Search

Killer cell lectin-like receptor B1 (KLRB1) is implicated in cancer progression and immunity. In this study, we aimed to evaluate the expression levels of KLRB1 in lung adenocarcinoma (LUAD) and analyze the relationship between KLRB1 expression levels, LUAD progression, and the tumor immune microenvironment. KLRB1 levels in LUAD were analyzed using data from the TCGA and XENA databases. Additionally, the diagnostic values of KLRB1 were analyzed in patients with LUAD. Survival and meta-analyses were employed to investigate the relationship between KLRB1 levels and other prognostic factors in patients with LUAD. Bioinformatics and cellular experiments were used to understand the functions and mechanisms of KLRB1. In addition, correlation analysis was used to investigate the relationship between KLRB1 levels and the immune microenvironment in LUAD. Reduced KLRB1 expression in LUAD was found to positively correlate with tumor size, distant metastasis, pathological stage, age, overall survival, diagnostic value, and disease-specific survival in patients with LUAD (P < 0.05). Conversely, increased KLRB1 expression was found to positively correlate with the overall survival and disease-specific survival in patients with LUAD (P < 0.05). We also found that the overexpression of KLRB1 can inhibit the proliferation, migration, and invasion of LUAD cells and promote apoptosis. KLRB1 was involved in immune cell differentiation, NF-kB, PD-L1, and PD-1 checkpoint pathways and others. Additionally, KLRB1 expression was linked to tumor purity, stromal, immune, and estimate scores, the levels of immune cells including B cells, CD8 + T cells, and CD4 + T cells, and immune cell markers in LUAD. Reduced KLRB1 expression has a significant positive correlation with diagnosis, poor prognosis, and immunity to cancer in patients with LUAD. KLRB1 inhibited cell proliferation and migration in patients with LUAD. These results suggest that KLRB1 may serve as a potential therapeutic target in patients with LUAD., (© 2024. The Author(s).)

Background: Overexpression of solute carrier family 7 member 8 (SLC7A8) has been shown to relate to the survival time and tumor progression in cancer patients. However, the role of SLC7A8 in lung adenocarcinoma (LUAD) is still obscure., Method: The relationships between SLC7A8 expression in LUAD tissues and clinical values as well as immune infiltration were explored through bioinformatics. The functions and pathways of SLC7A8 in LUAD were investigated using Kyoto Encyclopedia of Genes and Genomes enrichment analysis, Gene Set Enrichment Analysis, Western blotting, and other methods., Results: We found that the expression of SLC7A8 was decreased significantly in LUAD tissues compared with normal tissues, which was related to the dismal survival time and disease progression. Moreover, it carried diagnostic value in LUAD and was a risk factor for dismal prognosis. Receiver operating characteristic curve analysis indicated that the expression level of SLC7A8 carried significant diagnostic value in LUAD. Overexpression of SLC7A8 inhibited the proliferation, invasion, and migration of LUAD cells, likely through a mechanism involving the cell cycle. SLC7A8 expression in LUAD was significantly correlated with the infiltration of immune cells, especially B cells, interstitial dendritic cells, mast cells, CD56 bright cells, natural killer cells, plasmacytoid dendritic cells, T follicular helper cells, T helper 2 and 17 cells, and immune factors., Conclusion: The downregulation of SLC7A8 was related to a dismal prognosis and immune cell infiltration in LUAD. Increasing the expression of SLC7A8 inhibited the growth and migration of LUAD cells, thereby improving the prognosis of patients.

Angiopoietin4(ANGPT4) which plays a significant role in endothelial cell proliferation, survival, angiogenesis and expansion in tumors and other pathological states is a significant regulator of tumor angiogenesis. ANGPT4 expression is enhanced in many cancer cells. For example, the overexpression of ANGPT4 promotes the formation, development and progress of lung adenocarcinoma, glioblastoma and ovarian cancer. Related studies show that ANGPT4 encourages the proliferation, survival and invasion of tumor cells, while promoting the expansion of the tumor vascular system and affecting the tumor immune microenvironment. ANGPT4 can also promote carcinogenesis by affecting the ERK1/2, PI3K/AKT and other signal pathways downstream of tyrosine kinase with immunoglobulin-like and EGF-like domains 2(TIE2) and TIE2. Therefore, ANGPT4 may be a potential and significant biomarker for predicting malignant tumor progression and adverse outcomes. In addition, inhibition of ANGPT4 may be a meaningful cancer treatment. This paper reviews the latest research results of ANGPT4 in preclinical research, and emphasizes its role in carcinogenesis. Additional research on the carcinogenic function of ANGPT4 could provide new insights into cancer biology and novel methods for cancer diagnosis and treatment., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Purpose: This phase 2 trial aimed to determine whether xenon-enhanced ventilation computed tomography (XeCT)-guided functional-lung-avoidance radiation therapy could reduce the radiation pneumonitis (RP) rate in patients with lung cancer undergoing definitive chemoradiation therapy., Methods and Materials: Functional lung ventilation was measured via pulmonary function testing (PFT) and XeCT. A standard plan (SP) without reference to XeCT and a functional-lung-avoidance plan (fAP) optimized for lowering the radiation dose to the functional lung at the guidance of XeCT were designed. Dosimetric parameters and predicted RP risks modeled by biological evaluation were compared between the 2 plans in a treatment planning system (TPS). All patients received the approved fAP. The primary endpoint was the rate of grade ≥2 RP, and the secondary endpoints were the survival outcomes. The study hypothesis was that fAP could reduce the rate of grade ≥2 RP to 12% compared with a 30% historical rate., Results: Thirty-six patients were evaluated. Xenon-enhanced total functional lung volumes positively correlated with PFT ventilation parameters (forced vital capacity, P = .012; forced expiratory volume in 1 second, P = .035), whereas they were not correlated with the diffusion capacity parameter. We observed a 17% rate of grade ≥2 RP (6 of 36 patients), which was significantly different (P = .040) compared with the historical control. Compared with the SP, the fAP significantly spared the total ventilated lung, leading to a reduction in predicted grade ≥2 RP (P = .001) by TPS biological evaluation. The median follow-up was 15.2 months. The 1-year local control (LC), disseminated failure-free survival (DFFS), and overall survival (OS) rates were 88%, 66%, and 91%, respectively. The median LC and OS were not reached, and the median DFFS was 24.0 months (95% confidence interval, 15.7-32.3 months)., Conclusions: This report of XeCT-guided functional-lung-avoidance radiation therapy provided evidence showing its feasibility in clinical practice. Its benefit should be assessed in a broader multicenter trial setting., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Lung cancer is the most common cause of cancer mortality worldwide. The advances in surgery, radiotherapy, chemotherapeutic and immunotherapeutic drugs have progressed in the past decades, but the prognosis of lung cancer is still poor. In this study, we developed cisplatin (CDDP)-loaded human serum albumin (HSA)-based gold nanoshells (HCP@GNSs) for synergistic chemo-photothermal therapy (chemo-PTT). The HCP@GNSs not only acted as drug nanocarriers for chemotherapy but also serve as a superior mediator for PTT, which could exhibit a temperature increase upon a near infrared (NIR) laser exposure that was sufficient for photothermal ablation. HCP@GNSs were highly biocompatible and hemocompatible nanocarriers, while the synergistic chemo-PTT resulting from HCP@GNSs plus NIR exposure displayed stronger cytotoxicity effect than HCP@GNSs or PTT alone, especially at a low CDDP concentration. In vivo analysis demonstrated that HCP@GNSs-mediated chemo-PTT increased necrosis in tumors to achieve a high tumor clearance rate with no adverse side effects. Moreover, HCP@GNSs-medicated chemo-PTT induced the recruitment of dendritic cells, B-cells, and natural killer T-cells in distal tumors to inhibit the growth of the tumors. Therefore, the CDDP-loaded HCP@GNSs may be a potential nanomedicine candidate for curative lung cancer treatment in the future., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier Masson SAS.)

Purpose: To evaluate the therapeutic efficacy of cyclin-dependent kinase (CDK) inhibition in combination with ionizing radiation for lung cancer., Materials and Methods: Human lung adenocarcinoma (A549) and squamous cell carcinoma (H520) cells were used to evaluate the therapeutic efficacy of CDK inhibition in combination with ionizing radiation in vitro using colony formation assay, γH2AX immunofluorescence staining, western blotting, and cell cycle phase analysis. We also performed in vivo evaluations of ectopic tumor growth., Results: In vitro pretreatment with the CDK inhibitor, seliciclib, before irradiation significantly decreased the survival of A549 and H520 cells in a dose-dependent manner. Although CDK inhibition alone did not increase the intensity of γH2AX foci, its combination with ionizing radiation increased DNA double-strand breaks, as shown by γH2AX immunofluorescence staining and western blotting. The combination of CDK inhibition and ionizing radiation-induced G2/M arrest and increased apoptosis, as evidenced by the increased proportion of cells in G2/M arrest, subG1 apoptotic population, and expression of apoptotic markers (cleaved PARP-1 and cleaved caspase-3). Mechanistic studies showed reduced expression of cyclin A with combined treatment, indicating cell cycle shifting effects. An in vivo xenograft model showed that the combination of CDK inhibition and ionizing radiation delayed xenograft tumor growth, and increased the proportion of cleaved PARP-1- and cleaved caspase-3-positive cells, compared to either treatment alone., Conclusions: We provide preclinical tumoricidal evidence that the combination of CDK inhibition and ionizing radiation is an efficacious treatment for lung cancer.

Purpose: Development of a safe and effective systemic chemotherapeutic agent for concurrent administration with definitive thoracic radiotherapy remains a major goal of lung cancer management. The synergistic effect of PEGylated liposomal doxorubicin and irradiation was evaluated in lung cancer cell lines both in vitro and in vivo., Methods: In vitro radiosensitization of A549 and LLC cell lines was evaluated by colony formation assay, γH2AX fluorescent staining and western blot assay, and annexin V staining. A radiosensitization study with healthy human lung-derived cell line BEAS-2B was performed for comparative purposes. In vivo radiosensitization was evaluated by tumor ectopic growth, cell survival, pharmacokinetics, and biodistribution analyses. Cleaved caspase‑3, the marker for apoptosis, was assessed immunohistochemically in A549 xenograft tumors., Results: Treatment with PEGylated liposomal doxorubicin decreased A549 and LLC cell proliferation in a dose-dependent manner. In vitro studies revealed comparable radiosensitizer advantages of PEGylated liposomal doxorubicin and free doxorubicin, showing equivalent DNA double-strand breaks according to γH2AX fluorescent staining and western blot assays, similar numbers of apoptotic cells in the annexin‑V staining assay, and moderately decreased clonogenic survival. In vivo studies demonstrated markedly slow ectopic tumor growth with prolonged survival following treatment with PEGylated liposomal doxorubicin plus irradiation in both A549 and LLC mouse models, suggesting that PEGylated liposomal doxorubicin is more effective as a radiosensitizer than free doxorubicin in vivo. Pharmacokinetics evaluation showed a longer half-life of approximately 40 h for PEGylated liposomal doxorubicin, confirming that the liposomal carrier achieved controlled release. Biodistribution evaluation of PEGylated liposomal doxorubicin confirmed high accumulation of doxorubicin in tumors, indicating the promising drug delivery attributes of PEGylated liposomal doxorubicin. Although free doxorubicin caused histopathologic myocarditis with the cardiac muscle fibers showing varying degrees of damage, PEGylated liposomal doxorubicin caused no such effects. The immunohistochemical expression of cleaved caspase-3-positive cells was greatest expressed in the irradiation and PEGylated liposomal doxorubicin combined treatment group, indicating prolonged tumoricidal effects., Conclusions: Our study provides preclinical in vitro and in vivo evidence of the effectiveness of PEGylated liposomal doxorubicin as a radiosensitizer, supporting its potential clinical development as a component of chemoradiotherapy., (© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.)

Background/purpose: Stereotactic ablative radiotherapy (SABR) is the treatment of choice for medically inoperable, early-stage non-small cell lung cancer (ES-NSCLC). The influence of oncogenic driver alterations and comorbidities are not well known. Here we present treatment outcomes based on clinicopathologic features and molecular profiles., Methods: We retrospectively analyzed patients treated with SABR for inoperable ES-NSCLC. Molecular features of oncogenic driver alterations included EGFR, ALK, and ROS1. Comorbidities were assessed using the age-adjusted Charlson Comorbidity Index (ACCI). Survival was calculated using the Kaplan-Meier method. The Cox regression model was performed for univariate and multivariate analyses of prognostic factors. Competing risk analysis was used to evaluate the cumulative incidence of disease progression., Results: From 2008 to 2020, 100 patients (median age: 82 years) were enrolled. The majority of patients were male (64%), ever-smokers (60%), and had adenocarcinoma (65%). With a median follow-up of 21.5 months, the median overall survival (OS) and real-world progression-free survival were 37.7 and 25.1 months, respectively. The competing-risk-adjusted 3-year cumulative incidences of local, regional, and disseminated failure were 8.2%, 14.5%, and 31.2%, respectively. An ACCI ≥7 was independently associated with inferior OS (hazard ratio [HR] 2.45, p = 0.03). Tumor size ≥4 cm (HR 4.16, p < 0.001) was the most important independent prognostic factor predicting real-world progression. EGFR mutation status had no impact on the outcomes., Conclusion: SABR provides excellent local control in ES-NSCLC, although disseminated failures remains a major concern. ACCI is the best indicator for OS, while tumor sizes ≥4 cm predicts poor disease control., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare. All co-authors have seen and agree with the contents of the manuscript and there is no financial interest to report., (Copyright © 2020 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

AgNPs are nanomaterials with many potential biomedical applications. In this study, the two novel yeast strains HX-YS and LPP-12Y capable of producing biological silver nanoparticles were isolated. Sequencing of ribosomal DNA-ITS fragments, as well as partial D1/D2 regions of 26S rDNA indicated that the strains are related to species from the genus Metschnikowia. The BioAgNPs produced by HX-YS and LPP-12Y at pH 5.0-6.0 and 26 °C ranged in size from 50 to 500 nm. The antibacterial activities of yeast BioAgNPs against five pathogenic bacteria were determined. The highest antibacterial effect was observed on P. aeruginosa, with additional obvious effects on E. coli ATCC8099 and S. aureus ATCC10231. Additionally, the BioAgNPs showed antiproliferative effects on lung cancer cell lines H1975 and A579, with low toxicity in Beas 2B normal lung cells. Therefore, the AgNPs biosynthesized by HX-YS and LPP-12Y may have potential applications in the treatment of bacterial infections and cancer., (© 2021. The Author(s).)

Tumor cells have long been recognized as a relative contraindication to hyperbaric oxygen treatment (HBOT) since HBOT might enhance progressive cancer growth. However, in an oxygen deficit condition, tumor cells are more progressive and can be metastatic. HBOT increasing in oxygen partial pressure may benefit tumor suppression. In this study, we investigated the effects of HBOT on solid tumors, such as lung cancer. Non-small cell human lung carcinoma A549-cell-transferred severe combined immunodeficiency mice (SCID) mice were selected as an in vivo model to detect the potential mechanism of HBOT in lung tumors. HBOT not only improved tumor hypoxia but also suppressed tumor growth in murine xenograft tumor models. Platelet endothelial cell adhesion molecule (PECAM-1/CD31) was significantly increased after HBOT. Immunostaining of cleaved caspase-3 was demonstrated and apoptotic tumor cells with nuclear debris were aggregated starting on the 14th-day after HBOT. In vitro, HBOT suppressed the growth of A549 cells in a time-dependent manner and immediately downregulated the expression of p53 protein after HBOT in A549 cells. Furthermore, HBOT-reduced p53 protein could be rescued by a proteasome degradation inhibitor, but not an autophagy inhibitor in A549 cells. Our results demonstrated that HBOT improved tissue angiogenesis, tumor hypoxia and increased tumor apoptosis to lung cancer cells in murine xenograft tumor models, through modifying the tumor hypoxic microenvironment. HBOT will merit further cancer therapy as an adjuvant treatment for solid tumors, such as lung cancer.

Background: Angiogenesis assessment is important for personalized therapeutic intervention in patients with non-small-cell lung cancer (NSCLC). This study investigated whether radiologic parameters obtained by dynamic contrast-enhanced (DCE)-integrated magnetic resonance-positron emission tomography (MR-PET) could be used to quantitatively assess tumor angiogenesis in NSCLC., Methods: This prospective cohort study included 75 patients with NSCLC who underwent DCE-integrated MR-PET at diagnosis. The following parameters were analyzed: metabolic tumor volume (MTV), maximum standardized uptake value (SUV max ), reverse reflux rate constant (k ep ), volume transfer constant (K trans ), blood plasma volume fraction (v p ), extracellular extravascular volume fraction (v e ), apparent diffusion coefficient (ADC), and initial area under the time-to-signal intensity curve at 60 s post enhancement (iAUC 60 ). Serum biomarkers of tumor angiogenesis, including vascular endothelial growth factor-A (VEGF-A), angiogenin, and angiopoietin-1, were measured by enzyme-linked immunosorbent assays simultaneously., Results: Serum VEGF-A (p = 0.002), angiogenin (p = 0.023), and Ang-1 (p <  0.001) concentrations were significantly elevated in NSCLC patients compared with healthy individuals. MR-PET parameters, including MTV, K trans , and k ep , showed strong linear correlations (p <  0.001) with serum angiogenesis-related biomarkers. Serum VEGF-A concentrations (p = 0.004), MTV values (p <  0.001), and k ep values (p = 0.029) were significantly higher in patients with advanced-stage disease (stage III or IV) than in those with early-stage disease (stage I or II). Patients with initial higher values of angiogenesis-related MR-PET parameters, including MTV > 30 cm 3 (p = 0.046), K trans  > 200 10 - 3 /min (p = 0.069), and k ep  > 900 10 - 3 /min (p = 0.048), may have benefited from angiogenesis inhibitor therapy, which thus led to significantly longer overall survival., Conclusions: The present findings suggest that DCE-integrated MR-PET provides a reliable, non-invasive, quantitative assessment of tumor angiogenesis; can guide the use of angiogenesis inhibitors toward longer survival; and will play an important role in the personalized treatment of NSCLC.

C57BL/6 mice implanted in the flank with murine Lewis lung carcinoma cells were randomized into control, anti-angiogenic, anti-PD-L1, radiotherapy (RT), RT + anti-angiogenic, RT + anti-PD-L1, and RT + anti-PD-L1 + anti-angiogenic therapy groups. Immune response and immunophenotyping were determined by flow cytometry. Vasculature analysis after RT and anti-angiogenic therapy was assessed by quantified power Doppler sonography. Antitumor response, survival, and rechallenged tumor growth were evaluated. RT increased PD-L1 expression on CD8+ T, CD4+ T, dendritic, myeloid-derived suppressor cells (MDSCs), and tumor cells and increased PD-1 expression on CD8+ and CD4+ T cells. Anti-angiogenic therapy insignificantly decreased the RT-induced PD-1 expression on CD8+ and CD4+ T cells, implying a weak reversal of the immune-suppressive environment. Transient vessel collapse was observed within days after RT, and blood flow recovered at 1 week after RT. RT + anti-PD-L1 suppressed the tumor growth, improved survival, and prolonged immune memory capable of protecting against tumor recurrence, evidenced by local accumulation of CD8+ T cells and reduction in MDSCs in microenvironment. Similar and more prominent effects were observed when anti-VEGF was added to RT + anti-PDL1 therapies, implying an additive, rather than synergistic, antitumor immunity. Phenotypic analyses revealed that anti-cancer treatments increased the proportion of effector memory T cells in TILs and splenocytes, and RT, alone or in combination with other treatments, further increased the proportion of central memory T cells in splenocytes. These results provide evidence on operating the immunosuppressive tumor environment and offer insights into the design of the new combination treatment.

Introduction: The aim of the study was to investigate the clinical significance of Ly-1 antibody reactive clone (LYAR) in non-small-cell lung cancer (NSCLC)., Material and Methods: The expressions of LYAR at the protein level in representative paired NSCLC tumor tissues and adjacent non-tumor tissues were measured by Western blot and immunohistochemistry. Kaplan-Meier method was used to calculate the survival curve of patients with NSCLC. Cell Counting Kit-8 assay and flow cytometry were used to estimate the cell proliferation and cell cycle, respectively. Terminal-deoxynucleotidyl-transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay was performed to detect cell apoptosis., Results: LYAR was dramatically overexpressed in NSCLC tissues which were closely related to the survival of patients with NSCLC. In clinical studies, the expression of LYAR was related to the clinical stage, histological differentiation, and Ki-67 expression. A positive correlation was found between LYAR and Ki-67 expression by Spearman's correlation test. After serum starvation for 72 h, serum re-addition significantly increased the expression of LYAR, PCNA, and Cyclin A and promoted the cell cycle progression. LYAR knockdown inhibited the proliferation and induced the G0/G1 cell cycle arrest and apoptosis of A549 cells., Conclusions: The present study revealed the clinical significance of LYAR in NSCLC. LYAR might serve as a tumor promoter in NSCLC progression by promoting the proliferation and inhibiting the apoptosis of NSCLC cells. Inhibiting the expression of LYAR was considered as a potential novel therapeutic strategy for NSCLC.

Farnesoid X receptor (FXR) is a bile acid receptor encoded by the Nr1h4 gene. FXR plays an important role in maintaining the stability of the internal environment and the integrity of many organs, including the liver and intestines. The expression of FXR in nondigestible tissues other than in the liver and small intestine is known as the expression of "nonclassical" bile acid target organs, such as blood vessels and lungs. In recent years, several studies have shown that FXR is widely involved in the pathogenesis of various respiratory diseases, such as chronic obstructive pulmonary disease, bronchial asthma, and idiopathic pulmonary fibrosis. Moreover, a number of works have confirmed that FXR can regulate the bile acid metabolism in the body and exert its anti-inflammatory and antifibrotic effects in the airways and lungs. In addition, FXR may be used as a potential therapeutic target for some respiratory diseases. For example, FXR can regulate the tumor microenvironment by regulating the balance of inflammatory and immune responses in the body to promote the occurrence and development of non-small-cell lung cancer (NSCLC), thereby being considered a potential target for immunotherapy of NSCLC. In this article, we provide an overview of the internal relationship between FXR and respiratory diseases to track the progress that has been achieved thus far in this direction and suggest potential therapeutic prospects of FXR in respiratory diseases., Competing Interests: The authors declare no conflicts of interest regarding the article., (Copyright © 2020 Jin-nan Wu et al.)

Background: Lung cancer is the leading cause of cancer-related deaths worldwide, with non-small cell lung cancer (NSCLC) accounting for 85% of all lung cancer cases. Inflammation has been proven to be one of the characteristics of malignant tumors. Chronic inflammatory response mediated by cytokines in the tumor microenvironment is an important factor in tumorigenesis. The purpose of this study was to observe and evaluate the value of red blood cell distribution width (RDW), neutrophil-to-lymphocyte ratio (NLR), and hemoglobin-to-red blood cell distribution width ratio (HRR) in the progression of NSCLC., Methods: A total of 245 patients with NSCLC, 97 patients with benign pulmonary nodules, and 94 healthy volunteers were included in this study. Factors, such as age, gender, smoking history, histological type, lymph node metastasis, distant metastasis, TNM stage, and differentiation degree were statistically analyzed. The correlation of RDW, NLR, and HRR of patients with NSCLC with other clinical experimental parameters were also analyzed. Then, the diagnostic value of RDW, NLR, and HRR in the progression of NSCLC was evaluated., Results: RDW, NLR, and HRR could be used to distinguish patients with NSCLC from healthy controls (p < 0.05). In addition, only the RDW in the NSCLC group with III-IV stage was significantly different from that in the benign pulmonary nodules group (p = 0.033), while NLR and HRR could significantly distinguish patients with NSCLC and benign pulmonary nodules (p < 0.001). RDW and NLR were positively correlated with NSCLC stage, whereas HRR was negatively correlated with NSCLC stage. RDW, NLR, and HRR were also significantly associated with the differentiation degree of NSCLC (p < 0.05). The ROC curve analysis showed that the combination of RDW with NLR, HRR, and CEA could show significantly higher diagnostic value than any one marker alone (AUC = 0.925, 95% CI: 0.897-0.954, and sensitivity and specificity of 79.60% and 93.60%, respectively)., Conclusion: RDW, NLR, and HRR can be utilized as simple and effective biomarkers for the diagnosis and evaluation of NSCLC progression., Competing Interests: The authors have declared that no competing interests exist.

Lung cancer is a major reason of mortalities. Estimating the survivability for this disease has become a key issue to families, hospitals, and countries. A conditional Gaussian Bayesian network model was presented in this study. This model considered 15 risk factors to predict the survivability of a lung cancer patient at 4 severity stages. We surveyed 1075 patients. The presented model is constructed by using the demographic, diagnosed-based, and prior-utilization variables. The proposed model for the survivability prognosis at different four stages performed R 2 of 93.57%, 86.83%, 67.22%, and 52.94%, respectively. The model predicted the lung cancer survivability with high accuracy compared with the reported models. Our model also shows that it reached the ceiling of an ideal Bayesian network.

Enrichment of CD103 + tumor-infiltrating T lymphocytes (TIL) is associated with improved outcomes in patients. However, the characteristics of human CD103 + cytotoxic CD8 + T cells (CTL) and their role in tumor control remain unclear. We investigated the features and antitumor mechanisms of CD103 + CTLs by assessing T-cell receptor (TCR)-matched CD103 + and CD103 - cancer-specific CTL immunity in vitro and its immunophenotype ex vivo Interestingly, we found that differentiated CD103 + cancer-specific CTLs expressed the active form of TGFβ1 to continually self-regulate CD103 expression, without relying on external TGFβ1-producing cells. The presence of CD103 on CTLs improved TCR antigen sensitivity, which enabled faster cancer recognition and rapid antitumor cytotoxicity. These CD103 + CTLs had elevated energetic potential and faster migration capacity. However, they had increased inhibitory receptor coexpression and elevated T-cell apoptosis following prolonged cancer exposure. Our data provide fundamental insights into the properties of matured human CD103 + cancer-specific CTLs, which could have important implications for future designs of tissue-localized cancer immunotherapy strategies., (©2019 American Association for Cancer Research.)

Objective: To evaluate the role of endobronchial ultrasound guided transbronchial needle aspiration (EBUS-TBNA) in lymph node staging and resectability assessment of patients with non-small cell lung cancer (NSCLC). Methods: The clinical data of 154 patients with NSCLC who underwent EBUS-TBNA from March 2015 to December 2018 were collected. All accessible mediastinal and hilar lymph nodes were systematically explored and punctured using EBUS-TBNA. EBUS-TBNA and CT were used for preoperative staging and resectability evaluation. Results: The sensitivity, specificity and accuracy of EBUS-TBNA were 94.2%, 100.0% and 96.0%, respectively, while those of CT were 89.9%, 31.8% and 72.0%, respectively. The differences were statistically significant ( P <0.05). The sensitivity, specificity and accuracy of EBUS-TBNA in lymph nodes with short diameter less than 15 mm were 92.4%, 100.0% and 96.0%, respectively, while those of CT were 80.7%, 34.8% and 60.1%, respectively, with statistical differences ( P <0.05). The staging of 62 patients was changed, 27 cases were up-regulated and 35 cases were down-regulated. Among them, 32 cases had been changed to resectable. The evaluating resectability of EBUS-TBNA showed excellent consistency with that of pathological results ( Kappa =0.95). The sensitivity and specificity were 100.0% and 97.2%, respectively. Conclusion: EBUS-TBNA can systemically evaluate the metastatic status of NSCLC patients and improve the accuracy of preoperative lymph node staging and resectability assessment.

Purpose: We investigated whether radiologic parameters by dynamic contrast-enhanced (DCE) integrated magnetic resonance-positron-emission tomography (MR-PET) predicts tumor response to treatment and survival in non-metastatic non-small-cell lung cancer (NSCLC) patients receiving chemoradiotherapy (CRT)., Methods: Patients underwent DCE integrated MR-PET imaging 1 week before CRT. The following parameters were analyzed: primary tumor size, gross tumor volume, maximal standardized uptake value (SUV max ), total lesion glycolysis (TLG), apparent diffusion coefficient (ADC), volume transfer constant (K trans ), reverse reflux rate constant (k ep ), extracellular extravascular volume fraction (v e ), blood plasma volume fraction (v p ), and initial area under the time-concentration curve defined over the first 60 s post-enhancement (iAUC 60 ). CRT responses were defined using the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1)., Results: Thirty patients were included. Non-responders demonstrated higher baseline TLG (p = 0.012), and lower baseline K trans (p = 0.020) and iAUC 60 (p = 0.016) compared to responders, indicating the usefulness of DCE integrated MR-PET to predict treatment responses. Receiver operating characteristic curve indicated that TLG has the best differentiation capability to predict responders. By setting the threshold of TLG to 277, the sensitivity, specificity, and accuracy were 66.7%, 83.3%, and 75.0%, respectively, with an area under the curve of 0.776. The median follow-up time was 19.6 (range 7.8-32.0) months. In univariate analyses, baseline TLG >277 (p = 0.005) and baseline K t rans <254 (10 -3  min -1 ; p = 0.015) correlated with poor survival after CRT. In multivariate analysis, baseline TLG >277 remained the significant factor in predicting progression (p = 0.012) and death (p = 0.031)., Conclusions: The radiologic parameters derived from DCE integrated MR-PET scans are useful for predicting treatment response in NSCLC patients treated with CRT; furthermore, these parameters are correlated with clinical and survival outcomes including tumor progression and death.

Lung cancer is one of the leading causes of mortality, and its medical expenditure has increased dramatically. Estimating the expenditure for this disease has become an urgent concern of the supporting families, medial institutes, and government. In this study, a conditional Gaussian Bayesian network (CGBN) model was developed to incorporate the comprehensive risk factors to estimate the medical expenditure of a lung cancer patient at different stages. A total of 961 patients were surveyed by the four severity stages of lung cancer. The proposed CGBN model identified the correlation and association of 15 risk factors to the medical expenditure of different severity stages of lung cancer patients. The relationships among the demographic, diagnosed-based, and prior-utilization variables are constructed. The model predicted the lung cancer-related medical expenditure with high accuracy of 32.63%, 50.30%, 50.36%, and 66.58%, respectively for stages 1-4, as compared with the reported models. A greedy search was also applied to find the upper threshold of R 2 , while our model also shows that it approached the upper threshold., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Purpose: To evaluate the response in patients undergoing SBRT using dynamic contrast-enhanced (DCE) integrated magnetic resonance positron emission tomography (MR-PET). Stereotactic body radiation therapy (SBRT) is efficacious as a front-line local treatment for non-small cell lung cancer (NSCLC)., Materials and Methods: We prospectively enrolled 19 lung tumors in 17 nonmetastatic NSCLC patients who were receiving SBRT as a primary treatment. They underwent DCE-integrated 3T MR-PET before and 6 weeks after SBRT. The following image parameters were analyzed: tumor size, standardized uptake value (SUV), apparent diffusion coefficient, K trans , k ep , v e , v p , and iAUC 60 . Chest computed tomography (CT) was performed at 3 months after SBRT., Results: SBRT treatment led to tumor changes including significant decreases in the SUV max (-61%, P < 0.001), K trans mean (-72%, P = 0.005), K trans standard deviation (SD; -85%, P = 0.046), k ep mean (-53%, P = 0.014), k ep SD (-63%, P = 0.001), and v p SD (-58%, P = 0.002). The PET SUV max was correlated with the MR k ep mean (P = 0.002) and k ep SD (P < 0.001). The percentage reduction in K trans mean (P < 0.001) and k ep mean (P = 0.034) at 6 weeks post-SBRT were significantly correlated with the percentage reduction in tumor size, as measured using CT at 3 months after SBRT. Univariate analyses revealed a trend toward disease progression when the initial SUV max > 10 (P = 0.083)., Conclusion: In patients with NSCLC who are receiving SBRT, DCE-integrated MR-PET can be used to evaluate the response after SBRT and to predict the local treatment outcome., Level of Evidence: 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018;47:191-199., (© 2017 International Society for Magnetic Resonance in Medicine.)

BACKGROUND Ultrasound elastography is an imaging modality used to show tissue stiffness in tumor pathophysiological processes that promote the formation of stiffer tissues. Endobronchial ultrasound (EBUS) elastography is an ultrasound elastography-based technique for measuring tissue stiffness during EBUS-guided transbronchial needle aspiration (EBUS-TBNA). The diagnostic value of EBUS elastography in central lung lesions remains largely unknown. MATERIAL AND METHODS A total of 57 patients with central lung lesions underwent ultrasonic bronchoscope examination. EBUS with standard B mode evaluation and elastography with grading score measurement were performed before EBUS-guided transbronchial needle aspiration (EBUS-TBNA). Comparison of the diagnosis accuracy in malignant lung lesions between elastography and standard EBUS was made. RESULTS Our data showed that the hypoechoic lesions, uneven echo, distinct boundary, and no air bronchogram were significant indicators of standard EBUS in diagnosis of malignant lung lesions (P<0.01). The differences in elastosonography grading scores between the benign and malignant lung lesions were statistically significance (P<0.01), and the elastography grading score was more sensitive and specific than the standard EBUS criteria in diagnosing malignant lung lesions. The area under the receiver operating characteristic curve (ROC) for the elastography grading score was 0.793. The best cut-off point of the elastography grading score for distinguishing malignant from benign lung lesions was 2.5. The elastography grading score had a sensitivity of 72.2%, specificity of 76.2%, positive predictive value of 83.4%, and negative predictive value of 61.5% for distinguishing malignant from benign lung lesions. The overall accuracy of elastography grading score was 73.7%. CONCLUSIONS BUS elastography can effectively diagnose central lung lesions. The diagnostic accuracy of elastography in malignant lung lesions is higher than that of standard EBUS criteria.

The WW domain-containing oxidoreductase (WWOX) is a tumor suppressor that is lost or decreased in most human tumors. The role of WWOX in human lung carcinoma invasion is still not clear. This study aimed to elucidate the potential role of WWOX in lung cancer cell invasion. WWOX mRNA levels in human lung cancers and lung cancer cell lines were assayed by quantitative real-time PCR. WWOX in lung cancer cell lines was manipulated by transfection of expression vector or small interfering RNA. Cell migration and invasion were assessed by wound healing and/or transwell migration and invasion assays. The protein levels of WWOX, E-cadherin and RUNX2 were analyzed by western blot or immunofluorescence. WWOX expression is inversely correlated to invasiveness of lung cancer. WWOX overexpression in highly invasive H1299 cells reduced cell motility and invasiveness, and inhibited the expression of RUNX2 and its target gene matrix metalloproteinase-9 (MMP-9). Silencing WWOX in less invasive NL9980 cells resulted in opposite effects. Overexpressing RUNX2 in H1299 or silencing RUNX2 in NL9980 cells reversed the effects of WWOX. These results suggested that WWOX inhibited the invasive phenotype of lung cancer through downregulating the expression of RUNX2.

Objective: To observe the effects of acupuncture at "Feishu" (BL 13) and "Lingtai" (GV 10) on distribution taxis of paclitaxel in mice with lung cancer to discuss targeted relationship between acupoints and corresponding viscera., Methods: According to randomized digital table, 315 SPF-grade BALB/C female mice were divided into 7 groups: blank group (group A), model group (group B), medication group (group C), acupuncture at non-acupoint group (group D), acupuncture at Feishu group (group E), acupuncture at Lingtai group (group F) and acupuncture at Feishu and Lingtai group (group G), 45 mice in each one. Except the blank group, the remaining groups were treated with N-nitroso-tris-chloroethyl urea (NTCU) to establish the model of squamous-cell carcinoma. After model establishment, group A, group B and group C were not treated with acupuncture; group A and group B were treated with intraperitoneal injection of 0.9% sodium chlorvde solution by 6 mL/kg while group C was treated with intraperitoneal injection of paclitaxel by 6 mL/kg. The group D, group E, group F and group G were treated with acupuncture at non-acupoint, "Feishu" (BL 13), "Lingtai" (GV 10) and "Feishu" (BL 13) plus "Lingtai" (GV 10), respectively, then were intraperitoneally injected with paclitaxel by 6 mL/kg. The treatment was all given once a day for continuous 10 days. 15 min, 30 min, 1 h, 2 h, 8 h, 12 h and 24 h after the treatments, 6 mice in each group were randomly selected and sacrificed to collect samples of lung, liver, spleen, kidney and heart, etc. High performance liquid chromatography was applied to measure the concentration of paclitaxel in each organ (lung, liver, spleen, kidney and heart) at different time points., Results: (1) The content of paclitaxel in lung, kidney and heart reached the peak at 2 h, then decreased significantly in group C, group D, group E, group F and group G; the content of paclitaxel in spleen showed downtrend at each time point. The content of paclitaxel in liver reached the peak at 2 h in group C and group D; the content of paclitaxel reached the peak at 8 h in group E, group F and group G. (2) The content of paclitaxel in lung in group E and group G was higher than that in group C and group D at each time point (all P < 0.01); the content of paclitaxel in lung in group F was higher than that in group C (P < 0.01) and group D (P < 0.01) only at time point of 2 h. The content of paclitaxel in lung in group G was higher than that in group F at each time point (all P < 0.05). There was no statistical difference between group G and group E (all P > 0.05)., Conclusion: Acupuncture at "Feishu" (BL 13) and "Lingtai" (GV 10) could influ- ence the metabolism of paclitaxel in lung-cancer mice, leading to distribution change in each organ. As a result, it could cause targeting effects, which is more significant at "Feishu" (BL 13) and "Lingtai" (GV 10).

Background: Non-small cell lung cancer is the most frequently cause of cancer-related death in the world. To explore the technical feasibility, we detected aberrant promoter methylation of P16 in exhaled breath condensate which was a new, non-invasive tool for diagnosis and screening program of NSCLC., Methods: We analyzed aberrant promoter methylation of P16 in 180 samples from 60 individuals, including 30 NSCLC patients (cancer tissues, adjacent normal lung tissues, blood plasma, and EBC), and 30 healthy controls (blood plasma and EBC) by fluorescent quantitative methylation-specific polymerase chain reaction (F-MSP)., Results: The positive rate of aberrant promoter methylation of P16 was 26 of 30 (86.66%) in tumor tissues, 15 of 30 (50%) in blood plasma, and 12 of 30 (40%) in EBC, we have not observed the positive methylation of P16 in the adjacent normal lung tissues, or in EBC or blood plasma from the healthy control group., Conclusion: We found that detected promoter methylation of P16 in EBC was feasibility, it should be an useful biomarker for diagnosis of NSCLC, it have potential prospect that detected the gene molecular in EBC because of noninvasive, specificity, convenient and repeatable., (Crown Copyright © 2013. Published by Elsevier Ireland Ltd. All rights reserved.)

Global analyses of DNA methylation contribute important insights into biology and the wide-ranging role of DNA methylation. We describe the use of online solid-phase extraction and isotope-dilution liquid chromatography/tandem mass spectrometry (LC-MS/MS) for the simultaneous measurement of 5-methyl-2'-deoxycytidine (5-medC) and 2'-deoxycytidine (dC) in DNA. With the incorporation of isotope internal standards and online enrichment techniques, the detection limit of this method was estimated to be as low as 0.065 pg which enables human global DNA methylation detection using only picogram amounts of DNA. This method was applied to assess the optimal amounts of enzymes required for DNA digestion regarding an accurate global DNA methylation determination and completeness of digestion and to determine global methylation in human tumor adjacent lung tissue of 79 lung cancer patients. We further determined methylated (N7-methylguanine (N7-meG), O (6)-methylguanine (O (6)-meG), and N3-methyladenine (N3-meA)) and oxidized DNA lesions (8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG)) in lung cancer patients by LC-MS/MS. Optimization experiments revealed that dC was liberated from DNA much more readily than 5-medC by nuclease P1 and alkaline phosphatase (AP) in DNA, which could lead to an error in the global DNA methylation measurement following digestion with insufficient enzymes. Nuclease P1 showed more differential activity for 5-medC and dC than AP. Global DNA methylation levels in adenocarcinoma and squamous cell carcinoma patients were similar in the range of 3.16-4.01 %. Global DNA methylation levels were not affected by smoking and gender and were not correlated with N7-meG or 8-oxodG in lung cancer patients. Levels of O (6)-meG and N3-meA were however found to be undetectable in all lung tissue samples.

Objective: To study the association between DNA double-strand break repair gene NBS1 (nijmegen breakage syndrome gene) polymorphisms and the susceptibility to lung cancer., Methods: A case-control study design was applied. PCR-RFLP was used to identify NBS1 polymorphisms among 575 lung cancer cases and 575 controls., Results: The frequencies of C/C, C/G and G/G genotypes at NBS1 rs1805794 site were 25.9%, 51.8%, 22.3% among controls compared to 20.5%, 52.3%, 27.1% among cases. There was significant difference between controls and cases (χ(2) = 6.38, P = 0.04). Individuals carrying C/G + G/G genotypes had an increased risk for lung cancer (OR = 1.46, 95%CI: 1.09 - 1.97) compared to the C/C genotype. The frequencies of G/G, G/C and C/C genotypes at NBS1 rs2735383 site were 37.9%, 47.0%, 15.1% among controls compared to 35.5%, 48.5%, 16.0% among cases, with no significant difference between the two groups (χ(2) = 0.75, P = 0.69). Individuals carrying Hap4-GC haplotype (OR = 1.70, 95%CI: 1.24 - 2.31) and Hap4/Hap2 dihaplotype (OR = 1.75, 95%CI: 1.11 - 2.76) had an increased risk on lung cancer. Joint associations of smoking and the NBS1 polymorphism with the risk of lung cancer were observed (P < 0.05)., Conclusion: The G/G genotype at NBS1 rs1805794 site and the Hap4-GC haplotype and Hap4/Hap2 di haplotype from rs1805794 and rs2735383 were both associated with lung cancer.

Leiomyosarcoma is a malignant tumor of the smooth muscle that rarely occurs in the gastrointestinal tract. High-grade leiomyosarcomas of the rectosigmoid usually metastasize to the liver and lungs. Although it is unusual, metastases to the heart have been reported. When this occurs, the metastatic tumor usually seeds in the right atrium and pulmonary artery. We report on and discuss a patient who had atrial fibrillation, peripheral emboli, and thrombocytopenia resulting from a low-grade rectosigmoid leiomyosarcoma metastatic to the pulmonary vein and left atrium. Atrial fibrillation is not a common manifestation of malignant neoplasms that have spread to the heart. Surgical removal of the tumor terminated the arrhythmia and thrombocytopenia.

A study was done to examine whether workers exposed to titanium tetrachloride had significantly higher risks of lung cancer, chronic respiratory disease, pleural thickening/plaques, or pulmonary fibrosis than referent groups. A total of 2477 employees from two titanium dioxide plants were studied. Of that group, 969 employees exposed to titanium tetrachloride were observed from 1956 through 1985 for cancer and chronic respiratory disease incidence and from 1935 through 1983 for mortality. A cross-sectional sample of 398 employees was evaluated for chest roentgenogram abnormalities. Cohort analyses showed that the risk of developing lung cancer and other fatal respiratory diseases was not statistically significantly higher for the titanium tetrachloride-exposed workers than for the referent group. Nested case-control analyses found no statistically significant association between titanium tetrachloride exposure and risk of lung cancer, chronic respiratory disease, and chest roentgenogram abnormalities. No cases of pulmonary fibrosis were observed among titanium tetrachloride-exposed employees. Smoking was found to be a strong predictor of lung cancer mortality in the nonexposed employees with an increased risk of dying from lung cancer up to 7-fold higher in current smokers than in nonsmokers.

The authors retrospectively reviewed data regarding 14 patients with sarcomatoid carcinomas of the lung seen and treated at M.D. Anderson Cancer Center from 1955 to 1986. The following were the histologic criteria for inclusion in the study: (1) the concurrent presence of malignant epithelial and sarcomatoid spindle cell components, and (2) positive immunoreactivity for antikeratin antibody or ultrastructural demonstration of epithelial differentiation in sarcomatoid tumors in which the epithelial component was inconspicuous. For the sarcomatoid components, the most frequent pattern was malignant fibrous histiocytoma, which was present in ten tumors. An unclassified sarcomatoid pattern was found in two cases and a fibrosarcomatous pattern in two remaining cases. Clinically, the median patient age was 59 years; 12 patients were male and 2 were female; 13 were smokers and 1 used snuff. Three patients had Stage I, ten had Stage III, and one had Stage IV disease. One patient with Stage I, seven with Stage III, and one with Stage IV disease died of their carcinomas 2 to 26 months after diagnosis (median survival time 12 months). All patients who had lymph node metastases at presentation died of disease. The authors concluded the following: (1) patients with sarcomatoid carcinoma of the lung usually presented at an advanced stage; (2) lymph node metastasis, as with a usual carcinoma of the lung, is an important prognostic factor; and (3) for all lung tumors with a sarcomatoid pattern, especially a malignant fibrous histiocytoma pattern, extensive samples should be obtained and immunoperoxidase or ultrastructural studies done to identify epithelial differentiation.

The objective of this study was to determine whether workers exposed to titanium dioxide (TiO2) had significantly higher risks of lung cancer, chronic respiratory disease, pleural thickening/plaques, or pulmonary fibrosis than referent groups. A total of 1,576 employees exposed to TiO2 were observed from 1956 through 1985 for cancer and chronic respiratory disease incidence, and from 1935 through 1983 for mortality. A cross-sectional sample of 398 employees was evaluated for chest roentgenogram abnormalities. Cohort analyses suggested that the risks of developing lung cancer and other fatal respiratory diseases were no higher for TiO2-exposed employees than for the referent groups. Nested case-control analyses found no statistically significant associations between TiO2 exposure and risk of lung cancer, chronic respiratory disease, and chest roentgenogram abnormalities. No cases of pulmonary fibrosis were observed among TiO2-exposed employees.