[Tumor-associated Macrophage: 
Emerging Targets for Modulating the Tumor Microenvironment].

Tumor-associated macrophage (TAM) play a crucial role in the immune microenvironment of lung cancer. Through changes in their phenotype and phagocytic functions, TAM contribute to the initiation and progression of lung cancer. By promoting the formation of an immune-suppressive microenvironment and accelerating the growth of abnormal tumor vasculature, TAM facilitate the invasion and metastasis of lung cancer. Macrophages can polarize into different subtypes with distinct functions and characteristics in response to various stimuli, categorized as anti-tumor M1 and pro-tumor M2 types. In tumor tissues, TAM typically polarize into the alternatively activated M2 phenotype, exhibiting inhibitory effects on tumor immunity. This article reviews the role of anti-angiogenic drugs in modulating TAM phenotypes, highlighting their potential to reprogram M2-type TAM into an anti-tumor M1 phenotype. Additionally, the functional alterations of TAM play a significant role in anti-angiogenic therapy and immunotherapy strategies. In summary, the regulation of TAM polarization and function opens up new avenues for lung cancer treatment and may serve as a novel target for modulating the immune microenvironment of tumors.
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Polyhexamethylene guanidine accelerates the macrophage foamy formation mediated pulmonary fibrosis.

Polyhexamethylene guanidine (PHMG) is manufactured and applied extensively due to its superior disinfectant capabilities. However, the inhalatory exposure to PHMG aerosols is increasingly recognized as a potential instigator of pulmonary fibrosis, prompting an urgent call for elucidation of the underlying pathophysiological mechanisms. Within this context, alveolar macrophages play a pivotal role in the primary immune defense in the respiratory tract. Dysregulated lipid metabolism within alveolar macrophages leads to the accumulation of foam cells, a process that is intimately linked with the pathogenesis of pulmonary fibrosis. Therefore, this study examines PHMG's effects on alveolar macrophage foaminess and its underlying mechanisms. We conducted a 3-week inhalation exposure followed by a 3-week recovery period in C57BL/6 J mice using a whole-body exposure system equipped with a disinfection aerosol generator (WESDAG). The presence of lipid-laden alveolar macrophages and downregulation of pulmonary tissue lipid transport proteins ABCA1 and ABCG1 were observed in mice. In cell culture models involving lipid-loaded macrophages, we demonstrated that PHMG promotes foam cell formation by inhibiting lipid efflux in mouse alveolar macrophages. Furthermore, PHMG-induced foam cells were found to promote an increase in the release of TGF-ß1, fibronectin deposition, and collagen remodeling. In vivo interventions were subsequently implemented on mice exposed to PHMG aerosols, aiming to restore macrophage lipid efflux function. Remarkably, this intervention demonstrated the potential to retard the progression of pulmonary fibrosis. In conclusion, this study underscores the pivotal role of macrophage foaming in the pathogenesis of PHMG disinfectants-induced pulmonary fibrosis. Moreover, it provides compelling evidence to suggest that the regulation of macrophage efflux function holds promise for mitigating the progression of pulmonary fibrosis, thereby offering novel insights into the mechanisms underlying inhaled PHMG disinfectants-induced pulmonary fibrosis.

Prognostic implications of neutrophil-to-lymphocyte ratio in patients with extensive-stage small cell lung cancer receiving chemoimmunotherapy: A multicenter, real-world study.

BACKGROUND: Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are closely related to the prognosis of patients with non-small cell lung cancer, but their effect on extensive-stage small cell lung cancer (ES-SCLC) remains uncertain. METHODS: This retrospective study was conducted in ES-SCLC patients treated with first-line atezolizumab or durvalumab and platinum-etoposide. Clinical data from three hospitals were analyzed. Significant risk factors for survival were identified using descriptive statistics and Cox regression. Homogeneity was assessed using t-tests or nonparametric tests. Kaplan-Meier analysis revealed an association between high NLR level and median PFS and OS. RESULTS: A total of 300 ES-SCLC patients were included in the study. Cox regression analysis revealed that an elevated NLR level after the second treatment cycle (defined as NLRT2) was an independent prognostic factor for survival. Stratifying patients based on median NLRT2 showed significant differences in both PFS (HR: 1.863, 95% CI: 1.62-2.12, p < 0.001) and OS (HR: 2.581, 95% CI: 2.19-3.04, p < 0.001) between NLR ≥ 1.75 and NLR < 1.75 groups. mPFS and mOS were 8.2 versus 6.1 months and 13.7 versus 9.5 months, respectively. NLR was also associated with treatment efficacy and occurrence of irAEs. Further stratification based on NLR and irAEs showed that in the NLR < 1.75 group, patients with irAEs had prolonged mPFS and mOS. In the NLR ≥ 1.75 group, only mPFS showed a significant difference between patients with and without irAEs. CONCLUSION: NLRT2 and irAEs can predict the prognosis of ES-SCLC patients with first-line ES-SCLC receiving PD-L1 inhibitors combined with chemotherapy.

A rare case of pulmonary artery embolism with choriocarcinoma: A case report and literature review.

Pulmonary embolism (PE) caused by malignant tumor is not uncommon, but pulmonary artery with choriocarcinoma is rare and difficult to timely diagnose and effectively treat. To the best of our knowledge, there are only 15 cases reported at present in the literature that present variable clinical characteristics and prognosis. In the current study reports a 21-year-old female with a history of chest pain and slight fever for 4 months who was treated as a case of pneumonia. Owing to the recurrence of the symptoms, a contrast-enhanced chest computer tomography scan was performed on the patient, which revealed complete occlusion of the right pulmonary artery. The patient was diagnosed to have pulmonary embolism (PE). However, no abnormalities were observed in D-dimer value, tumor antigen testing or ultrasonography. Positron emission tomography/computed tomography (PET/CT) was performed, which revealed the abnormal hypermetabolic lesion of the right pulmonary artery. Following the laboratory report of a significantly elevated human chorionic gonadotropin ß-subunit level combined with characteristic appearance of PET-CT, the diagnosis of primary pulmonary artery with choriocarcinoma was established based on guidelines of the European Society for Medical Oncology and the criteria formulated by the International Federation of Gynecology and Obstetrics. The patient underwent chemotherapy and responded well to the treatment. Although rare, choriocarcinoma should be considered for any fertile women who presents with a massive PE. These findings emphasize the importance of the early diagnosis and treatment of this disease.

A predictive role of C-reactive protein in colorectal cancer risk: an updated meta-analysis from 780,985 participants and 11,289 cancer cases.

PURPOSE: This meta-analysis is aimed at understanding the potential role of circulating C-reactive protein (CRP) in the prediction of colorectal cancer (CRC) risk and the potential effect of relevant variables, with specific concern to determine the incorporation of CRP into a CRC risk prediction model. METHODS: Relevant articles on the association between circulating CRP and CRC risk were searched from PubMed, Embase, Web of Science, and Cochrane Database of Systematic Reviews through August 2022. Random-effects models were used to estimate the pooled relative risk (RR) for the highest versus lowest CRP categories. Linear and non-linear trend analyses were conducted to explore the dose-response associations between CRP and CRC risk. RESULTS: Twenty-three articles including 780,985 participants and 11,289 cancer cases met the selection criteria. The overall result demonstrated a remarkable association between elevated CRP levels and CRC risk (RR, 1.259; 95% CI, 1.060-1.457), but not in dose-response analysis (RR, 1.002 (95% CI, 0.964-1.041) per natural log unit change in CRP). Subgroup analyses indicated a significant difference when grouped by study location, the length of follow-up, and gender composition. No evidence of publication bias was observed. CONCLUSION: The predictive role of CRP in CRC incidence is limited to colon cancer and a period of 10 years after the initial discovery of CRP elevation. The result did not support the etiological role of CRP in CRC and the inclusion of CRP into the CRC risk prediction model.

[Research Progress of Immune Checkpoint TIGIT in Lung Cancer Immunotherapy].

T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibition motif domain (TIGIT) is a newly discovered immune checkpoint molecule, mainly expressed on the surface of T cells and natural killer (NK) cells. By binding to cluster of differentiation 155 (CD155) and other ligands, it inhibits T cell and NK cell-mediated immune responses and affects the tumor microenvironment. Multiple preclinical studies have demonstrated that the TIGIT/CD155 pathway plays a role in a variety of solid and hematological tumors. Clinical trials investigating TIGIT inhibitors alone or in combination with programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitors for lung cancer are currently underway.
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[Two Cases of TKI-resistant Small Cell Lung Cancer Transformation 
in Advanced Adenocarcinoma and Literature Review].

Treatment of advanced non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutation with EGFR-tyrosine kinase inhibitors (EGFR-TKIs) can achieve good disease control, but it will inevitably produce drug resistance. About 3%-10% of the resistance mechanism is small cell transformation. Two cases of stage IV lung adenocarcinoma with EGFR mutation were reported and the disease was controlled after EGFR-TKIs treatment. In case 1, progression-free survival (PFS) before small cell carcinoma transformation was 16 months, and in case 2, PFS before small cell carcinoma transformation was 24 months. Subsequent biopsy after disease progression indicated a shift to small cell lung cancer. Case 1 PFS after small cell carcinoma transformation was 6 months, and case 2 PFS after small cell carcinoma transformation was 8 months, and overall survival (OS) was 36 months, which significantly prolonged the patient's survival. At the same time, the literature of such drug resistance mutations was reviewed. For patients with advanced NSCLC with sensitive mutations, it is necessary to conduct secondary histopathological tests after TKIs treatment resistance, and select subsequent treatment according to different resistance mechanisms for the whole course of disease management.
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Chronic carbon black nanoparticles exposure increases lung cancer risk by affecting the cell cycle via circulatory inflammation.

As a widely used pure elemental carbon in colloidal particles, carbon black was listed as a group 2B carcinogen by IARC in 2010. The most available mechanism information about carbon black and carcinogenesis are from in vivo or in vitro studies. However, few studies concerned the nanoparticle's real-ambient exposure causing systemic change and further affecting the target organ. Herein, we used an ex vivo biosensor assay to investigate the transcriptome change of primary bronchial epithelial cells after treatment with the plasma from workers with long-term occupational carbon black exposure history. Based on ex vivo biosensor assay and transcriptome sequencing, we found the effect of internal systemic environment on epithelial cells after carbon black exposure was an inflammatory response, which mainly activates cell cycle-related pathways. After exposure to carbon black, the internal systemic environment could activate cancer-related pathways like epithelial-mesenchymal transition, hypoxia, TNF-α signaling via NF-κB. The hub genes in the carbon black group (CDC20 and PLK1) and their correlation with the systemic environment were uncovered by constructing the protein-protein interaction network. Inflammatory cytokines, especially CRP, were strongly correlated with the expression of CDC20 and PLK1. Besides, we also find a strong correlation between CDC20 and cytokinesis-block micronucleus endpoints in peripheral blood (rho = 0.591, P < 0.001). Our results show that long-term carbon black exposure might activate cell cycle-related pathways through circulating inflammation and increase the risk of cancer, while the oxidative stress caused by diesel exhaust particles are mainly related to PAHs exposure. After exposure to carbon black, the systemic environment could activate cancer-related pathways like diesel exhaust particles, increasing the risk of lung cancer. These attempts might provide a further understanding of the indirect effect of chronic occupational inhaled carbon black exposure on pulmonary carcinogenesis.

Niclosamide Ethanolamine Salt Alleviates Idiopathic Pulmonary Fibrosis by Modulating the PI3K-mTORC1 Pathway.

Idiopathic pulmonary fibrosis (IPF) is an interstitial pneumonia characterized by chronic progressive fibrosis, ultimately leading to respiratory failure and early mortality. Although not fully explored, the major causative factors in IPF pathogenesis are dysregulated fibroblast proliferation and excessive accumulation of extracellular matrix (ECM) deposited by myofibroblasts differentiated from pulmonary fibroblasts. More signalling pathways, including the PI3K-Akt-mTOR and autophagy pathways, are involved in IPF pathogenesis. Niclosamide ethanolamine salt (NEN) is a highly effective multitarget small-molecule inhibitor reported in antitumor studies. Here, we reported that in an IPF animal model treated with NEN for 14 days, attractive relief of pulmonary function and hydroxyproline content were observed. To further explore, the therapeutic effect of NEN in IPF and pathological changes in bleomycin-challenged mouse lung sections were assessed. Additionally, the effects of NEN on abnormal proliferation and ECM production in IPF cell models established with TGF-ß1-stimulated A549 cells or DHLF-IPF cells were studied. In nonclinical studies, NEN ameliorated lung function and histopathological changes in bleomycin-challenged mice, and the lung hydroxyproline content was significantly diminished with NEN treatment. In vitro, NEN inhibited PI3K-mTORC1 signalling and arrested the cell cycle to prevent uncontrolled fibroblast proliferation. Additionally, NEN inhibited TGF-ß1-induced epithelial-mesenchymal transition (EMT) and ECM accumulation via the mTORC1-4EBP1 axis. Furthermore, NEN-activated noncanonical autophagy resensitized fibroblasts to apoptosis. The above findings demonstrated the potential antifibrotic effect of NEN mediated via modulation of the PI3K-mTORC1 and autophagy pathways. These data provide strong evidence for a therapeutic role for NEN in IPF.

Immune checkpoint inhibitor-induced myocarditis in lung cancer patients: a case report of sintilimab-induced myocarditis and a review of the literature.

Since its initial approval by the United States Food and Drug Administration (FDA) in 2014, the indications for the use of the immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC) patients has increased. However, to date, there has no report on immune myocarditis caused by the ICI sintilimab. In addition, there has been no literature review on ICI-induced myocarditis in lung cancer patients. This is a case report of an elderly male patient who presented with a productive cough and progressive dysphagia for 3 days. The symptoms started on day 6 after the third cycle of sintilimab treatment for his lung carcinoma. In accordance with his clinical manifestations of progressive dysphagia, a previous history of lung cancer, abnormal electrocardiograph, significantly increased serum myocardial enzyme levels, and normal coronary angiography results, sintilimab-induced myocarditis was diagnosed. Methylprednisolone (80-40 mg) was used to inhibit the immune injury and the patient was safely discharged on the 13th day following admission. Since ICI-induced myocarditis is rare and fatal, we summarized the characteristics of 20 cases of the disease in lung cancer patients to highlight to oncologists, respiratory experts, and cardiologists the serious side effects of the drug when they encounter lung cancer patients using ICIs. Like most ICIs, sintilimab induces severe immune myocarditis and requires corticosteroids therapy, and this should be recognized by doctors in multiple departments.

Lung squamous cell carcinoma with rare epidermal growth factor receptor mutation G719X: a case report and literature review.

Asians who develop non-small cell lung cancer (NSCLC) have a chance of approximately 50% of harboring the epidermal growth factor receptor (EGFR) mutation. The G719X mutation in EGFR has 3 subtypes (i.e., G719A, G719C, or G719S), all of them being classified as uncommon EGFR mutations. The EGFR mutation G719X is most often associated with lung adenocarcinoma. Conversely, its occurrence in lung squamous cell carcinoma is rare. Its response to tyrosine kinase inhibitor (TKI) treatment remains unknown. A 50-year-old Asian male with no smoking history was admitted to our hospital (Affiliated Hospital of Qingdao University) with an irritating dry cough and 1 month of progressive dyspnea. The patient was diagnosed with lung squamous cell carcinoma (cT4N3M0, stage IIIC). Lung biopsy revealed the presence of EFGR G719X mutation. The patient received a tracheobronchial stent, targeted therapy, chemotherapy, seed implantation and radiotherapy, and survived for 25.4 months following diagnosis. It is crucial that gene mutation analysis is performed in non-smoking male squamous cell carcinoma patients. Compared to lung adenocarcinoma patients with rare G719X mutation, this lung squamous cell carcinoma patient with G719X-mutant tumor had a higher sensitivity to 2nd-generation EGFR-TKI treatment, but similar progression-free survival. Importantly, the patient clearly benefited from the used comprehensive treatment plan. This article seeks to shed light on the treatment of lung squamous cell carcinoma patients with the uncommon EGFR G719X mutation.

TGFß/Smad mediated the polyhexamethyleneguanide areosol-induced irreversible pulmonary fibrosis in subchronic inhalation exposure.

AIM: Polyhexamethylene guanidine (PHMG) is widely used as a disinfectant with broad spectra of bactericidal activity and low oral toxicity. However, inhalation of PHMG can cause pulmonary injury and severe pulmonary fibrosis. The mechanism underlying PHMG aerosol induced pulmonary fibrosis remains unclear. In this study, we aimed to examine the subchronic lung injury and determine potential cytokines involved in PHMG aerosol induced fibrosis. METHODS: C57BL/6N mice were exposed to 1.03 mg/m3 PHMG through aerosol inhalation for 3 weeks, or 3 weeks followed by other 3 weeks recovery. RESULTS: The results indicated that the expression of transforming growth factor-beta1 (TGF-ß1) and extracellular matrix remodeling markers were up-regulated in the PHMG-treated mice and these parameters were aggravated after 3 weeks recovery. Bronchoalveolar lavage fluids (BALFs) analysis showed that the number of total cells was significantly decreased in exposure group. The percentage of macrophages in BALFs decreased significantly whereas the percentage of neutrophils and lymphocytes increased. Extensive collagen deposition was observed in the peribronchiolar and interstitial areas in the PHMG exposed lungs. CONCLUSION: In conclusion, even low-does PHMG aerosol exposure could induce mice pulmonary local inflammation and irreversible fibrosis. In addition, TGF-ß/Smad signaling pathway mediated the extracellular matrix remodeling involved in the development of pulmonary fibrosis.

[Advances in Exosomes in the Pathogenesis and Diagnosis of Lung Cancer].

The incidence of lung cancer is high worldwide, and lung cancer is the leading cause of death from malignant tumors in both men and women. Early diagnosis of lung cancer can significantly improve the patient's prognosis. Therefore, searching for specific markers to assist in the early diagnosis of lung cancer is urgent question. Exosomes are nano-sized microvesicles and contain various biomaterial, including nucleic acids, proteins, and lipids. Exosomes are important carriers of these biomaterial, serve important roles in intracellular communications and signal transduction among tissues. Due to its unique enrichment mechanism, it has the stability and specificity as a biomarker. Exosomes are not only involved in the formation of tumor microenvironment and new blood vessels in lung cancer, but also involved in chemotherapy, targeted therapy response and prognosis assessment. Many research advances bring new hope for prolonging the survival of lung cancer patients. This article reviews the value of exosome specific protein and microRNA (miRNA) in lung cancer in the diagnosis and prognosis of lung cancer.

Association between air pollution and lung development in schoolchildren in China.

BACKGROUND: China has been facing nationwide air pollution at unprecedented high levels primarily from fossil-fuel combustion in the past decade. However, few studies have been conducted on the adverse effect of severe air pollution on lung development in school-age children. METHODS: Using wellness check and air pollution data from 2014 to 2017, we conducted a retrospective analysis of lung development in 21 616 school-age children from Shijiazhuang and Qingdao from North China with severe vs mild air pollution. Linear mixed effects model was performed to assess the effect of air pollution on forced vital capacity (FVC) growth. RESULTS: Exposure to severe air pollution was associated with a dramatic reduction in annual FVC growth rate (-71.3 mL,  p< 0.001). In addition, every 10 µg/m3 increase in annual PM2.5 level was associated with a reduction of annual FVC growth by 12.2 mL ( p< 0.001). Sex discrepancy (boys vs girls) in FVC growth was greater in Qingdao (35.4 mL/year, 95% CI: 26.0 to 44.7) than in Shijiazhuang (19.8 mL/year, 95% CI: 9.3 to 30.3) (p for interaction=0.063). Exposure to indoor coal- or wood-burning stove heating (-79.4 mL,  p< 0.001) and secondhand smoke at home (-59.3 mL,  p= 0.003) were inversely associated with FVC growth. CONCLUSION: Our study raised serious alarm over the threat of severe air pollution to lung development in school-age children. Sex discrepancy in lung development was reduced dramatically in heavily polluted area.

Clinical characteristics of patients with ROS1 gene rearrangement in non-small cell lung cancer: a meta-analysis.

BACKGROUND: ROS1 gene rearrangement has been reported in several types of cancers, including non-small cell lung cancer (NSCLC). It is reported that tyrosine kinase inhibitors are effective in the treatment of ROS1-rearranged NSCLC. Therefore, the identification of ROS1 rearrangement can be used as potential therapeutic target in lung cancer. Epidemiological data indicates that ROS1 gene rearrangement occurs in approximately 1-2% of NSCLC patients. The small sample sizes of the existing associated studies only represent the characteristics of patients in specific regions or countries, and there is still no latest statistical analysis on ROS1 gene rearrangement anywhere in the world. METHODS: We conducted a systematic search of the PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), CBM, CNKI, Wanfang, and VIP databases to identify studies on ROS1 gene rearrangement in NSCLC patients from January 1, 2015 to October 27, 2019. We conducted a meta-analysis to investigate the relationship between ROS1 gene rearrangement and clinical characteristics of NSCLC patients. The four clinical features are as follows: gender, smoking status, pathological type, and lung cancer stage. RESULTS: Thirty-nine studies constituting of 25,055 NSCLC patients were eligible for inclusion in this meta-analysis. A prominently higher rate of ROS1 gene rearrangement was observed in female NSCLC patients (OR =1.94, 95% CI: 1.62-2.32%, P<0.05), patients with no smoking history (OR =2.82, 95% CI: 2.24-3.55%, P<0.05), patients with adenocarcinoma (OR =1.55, 95% CI: 1.14-2.11%, P<0.05), and patients with stage III-IV disease (OR =1.50, 95% CI: 1.15-1.94%, P<0.05). Our meta-analysis also showed that the prevalence of ROS1 rearrangement in adenocarcinoma was 2.49% (95% CI: 1.92-3.11%), while it was lower in non-adenocarcinoma patients (1.37%). CONCLUSIONS: ROS1 gene rearrangement was more predominant in female patients, patients without smoking history, patients with adenocarcinoma and patients with advanced-stage disease (stages III to IV).

[Clinical Features of EGFR Double Mutation in Non-small Cell Lung Cancer].

BACKGROUND: The clinical features of patients with common single-mutation of epidermal growth factor receptor (EGFR) in non-small cell lung cancer (NSCLC) has been well characterized. There is a high adenocarcinoma incidence rate among female patients with none or shorter smoking history. Those patients have higher objective response rate (ORR) and progression free survival (PFS) treated with EGFR tyrosine kinase inhibitors (EGFR-TKIs). However, it is still unclear that the clinical features of patients with EGFR double mutation and the sensitivity towards EGFR-TKIs treatment. METHODS: We performed a retrospective cohort study of 1,238 primary NSCLC patients who had EGFR gene testing in Affiliated Hospital of Qingdao University from January 1, 2015 to December 31, 2016 and identified 603 patients with single mutation and 59 patients with double mutation. All genes were uniformly detected by using ARMS-PCR technology. We analyze the gene of 32 double-mutant patients with specific genotyping, and randomly selected 60 patients with single mutation and compared the clinical features with 59 patients with double mutation. Furthermore, we examined the efficacy of EGFR-TKIs treatment in lung cancer patients with double mutation and single mutation in EGFR. RESULTS: The rare single mutation gene is the most common in patients with double mutation of EGFR. There is no significant statistical difference in gender, smoking history, age, pathological type or tumor-node-metastasis (TNM) staging among patients with single and double EGFR mutantion. In the double mutation patients treated with EGFR-TKIs, the objective response rate was 36.80%, the disease control rate was 68.40%. The objective response rate was 60.00% and the disease control rate was 90.00% in the patients with single mutation. However, overall PFS was significantly higher in EGFR single mutation patients (P=0.003), with median PFS of 12.0 months compared with 6.0 months in EGFR double mutation patients. CONCLUSIONS: There was no significant difference between the clinical features of patients with EGFR double mutation and single mutation. Patients with EGFR double mutation is associated with poor survival underwent the first generation of EGFR-TKIs treatment compared with patients with a single mutation.

Associations between abnormal vitamin D metabolism pathway function and non-small cell lung cancer.

Lung cancer is a type of malignant tumor derived from the respiratory system, which is the leading cause of cancer-associated mortality worldwide, of which ~80% of cases are attributable to non-small cell lung cancer (NSCLC). A previous study demonstrated that 1α,25-Dihydroxyvitamin D3 (1α,25(OH)2D3), derived from the vitamin D metabolic pathway contributes an antitumor effect. Aberrant expression of the essential enzyme encoding genes, Cytochrome P450 Family 27 Subfamily A Member 1 (CYP27A1), Cytochrome P450 Family 27 Subfamily B Member 1 (CYP27B1), and Cytochrome P450 Family 24 Subfamily A Member 1 (CYP24A1) may be associated with lung cancer. However, a lack of evidence exists concerning the association between CYP27A1, CYP27B1, CYP24A1 expression and NSCLC. The aim of the present study was to investigate the functions of CYP27A1, CYP27B1 and CYP24A1 expression in NSCLC. Lung cancer tissue and para-carcinoma control tissue were collected from patients with NSCLC. Reverse transcription-quantitative polymerase chain reaction was applied to analyze CYP27A1, CYP27B1 and CYP24A1 mRNA expression in lung cancer tissues. An association analysis was performed between the aforementioned metabolic enzymes and patients with NSCLC age, gender, tumor node metastasis (TNM) stage, pathological type, differentiation and prognosis. CYP27B1 and CYP24A1 mRNA were upregulated in NSCLC compared with controls (P<0.05). However, no significant differences in CYP27A1 expression were observed between NSCLC and control. In addition, CYP24A1 expression was not associated with age, sex, smoking or TNM stage, but was associated with pathological type, differentiation and prognosis (P<0.05). CYP27B1 expression was significantly associated with TNM stage, differentiation, and prognosis, but not age, sex, smoking or pathological type. In conclusion, CYP27B1 and CYP24A1 may be considered as independent prognostic factors of NSCLC and may be novel therapeutic targets to assist clinical diagnosis, treatment and prognosis of the disease.

Immunomodulation by mesenchymal stem cells in treating human autoimmune disease-associated lung fibrosis.

BACKGROUND: Interstitial pneumonia in connective tissue diseases (CTD-IP) featuring inflammation and fibrosis is a leading cause of death in CTD-IP patients. The related autoimmune lung injury and disturbed self-healing process make conventional anti-inflammatory drugs ineffective. Equipped with unique immunoregulatory and regenerative properties, mesenchymal stem cells (MSCs) may represent a promising therapeutic agent in CTD-IP. In this study, we aim to define the immunopathology involved in pulmonary exacerbation during autoimmunity and to determine the potential of MSCs in correcting these disorders. METHODS: Lung and blood specimens, bronchoalveolar lavage fluid cells collected from CTD-IP patients, and human primary lung fibroblasts (HLFs) from patients pathologically diagnosed with usual interstitial pneumonia (UIP) and healthy controls were analyzed by histology, flow cytometry and molecular biology. T cell subsets involved in the process of CTD-IP were defined, while the regulatory functions of MSCs isolated from the bone marrow of normal individuals (HBMSCs) on cytotoxic T cells and CTD-UIP HLFs were investigated in vitro. RESULTS: Higher frequencies of cytotoxic T cells were observed in the lung and peripheral blood of CTD-IP patients, accompanied with a reduced regulatory T cell (Treg) level. CTD-UIP HLFs secreted proinflammatory cytokines in combination with upregulation of α-smooth muscle actin (α-SMA). The addition of HBMSCs in vitro increased Tregs concomitant with reduced cytotoxic T cells in an experimental cell model with dominant cytotoxic T cells, and promoted Tregs expansion in T cell subsets from patients with idiopathic pulmonary fibrosis (IPF). HBMSCs also significantly decreased proinflammatory chemokine/cytokine expression, and blocked α-SMA activation in CTD-UIP HLFs through a TGF-ß1-mediated mechanism, which modulates excessive IL-6/STAT3 signaling leading to IP-10 expression. MSCs secreting a higher level of TGF-ß1 appear to have an optimal anti-fibrotic efficacy in BLM-induced pulmonary fibrosis in mice. CONCLUSIONS: Impairment of TGF-ß signal transduction relevant to a persistent IL-6/STAT3 transcriptional activation contributes to reduction of Treg differentiation in CTD-IP and to myofibroblast differentiation in CTD-UIP HLFs. HBMSCs can sensitize TGF-ß1 downstream signal transduction that regulates IL-6/STAT3 activation, thereby stimulating Treg expansion and facilitating anti-fibrotic IP-10 production. This may in turn block progression of lung fibrosis in autoimmunity.

Aptamer-Dendrimer Bioconjugates for Targeted Delivery of miR-34a Expressing Plasmid and Antitumor Effects in Non-Small Cell Lung Cancer Cells.

Metastasis and drug resistance are major barriers for the treatment of non-small cell lung cancer (NSCLC). To explore new therapeutic options, we successfully encapsulated MicroRNA-34a (miR-34a), a potent endogenous tumor suppressor in NSCLC into S6 aptamer-conjugated dendrimer to form lung cancer-targeted gene delivery nanoparticles (PAM-Ap/pMiR-34a NPs). PAM-Ap/pMiR-34a NPs had a diameter of 100-200 nm and Zeta potential of ~30 mV at applied N/P ratio. The aptamer conjugation significantly improved cellular uptake as well as gene transfection efficiency of PAM-Ap/pMiR-34a NPs in cultured NSCLC cells. We showed that PAM-Ap/pMiR-34a NPs enhanced the regulation of targeted genes, BCL-2 and p53 in vitro. In addition, we revealed PAM-Ap/pMiR-34a NPs significantly inhibited cell growth, migration, invasion and induced apoptosis of lung cancer cells compared with non-targeted NPs. The method provided a novel therapeutic strategy for the experimental treatment of NSCLC.

Stem Cell and Idiopathic Pulmonary Fibrosis: Mechanisms and Treatment.

Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal lung disease resulting from multiplex causes. Evidence indicates that stem/progenitor cells might play a key role in IPF pathogenesis and repair, which may provide some novel potential strategies for the future treatment of IPF. In this review, we first summarize the current understanding of the relationship between stem cells and IPF and then review the advancements made in recent clinical trials using stem/progenitor cells, especially mesenchymal stem cells, in treating IPF and their interpretations.