site-specific doxorubicin release in cancer therapy.

Hydrogels are promising candidates for the delivery of therapeutics in the treatment of human cancers. Regarding to the biocomaptiiblity, high drug and encapsulation efficacy and adjustable physico-chemical features, the hydrogels have been widely utilized for the delivery of chemotherapy drugs. Doxorubicin (DOX) is one of the most common chemotherapy drugs used in cancer therapy through impairing topoisomerase II function and increasing oxidative damage. However, the tumor cells have developed resistance into DOX-mediated cytotoxic impacts, requiring the delivery systems to increase internalization and anti-cancer activity of this drug. The hydrogels can deliver DOX in a sustained manner to maximize its anti-cancer activity, improving cancer elimination and reduction in side effects and drug resistance. The natural-based hydrogels such as chitosan, alginate and gelatin hydrogels have shown favourable biocompatibility and degradability in DOX delivery for tumor suppression. The hydrogels are able to co-deliver DOX with other drugs or genes to enhance drug sensitivity and mediate polychemotherapy, synergistically suppressing cancer progression. The incorporation of nanoparticles in the structure of hydrogels can improve the sustained release of DOX and enhancing intracellular internalization, accelerating DOX's cytotoxicity. Furthermore, the stimuli-responsive hydrogels including pH-, redox- and thermo-sensitive platforms are able to improve the specific release of DOX at the tumor site. The DOX-loaded hydrogels can be further employed in the clinic for the treatment of cancer patients and improving efficacy of chemotherapy.

Triple therapy boosts survival in NSCLC patients with brain metastases: a retrospective cohort study of chemotherapy, ICIs, and antiangiogenic agents.

BACKGROUND: Treatment of brain metastases (BMs) in non-small cell lung cancer (NSCLC) patients, especially those with non-sensitive genetic mutations, is hindered by limited drug delivery through the blood-brain barrier (BBB). This retrospective study explores the efficacy of systemic treatments during brain metastasis to radiotherapy evaluation window in improving patient survival. METHODS: In this retrospective cohort study, we evaluated 209 NSCLC patients with non-sensitive mutations and BMs, treated between 2016 and 2023 at two tertiary medical centers (Chongqing University Cancer Hospital and Guangxi Medical University Cancer Hospital). The patients were divided into three groups, namely chemotherapy alone (C; n = 95), chemotherapy plus immune checkpoint inhibitors (ICIs) (C + I; n = 62), and chemotherapy with ICIs and antiangiogenic therapy (A) (C + I + A; n = 52). Statistical analyses were performed using R software, version 4.3.3. Categorical variables were compared using Fisher's exact test, and survival curves were estimated with the Kaplan-Meier method and compared via the log-rank test. Univariate and multivariate Cox regression models were used to assess factors associated with overall survival (OS). Bayesian model averaging (BMA) was employed to address model uncertainty and improve result robustness. Subgroup analyses evaluated treatment-related mortality risk. RESULTS: From an initial cohort of 658 NSCLC patients with BMs, 209 were analyzed with a median age of 59; the majority were male (80.9%) and diagnosed with adenocarcinoma (78.9%). Univariate analysis identified significant variables influencing outcomes, including BMs radiotherapy EQD2, BMs count, local thoracic treatment, BMs radiotherapy field, intracranial response, and systemic treatment post-BMs diagnosis. The C + I + A regimen significantly improved median OS to 23.6 months compared to 11.4 months with C and 16.2 months with C + I, with a hazard ratio (HR) of 0.60 (95% CI: 0.43-0.82; P < 0.0001). The two-year OS rate was highest in the C + I + A group at 38.5%, versus 10.5% in C and 20.4% in C + I (P < 0.001). Cox regression and BMA analyses confirmed the stability of BMA in providing HR estimates, yielding area under the curve (AUC) values of 0.785 for BMA and 0.793 for the Cox model, with no significant difference in predictive performance. Subgroup analysis revealed a 71% mortality risk reduction with C + I + A (HR: 0.29; 95% CI: 0.18-0.47; P < 0.0001), showing consistent benefits regardless of patient sex, BMs count, extracranial metastases presence, and local thoracic treatments. Treatment sequence analysis indicated a median OS of 33.4 months for patients starting with A, though not statistically significant (HR: 0.59; P = 0.36). The overall incidence of radiation-induced brain injury was low at 3.3%, with rates in the C, C + I, and C + I + A groups being 3.2%, 4.8%, and 1.9%, respectively (P = 0.683). CONCLUSION: Our study demonstrates the significant benefit of the C + I + A combination therapy in improving OS and reducing mortality risk in NSCLC patients with non-sensitive gene-mutated BMs. The sequential administration of A followed by ICIs shows a promising synergistic effect with cranial radiotherapy, highlighting the potential for optimized treatment sequencing. These findings emphasize the efficacy of tailored combination therapies in complex oncological care and suggest that our approach could lead to meaningful improvements in clinical outcomes for this challenging patient population.

Decreased zinc-fingers and homeoboxes family expression was associated with unfavorable outcomes and immune infiltration in lung adenocarcinoma.

Background: The zinc-fingers and homeoboxes (ZHX) family is a group of nuclear homodimeric transcriptional repressors that play an essential role in developing and progressing diverse malignancies. However, the association of ZHX family expression with prognosis and immune infiltration in lung adenocarcinoma (LUAD) is still unclear. The current study aimed to investigate the relationship between ZHX family expression and clinical outcomes and immune infiltration in LUAD patients. Methods: ZHXs family expression was determined by using the Oncomine database and Cancer Cell Line Encyclopedia (CCLE). The impact of ZHXs family expression on prognosis was analyzed by using the Kaplan-Meier-plotter online database. The Search Tool for the Retrieval of Interacting Genes (STRING) database was utilized to construct the interaction network based on the selected differentially expressed genes associated with ZHXs. The Database for Annotation, Visualization, and Integrated Discovery (DAVID) was used to perform the enrichment of the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. The functional state of the ZHXs family in diverse types of malignancies was determined by CancerSEA. The Tumor Immune Estimation Resource (TIMER) database was used to evaluate the association of the ZHXs family with immune cell infiltrates. ZHXs family expression was validated by the Gene Expression Omnibus (GEO) database and real-time polymerase chain reaction (RT-PCR) in 10 paired tumors and normal tissues. Results: ZHX1-3 expression level significantly decreased in LUAD compared with normal tissues. Attenuated ZHXs expression was significantly associated with unfavorable overall survival in LUAD patients. ZHX family members were positively associated with immune infiltration of monocytes, tumor-associated macrophages (TAMs), M1 and M2 macrophages in LUAD. ZHX family expression was also significantly related to a variety of immune marker sets in LUAD. GEO analysis and RT-PCR validated the significant decrease of ZHXs expression level in LUAD. Conclusions: The current study revealed that ZHX family expression was significantly correlated with unfavorable outcomes and immune infiltration in LUAD. The findings herein provide a promising basis for further study into the potential biological function of the ZHX family in LUAD and lay a foundation for developing therapeutic targets for LUAD patients.

Nomogram prediction for the risk of venous thromboembolism in patients with lung cancer.

OBJECTIVE: The aim of this study was to establish a nomogram graph model to accurately predict the venous thromboembolism (VTE) risk probability in the general population with lung cancer. METHODS: Based on data from patients with lung cancer in Chongqing University Cancer Hospital of China, the independent risk factors of VTE were identified by the logistic univariable and multivariable analysis and were integrated to construct a nomogram, which was validated internally. The predictive effectiveness of the nomogram was evaluated by the receiver operating characteristic curve (ROC) and calibration curve. RESULTS: A total of 3398 lung cancer patients were included for analysis. The nomogram incorporated eleven independent VTE risk factors including karnofsky performance scale (KPS), stage of cancer, varicosity, chronic obstructive pulmonary disease (COPD), central venous catheter (CVC), albumin, prothrombin time (PT), leukocyte counts, epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), dexamethasone, and bevacizumab. The C-index of the nomogram model was 0.843 and 0.791 in the training and validation cohort, respectively, demonstrating good discriminative power. The calibration plots of the nomogram revealed excellent agreement between the predicted and actual probabilities. CONCLUSIONS: We established and validated a novel nomogram for predicting the risk of VTE in patients with lung cancer. The nomogram model could precisely estimate the VTE risk of individual lung cancer patients and identify high-risk patients who are in need of a specific anticoagulation treatment strategy.

Piezo-Activated Atomic-Thin Molybdenum Disulfide/MXene Nanoenzyme for Integrated and Efficient Tumor Therapy via Ultrasound-Triggered Schottky Electric Field.

Monolayer molybdenum disulfide (MoS2 ) nanoenzymes exhibit a piezoelectric polarization, which generates reactive oxygen species to inactivate tumors under ultrasonic strain. However, its therapeutic efficiency is far away from satisfactory, due to stackable MoS2 , quenching of piezo-generated charges, and monotherapy. Herein, chitosan-exfoliated monolayer MoS2 (Ch-MS) is composited with atomic-thin MXene, Ti3 C2 (TC), to self-assemble a multimodal nanoplatform, Ti3 C2 -Chitosan-MoS2 (TC@Ch-MS), for tumor inactivation. TC@Ch-MS not only inherits piezoelectricity from monolayer MoS2 , but also maintains remarkable stability. Intrinsic metallic MXene combines with MoS2 to construct an interfacial Schottky heterojunction, facilitating the separation of electron-hole pairs and endowing TC@Ch-MS increase-sensitivity magnetic resonance imaging responding. Schottky interface also leads to peroxidase mimetics with excellent catalytic performance toward H2 O2 in the tumor microenvironment under mechanical vibration. TC@Ch-MS possesses the superior photothermal conversion efficiency than pristine TC under near-infrared ray illumination, attributed to its enhanced interlaminar conductivity. Meanwhile, TC@Ch-MS realizes optimized efficiency on tumor apoptosis with immunotherapy. Therefore, TC@Ch-MS achieves an integrated diagnosis and multimodal treatment nanoplatform, whereas the toxicity to normal tissue cells is negligible. This work may shed fresh light on optimizing the piezoelectric materials in biological applications, and also give prominence to the significance of intrinsic metallicity in MXene.

Pseudo-siamese network combined with dosimetric and clinical factors, radiomics features, CT images and 3D dose distribution for the prediction of radiation pneumonitis: A feasibility study.

Purpose: Radiation pneumonitis (RP)(grade ≥ 2) can have a considerable impact on patient quality-of life. In previous studies, the traditional method commonly used radiomics and clinical factors for RP prediction. This study aims to develop and evaluate a novel pseudo-siamese network (PSN) to assist radiologists predict RP before radiotherapy based on combination of dosimetric and clinical factors, radiomics features, CT (computed tomography) images, and dose distribution (hybrid model). Method: One hundred and ten patients with lung cancer (19 RP ≥ 2) who received radiotherapy between 2016 and 2020 were retrospectively enrolled in this study. Dosimetric factors were calculated from DVH (dose-volume histogram), such as lung mean dose, lung V5, and prescription dose. Clinical characteristics were recorded, such as age, sex, smoking status, TN stage, and overall stage. A total of 1419 radiomics features were extracted. Cluster analysis was used for detecting radiomics features that associated with RP. Patients were randomly split into a training set (90 %, 85 non-RP, and 14 RP) and a validation set (10 %, 6 non-RP, and 5 RP). A PSN architecture was designed for combining 1D (dosimetric and clinical factors, radiomics) and 3D (CT images, 3D dose distribution) features. 5-fold cross-validation procedure for estimating the skill of the model on new data. Results: For cluster analysis, totally of 106 radiomics features with high correlation were selected. The accuracy was 0.727, 0.636, 0.545, and 0.727 for input dosimetric and clinical factors, dose distribution, CT images, and radiomics features, respectively. The accuracy of hybrid model was 0.818. The sensitivity of hybrid model was 0.800 (95 % confidence interval (CI) [0.299, 0.989]), and specificity was 0.833(95 % CI [0.364, 0.991]). The areas under the receiver operating characteristic curves (AUCs) result in 5-fold cross-validation was 0.77-0.90(mean AUC ± std was 0.85 ± 0.05). Conclusion: This study firstly propose method that the combination of high dimensional and low dimensional features for RP prediction. The results confirm the feasibility of multi-dimensional features predict RP.

Identification of Angiogenesis-Related Prognostic Biomarkers Associated With Immune Cell Infiltration in Breast Cancer.

Background: This study aimed to explore the prognostic value of angiogenesis-related genes (ARGs) and their association with immune cell infiltration (ICI) in breast cancer (BC). Methods: Transcriptome data of BC were obtained from the TCGA and GEO databases. Differentially expressed ARGs were identified by the limma package. The identification of key genes and construction of the risk score model were performed by univariate and multivariate Cox regression algorithms. The prognostic value of the risk score was assessed by ROC curves and nomogram. GO, KEGG pathway, and GSEA were used to investigate the biological functions of differentially expressed genes (DEGs), and CIBERSORT, ssGSEA, and xCell algorithms were performed to estimate the ICI in high-risk and low-risk groups. The correlations between prognostic biomarkers and differentially distributed immune cells were assessed. Moreover, a ceRNA regulatory network based on prognostic biomarkers was constructed and visualized by Cytoscape software. Results: A total of 18 differentially expressed ARGs were identified between tumor and adjacent normal tissue samples. TNFSF12, SCG2, COL4A3, and TNNI3 were identified as key prognostic genes by univariate and multivariate Cox regression analyses. The risk score model was further constructed based on the four-gene signature and validated in GSE7390 and GSE88770 datasets. ROC curves and nomogram indicated that the risk score had good accuracy for determining BC patient survival. Biological function analysis showed that DEGs in high- and low-risk groups had a high enrichment in immune-related biological processes and signaling pathways. Moreover, significantly different ICIs were found between high- and low-risk groups, such as memory B cells, CD8+ T cells, resting memory CD4+ T cells, follicular helper T cells, regulatory T cells, monocytes, M2 macrophages, and neutrophils, and each prognostic biomarker was significantly correlated with one or more immune cell types. Conclusion: The current study identified novel prognostic ARGs and developed a prognostic model for predicting survival in patients with BC. Furthermore, this study indicated that ICI may act as a bond between angiogenesis and BC. These findings enhance our understanding of angiogenesis in BC and provide novel guidance on developing therapeutic targets for BC patients.

Polyphenols in Ilex latifolia Thunb. inhibit human lung cancer cell line A549 by regulation of the PI3K-Akt signaling pathway.

BACKGROUND: The leaves of the plant Ilex latifolia Thunb. can be made into Kuding tea, which is a drink rich in polyphenols. This study aimed to observe the effect of Ilex latifolia Thunb. polyphenols (ILTPs) on human lung cancer cell line A549 (A549 cells) by regulating the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling pathway. METHODS: In vitro cultured cells were treated with ILTPs; the proliferation of A549 cells and BEAS-2B human normal lung epithelial cells (Beas-2B cells) was observed using the 3-(4,5-dimethylazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and the survival status of A549 cells was observed by fluorescence staining. The expression of A549 cells was observed by quantitative polymerase chain reaction (qPCR) assay and Western blot analysis, while the compound composition of ILTPs was detected using high-performance liquid chromatography (HPLC). RESULTS: The experimental results showed that the proliferation of Beas-2B cells was unaffected by treatment with 0-500 µg/mL of ILTPs, whereas the decreased proliferation of A549 cells was observed with the increasing concentrations of ILTPs. Additionally, ILTPs elevated the levels of lactate dehydrogenase (LDH) and reactive oxygen species (ROS) and promoted apoptosis in A549 cells. The results of qPCR experiments showed that ILTPs upregulated caspase-9 mRNA expression and downregulated phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt), mammalian target of rapamycin (mTOR), B-cell lymphoma-2 (Bcl-2), nuclear factor-κB (NF-κB), vascular endothelial growth factor (VEGF), hypoxia-inducible factor-1 alpha (HIF-1α), and cyclooxygenase-2 (COX-2) expression in A549 cells. The Western blot analysis results also showed that ILTPs could reduce the protein expression of PI3K and Akt. The HPLC results showed that the main compounds present in the ILTPs were rutin, kaempferol, isochlorogenic acid A, isochlorogenic acid B, and isochlorogenic acid C. CONCLUSIONS: Thus, this study indicated that the polyphenols of I. latifolia act as a class of natural functional food materials that potently suppress cancer by exerting their inhibitory effects on A549 cell proliferation through five key polyphenolic compounds.

Comparison of Radiation Pneumonitis in Lung Cancer Patients Treated with HT versus IMRT and Circulating Lymphocyte Subsets as Predicting Risk Factors.

PURPOSE: We sought to compare the symptomatic radiation pneumonitis (RP) in lung cancer patients treated with helical tomotherapy (HT) versus intensity-modulated radiotherapy (IMRT), and examine the predictive value of circulating lymphocyte subsets affecting the occurrence of RP. PATIENTS AND METHODS: Circulating lymphocyte subsets, clinical characteristics, dosimetric parameters and pulmonary function were collected from 130 lung cancer patients treated with HT (n = 53) or IMRT (n = 77) from 2016 through 2020. Symptomatic RP was compared between groups. Binary logistic regression was used to identify predictors of RP. RESULTS: The IMRT group had larger planning target volume (319.9 vs 240.8 cc, P = 0.041); more ECOG performance status 0-1 (96.1% vs 79.2%, P = 0.002); more stage III-IV disease (94.8% vs 37.6%, P = 0.028); and more combined systemic therapy (85.7% vs 69.8%, P = 0.022). Grade ≥2 RP were comparable between IMRT and HT groups (16.9% vs 15.1%, P = 0.785). For stage III-IV disease, IMRT was associated with lower lung V10 (31.9% vs 35.8%, P = 0.047) and lower incidence of grade 5 RP (0% vs 9.1%, P = 0.018). All lymphocyte subsets reduced after radiotherapy. The decrease degree of total T cell count and CD4+ T cell count were larger after IMRT than HT (P = 0.043, P = 0.021). In univariate analysis, the smoking status, lower baseline FEV1, and higher total T cell count, higher CD8+ T cell count, lower total B cell count, lower CD4+/CD8+ ratio after radiotherapy were associated with the development of grade ≥2 RP. The higher CD8+T cell count after radiotherapy was the only risk factor associated with grade ≥2 RP in multivariable analysis (OR 1.003; 95% CI: 1.000-1.005; P = 0.044). CONCLUSION: IMRT was associated with lower lung V10 and less grade 5 RP than HT for stage III-IV lung cancer. Higher CD8+ T cell count after radiotherapy was associated with an increased risk of RP. HT may better preserve total T cell and CD4+ T cell than IMRT.

Protective Effects of Silymarin Against D-Gal/LPS-Induced Organ Damage and Inflammation in Mice.

AIM: Silymarin contains various flavonoids and exhibits antioxidative, anti-inflammatory, and anticancer effects, in addition to other pharmacological properties. This study explored the alleviating effect of silymarin on multiple-organ damage induced by D-galactose/lipopolysaccharide in Kunming mice. METHODS: Kunming mice were injected intraperitoneally with D-galactose (30 mg/kg·BW)/LPS (3 µg/kg·BW) and then treated using silymarin with different doses (75 mg/kg·bw and 150 mg/kg·bw) via intragastric administration. Changes in organ indexes, pathological changes, liver-function index, biochemical indexes, molecular biological indexes, and genes related to the oxidation and inflammation of main organs were evaluated. RESULTS: After the mice were treated with silymarin, their body weight showed no significant change, and the liver, kidney, and lung indexes of the treated mice were higher than those of the model group; meanwhile, the corresponding histopathological formation was reduced. Compared with the model group, the silymarin-treated group showed reductions in ALT, AST, and liver function indexes in the mouse serum. Silymarin treatment also increased the SOD, CAT, GSH, GSH-Px, T-AOC, IL-10, and IL-12 levels, as well as reduced the MDA, NO, IL-6, IL-1ß, TNF-α, IFN-γ levels in the mouse serum and liver tissues. In addition, quantitative polymerase chain reaction analysis indicated that the mRNA expression levels of SOD1, SOD2, CAT, GSH-Px, IL-10, Nrf2, HO-1, NQO1, Trx, and IκB-α were higher in the liver tissue of the silymarin-treated mice than in those of the model group; meanwhile, the mRNA expression levels of IL-6, IL-1ß, TNF-α, IFN-γ, NF-κB, NLRP3, COX2, and p38 were lower than those in the model group. CONCLUSION: Silymarin, which exhibits antioxidative and anti-inflammatory effects, can alleviate the liver, lung, and kidney damage induced by D-galactose/lipopolysaccharide. High-dose (150 mg/kg·bw) silymarin can more effectively inhibit organ damage, compared with low-dose silymarin (75 mg/kg·bw) in Kunming mice.

Protective Effect of Blood Cora Polysaccharides on H9c2 Rat Heart Cells Injury Induced by Oxidative Stress by Activating Nrf2/HO-1 Signal Pathway.

The protective effect of blood cora polysaccharides (BCP) on H9c2 rat heart cells under oxidative stress was explored with the use of a H9c2 cell oxidative stress model. The ability of BCP to scavenge 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), 1,1-diphenyl-2-picrylhydrazyl (DPPH), and hydroxyl radicals and its reducing power were measured in vitro, indicating a more powerful antioxidant effect of BCP compared to a similar concentration of vitamin C. The cellular metabolic activity was tested through the MTT [3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide] assay. Additionally, the relevant oxidation indicator level within the cell supernatant and cells was tested with reagent kits, and mRNA and protein expression levels in the cells were tested through quantitative polymerase chain reaction (qPCR) and western blot. The chemical composition of BCP was determined through high performance liquid chromatography (HPLC). The results show that compared with the normal group, the model group's cell survival rate (28.75 ± 2.56%) decreased, lactate dehydrogenase (LDH) leakage and the malondialdehyde (MDA) content increased, and superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH) levels decreased. The results of qPCR and western blot show that compared with the normal group, the model group's Bcl-2 associated X protein (Bax), caspase-3, nuclear factor erythroid-2 related factor 2 (Nrf2), heme oxygenase-1 (HO-1) expression, NAD(P)H:quinoneoxidoreductase 1 (NQO1), and cytochrome c (Cyt C) decreased, and B-cell lymphoma-2 (Bcl-2) expression was increased, with significant statistical differences. Compared with the model group, the cell survival rate for each BCP-treated group increased, the LDH leakage decreased, the SOD, CAT, and GSH levels in the cells increased, the MDA content decreased, the Bax, caspase-3, Nrf2, HO-1, NQO1, and Cyt C expression was weakened, and the Bcl-2 expression was strengthened. BCP inhibited the reduction of mitochondrial membrane potential caused by H2O2 treatment. According to the component analysis, BCP mainly consist of mannitol, ribose, glucosum anhydricum, galactose, and xylose. It was observed that the Nrf2/HO-1 signaling pathway can be activated, regulated, and controlled by functional BCP to protect H9c2 cells injured by oxidative stress.

Characteristics of stereotactic radiotherapy clinical trials registered on ClinicalTrials.gov.

BACKGROUND: We aim to analyze the characteristics of stereotactic radiotherapy trials registered on ClinicalTrials.gov, and to compare completed and stopped early trials to identify predictors of trial failure. METHODS: All interventional stereotactic radiotherapy trials registered on ClinicalTrials.gov before Dec 31, 2019 were downloaded. Trial characteristics over time and between different regions were compared by Chi-square test. Binary logistic regression was used to explore characteristics associated with trials stopped early. RESULTS: A total of 760 trials were included. A higher proportion of trials were about lung cancer (20.4%), prostate cancer (14.7%) and central nervous system (14.6%). Most trials were phase1 and/or 2 trials (63.0%), single group (62.4%), nonrandomized (71.7%), open-label (95.0%) and single center (75.8%). The median sample size was 40 (0-1,716). Only 15.1% and 13.5% were funded by industry and National Institutes of Health (NIH), respectively. 15.4% stopped early with status includes "suspended", "terminated" and "withdrawn". Of the 113 "completed" trials, only 28 were published on PubMed. Compared with 2010 to 2014, trials from 2015 to 2019 were more likely to be randomized (20.0% vs. 34.4%; P=0.001), with 2 study arms (27.1% vs. 42.1%; P=0.002), industry-funded (11.0% vs. 19.1%; P=0.028) and conducted in Asia (7.6% to 15.8%; P=0.002). Trials from North America were more oriented toward phase 1 research (24.4% vs. 6.1% for Europe and 6.5% for Asia, P<0.001), nonrandomized (77.7% vs. 56.8% for Europe and 64.1% for Asia, P<0.001). Trials from Asia were more likely to have recruiting status (56.5% vs. 45.5% for Europe and 43.6% for North America, P<0.001). Multivariate regression analysis showed that randomized (OR 8.090, P=0.001), and enrollment patients ≤50 (OR 3.813, P<0.001) were associated with trials stopped early. CONCLUSIONS: Stereotactic radiotherapy trials are predominantly early-phase, small, single arm, nonrandomized and open label. Trials with randomized allocation or enrollment patients ≤50 were more likely to stop early.

Construction of a prognostic risk model of colorectal adenocarcinoma through integrated analysis of RNA-binding proteins.

BACKGROUND: RNA binding proteins (RBPs) play an important role in a variety of cancers. However, their mechanisms in cancer progression are still limited especially in colorectal adenocarcinoma (COAD). Integrated analysis of RBPs will provide a better understanding of disease genesis and new insights into COAD treatment. METHODS: The gene expression data and corresponding clinical information for COAD were downloaded from The Cancer Genome Atlas (TCGA) database. Univariate Cox regression analysis was used to screen for RBPs associated with COAD recurrence, and multivariate Cox proportional hazards regression analyses were used to identify genes that were associated with COAD recurrence. A nomogram was constructed to predict the recurrence of COAD, and a receiver operating characteristic (ROC) curve analysis was performed to determine the accuracy of the prediction models. The Human Protein Atlas database was used in prediction models to confirm the expression of key genes in COAD patients. RESULTS: A total of 177 differentially expressed RBPs was obtained, comprising 123 upregulated and 54 downregulated. GO and KEGG enrichment analysis showed that the differentially expressed RBPs were mainly related to mRNA metabolism, RNA processing and translation regulation. Seven RBP genes (TDRD6, POP1, TDRD7, PPARGC1A, LIN28B, LRRFIP2 and PNLDC1) were identified as prognosis-associated genes and were used to construct the prognostic model. CONCLUSIONS: We constructed a COAD prognostic model through bioinformatics analysis and the nomogram can effectively predict the 1-year, 2-year, and 3-year survival rate for COAD patients.

Construction of a Potential Breast Cancer-Related miRNA-mRNA Regulatory Network.

BACKGROUND: Breast cancer is a malignant tumor that occurs in the epithelial tissue of the breast gland and has become the most common malignancy in women. The regulation of the expression of related genes by microRNA (miRNA) plays an important role in breast cancer. We constructed a comprehensive breast cancer-miRNA-gene interaction map. METHODS: Three miRNA microarray datasets (GSE26659, GSE45666, and GSE58210) were obtained from the GEO database. Then, the R software "LIMMA" package was used to identify differential expression analysis. Potential transcription factors and target genes of screened differentially expressed miRNAs (DE-miRNAs) were predicted. The BRCA GE-mRNA datasets (GSE109169 and GSE139038) were downloaded from the GEO database for identifying differentially expressed genes (DE-genes). Next, GO annotation and KEGG pathway enrichment analysis were conducted. A PPI network was then established, and hub genes were identified via Cytoscape software. The expression and prognostic roles of hub genes were further evaluated. RESULTS: We found 6 upregulated differentially expressed- (DE-) miRNAs and 18 downregulated DE-miRNAs by analyzing 3 Gene Expression Omnibus databases, and we predicted the upstream transcription factors and downstream target genes for these DE-miRNAs. Then, we used the GEO database to perform differential analysis on breast cancer mRNA and obtained differentially expressed mRNA. We found 10 hub genes of upregulated DE-miRNAs and 10 hub genes of downregulated DE-miRNAs through interaction analysis. CONCLUSIONS: In this study, we have performed an integrated bioinformatics analysis to construct a more comprehensive BRCA-miRNA-gene network and provide new targets and research directions for the treatment and prognosis of BRCA.

Impact of CT slice thickness on volume and dose evaluation during thoracic cancer radiotherapy.

INTRODUCTION: Accurate delineation of targets and organs at risk (OAR) is required to ensure treatment efficacy and minimize risk of normal tissue toxicity with radiotherapy. Therefore, we evaluated the impacts of computed tomography (CT) slice thickness and reconstruction methods on the volume and dose evaluations of targets and OAR. PATIENTS AND METHODS: Eleven CT datasets from patients with thoracic cancer were included. 3D images with a slice thickness of 2 mm (2-CT) were created automatically. Images of other slice thickness (4-CT, 6-CT, 8-CT, 10-CT) were reconstructed manually by the selected 2D images using two methods; internal tumor information and external CT Reference markers. Structures and plans on 2-CT images, as a reference data, were copied to the reconstructed images. RESULTS: The maximum error of volume was 84.6% for the smallest target in 10-CT, and the maximum error (≥20 cm3) was 10.1%, 14.8% for the two reconstruction methods, internal tumor information and external CT Reference, respectively. Changes in conformity index for a target of <20 cm3 were 5.4% and 17.5% in 8-CT. Changes on V30 and V40 of the heart were considerable. In the internal tumor information method, volumes of hearts decreased by 3.2% in 6-CT, while V30 and V40 increased by 18.4% and 46.6%. CONCLUSION: The image reconstruction method by internal tumor information was less affected by slice thickness than the image reconstruction method by external CT Reference markers. This study suggested that before positioning scanning, the largest section through the target should be determined and the optimal slice thickness should be estimated.

A parameterized model for mean urinary inflow rate and its preliminary application in radiotherapy for cervical cancer.

Forty-nine patients with stage IIb cervical cancer were included to investigate the changes in bladder volume in response to different approaches to maintaining consistent bladder filling. The impacts of age (P age), water consumption (P wat ), and body mass index (BMI, P bmi ) on the mean urinary inflow rate (v tot ) were analysed. The bladder volume (BV) increased linearly over time. A large variation in v tot among individuals was observed, ranging from 0.19 to 5.13 ml/min. The v tot was correlated with P age (R = -0.53, p = 0.01) and P wat (R = 0.84, p = 0.00), and no correlation between v tot and P bmi was found (p > 0.05). Therefore, v tot could be parameterized using two methods: multivariable linear regression and iterative fitting. There was no statistically significant difference between the two methods. The model accuracy was successfully assessed with several validation tests for patients with good compliance (79.2% of all patients), and the proportion of radiotherapy (RT) fractions with zero wait time (one ultrasound (US) scan) increased from 6.5% to 41.2%. The optimal US scanning number and RT time could be provided using this model. This adaptive RT approach could reduce patient discomfort caused by holding onto urine and reduce technician labour as well as cost.

Interfractional variation in bladder volume and its impact on cervical cancer radiotherapy: Clinical significance of portable bladder scanner.

PURPOSE: A constant bladder volume (BV) is essential to direct the radiotherapy (RT) of pelvic tumors with precision. The purpose of this study was to investigate changes in BV and their impact on cervical cancer RT and to assess the clinical significance of a portable bladder scanner (BS) in achieving a constant BV. METHODS: A standard bladder phantom (133 ml) and measurements of actual urine volume were both used as benchmarks to evaluate the accuracy of the BS. Comparisons of BS with computed tomography (CT), cone-beam CT (CBCT), and an ultrasound diagnostic device (iU22) were made. Twenty-two consecutive patients with cervical cancer treated with external beam radical RT were divided into an experimental group (13 patients) and a control group (9 patients). In the experimental group, the BV was measured multiple times by BS pre-RT until it was consistent with that found by planning CT. Then a CBCT was performed. The BV was measured again immediately post-RT, after which the patient's urine was collected and recorded. In the control group, CBCT only was performed pre-RT. Interfractional changes in BV and their impact on cervical cancer RT were investigated in both groups. The time of bladder filling was also recorded and analyzed. RESULTS: In measuring the volume of the standard bladder phantom, the BS deviated by 1.4% in accuracy. The difference between the measurements of the BS and the iU22 had no statistical significance (linear correlation coefficient 0.96, P < 0.05). The BV measured by the BS was strongly correlated with the actual urine volume (R = 0.95, P < 0.05), planning CT (R = 0.95, P < 0.05), or CBCT (R = 0.91, P < 0.05). Compared with the BV at the time of CT, its value changed by -36.1% [1 SD (standard deviation) 42.3%; range, -79.1%-29.4%] in the control group, and 5.2% (1 SD 21.5%; range, -13.3%-22.1%) in the experimental group during treatment. The change in BV affected the target position in the superior-inferior (SI) direction but had little or no effect in the anterior-posterior and right-left directions. Based on the collected data, the target displacement in the SI direction was reduced from 2.0 to 0.4 mm, while the CTV-to-PTV (CTV: clinical target volume; PTV: planning target volume) margin in the SI direction was reduced from 11.1 to 6.4 mm. The BV increased by 3.7 ± 1.0 ml/min (range, 1.7-4.7 ml/min), which depended on the amount of water ingested by the patient (R = 0.96, P < 0.05). No correlation was found between the rate of urinary inflow and the patient's body mass. The authors were able to reduce the workload of measuring by using individual patient information including the patient's age, the water-drinking amount, time at which water-drinking began, and patient's diet. CONCLUSIONS: Changes in the BV have an influence on the RT of cervical cancer. A consistent and reproducible BV is acquired by using a portable BS, whereby the target displacement and CTV-to-PTV margin can be both reduced in the SI direction.

[Comparative Study on Evaluating the Bladder Volume between BladderScan BVI9400 and Ultrasound System iU22].

OBJECTIVE: To evaluate the accuracy of the latest BladderScan BVI9400 on measuring bladder volume. METHODS: Two bladder phantoms were selected for investigating the accuracy of BVI9400. 341 patients with the iU22 ultrasound examinations were followed by BVI 9400. The difference and correlation between BVI9400 and iU22 were contrastively analyzed. RESULTS: The relative difference between results from BVI9400 and phantom volume was 2.5% and 1.36%. There was a strong correlation for patients between BVI9400 and iU22 (R = 0.96, P < 0.001). The relative difference between BVI9400 and iU22 decreased with the increasing of bladder volume and had no significant difference with patient's gender (P > 0.1). CONCLUSION: BladderScan BVI9400 had the ability of high accuracy and good stability of measured data. In view of quick and conveniences, BVI9400 could be as auxiliary equipment on pelvic tumor to evaluate whether the bladder volume during fractional radiotherapy was consistency with that during CT positioning.

Comparative proteomic and radiobiological analyses in human lung adenocarcinoma cells.

In clinic, many non-small cell lung cancer (NSCLC) patients receive radiation therapy after chemotherapy failure. However, whether the multidrug resistance (MDR) can elevate the radioresistance (RDR) remains unclear. To evaluate the MDR's effect on the RDR, screen MDR- and RDR-related proteins in human lung adenocarcinoma (HLA) cells and tissues A549, and A549/DDP cells after irradiation were analyzed by colony-forming assay and flow cytometry. Two-dimensional electrophoresis (2-DE) and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) were utilized to identify differentially expressed proteins (DEPs) between them. The value of D0, Dq, and SF2 increased, the mean percentage in G2 phase and apoptosis rate significantly decreased in A549/DDP cells compared with A549 cells. 40 DEP points were found, and among them 27 were identified through proteomics. Four up-regulated proteins (HSPB1, Vimentin, Cofilin-1, and Annexin A4) in MDR cells compared with non-MDR cells, were confirmed by Western blot. Immuno-histochemistry showed that they were also over-expressed in MDR tissues compared with non-MDR counterparts of HLA. These results proved that the MDR in HLA cells and tissues increased the RDR. HSPB1, Vimentin, Cofilin-1, and Annexin A4 are potential biomarkers for predicting HLA response to MDR and RDR, and novel treatment targets of HLA.