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1.
BMC Pulm Med ; 24(1): 187, 2024 Apr 18.
Article in English | MEDLINE | ID: mdl-38637771

ABSTRACT

BACKGROUND: Coronavirus disease 2019 (COVID-19) has had a global social and economic impact. An easy assessment procedure to handily identify the mortality risk of inpatients is urgently needed in clinical practice. Therefore, the aim of this study was to develop a simple nomogram model to categorize patients who might have a poor short-term outcome. METHODS: A retrospective cohort study of 189 COVID-19 patients was performed at Shanghai Ren Ji Hospital from December 12, 2022 to February 28, 2023. Chest radiography and biomarkers, including KL-6 were assessed. Risk factors of 28-day mortality were selected by a Cox regression model. A nomogram was developed based on selected variables by SMOTE strategy. The predictive performance of the derived nomogram was evaluated by calibration curve. RESULTS: In total, 173 patients were enrolled in this study. The 28-day mortality event occurred in 41 inpatients (23.7%). Serum KL-6 and radiological severity grade (RSG) were selected as the final risk factors. A nomogram model was developed based on KL-6 and RSG. The calibration curve suggested that the nomogram model might have potential clinical value. The AUCs for serum KL-6, RSG, and the combined score in the development group and validation group were 0.885 (95% CI: 0.804-0.952), 0.818 (95% CI: 0.711-0.899), 0.868 (95% CI: 0.776-0.942) and 0.932 (95% CI: 0.862-0.997), respectively. CONCLUSIONS: Our results suggested that the nomogram based on KL-6 and RSG might be a potential method for evaluating 28-day mortality in COVID-19 patients. A high combined score might indicate a poor outcome in COVID-19 patients with pneumonia.


Subject(s)
COVID-19 , Humans , Retrospective Studies , SARS-CoV-2 , China/epidemiology , Radiography
2.
Signal Transduct Target Ther ; 8(1): 185, 2023 05 15.
Article in English | MEDLINE | ID: mdl-37183231

ABSTRACT

Genomic MET amplification and exon 14 skipping are currently clinically recognized biomarkers for stratifying subsets of non-small cell lung cancer (NSCLC) patients according to the predicted response to c-Met inhibitors (c-Metis), yet the overall clinical benefit of this strategy is quite limited. Notably, c-Met protein overexpression, which occurs in approximately 20-25% of NSCLC patients, has not yet been clearly defined as a clinically useful biomarker. An optimized strategy for accurately classifying patients with c-Met overexpression for decision-making regarding c-Meti treatment is lacking. Herein, we found that SYK regulates the plasticity of cells in an epithelial state and is associated with their sensitivity to c-Metis both in vitro and in vivo in PDX models with c-Met overexpression regardless of MET gene status. Furthermore, TGF-ß1 treatment resulted in SYK transcriptional downregulation, increased Sp1-mediated transcription of FRA1, and restored the mesenchymal state, which conferred resistance to c-Metis. Clinically, a subpopulation of NSCLC patients with c-Met overexpression coupled with SYK overexpression exhibited a high response rate of 73.3% and longer progression-free survival with c-Meti treatment than other patients. SYK negativity coupled with TGF-ß1 positivity conferred de novo and acquired resistance. In summary, SYK regulates cell plasticity toward a therapy-sensitive epithelial cell state. Furthermore, our findings showed that SYK overexpression can aid in precisely stratifying NSCLC patients with c-Met overexpression regardless of MET alterations and expand the population predicted to benefit from c-Met-targeted therapy.


Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/metabolism , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/metabolism , Transforming Growth Factor beta1 , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Epithelial Cells/metabolism , Syk Kinase/genetics
3.
Cell Cycle ; 22(7): 841-857, 2023 04.
Article in English | MEDLINE | ID: mdl-36536539

ABSTRACT

Rab-interacting lysosomal protein - like 2 (RILPL2) has been reported to be associated with prognosis and tumor biological functions in breast cancer and endometrial carcinoma. However, its expression and functional role in non-small cell lung cancer (NSCLC) remain unclear. The expression and clinical data of lung adenocarcinoma (LUAD) and lung squamous carcinoma (LUSC) were downloaded from the TCGA database. The expression of RILPL2 in NSCLC cell lines was verified by the Western blot. We used online databases and bioinformatics analysis tools to explore its prognostic value, potential biological functions, and correlations with tumor immune microenvironment.The expression of RILPL2 was significantly lower in NSCLC compared with adjacent normal tissues. Low RILPL2 expression was associated with worse overall survival (OS) in NSCLC. The GO analysis showed RILPL2 was comprehensively involved in immune activity. RILPL2 expression was significantly positively correlated with the infiltration levels of B cells, CD8+T cells, CD4+T cells, macrophages, neutrophils, dendritic cells (P < 0.001), and it was also significantly positively correlated with programmed cell death ligand 1 (PD-L1/CD274) (P < 0.001). High RILPL2 expression could predict better immunotherapy response and prognosis in the immunotherapy cohort. The GSEA analysis showed low RILPL2 expression was associated with glycolysis process in LUAD, which was verified in vitro.These results showed RILPL2 expression was correlated with prognosis, tumor microenvironment, and immunotherapy response in NSCLC. Besides, RILPL2 may regulate glycolysis in LUAD.


Subject(s)
Adenocarcinoma of Lung , Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Tumor Microenvironment , Prognosis , Adenocarcinoma of Lung/genetics , Adenocarcinoma of Lung/pathology
4.
Nat Commun ; 13(1): 2281, 2022 05 19.
Article in English | MEDLINE | ID: mdl-35589687

ABSTRACT

Advances in microfluidic technology towards flexibility, transparency, functionality, wearability, scale reduction or complexity enhancement are currently limited by choices in materials and assembly methods. Organized microfibrillation is a method for optically printing well-defined porosity into thin polymer films with ultrahigh resolution. Here we demonstrate this method to create self-enclosed microfluidic devices with a few simple steps, in a number of flexible and transparent formats. Structural colour, a property of organized microfibrillation, becomes an intrinsic feature of these microfluidic devices, enabling in-situ sensing capability. Since the system fluid dynamics are dependent on the internal pore size, capillary flow is shown to become characterized by structural colour, while independent of channel dimension, irrespective of whether devices are printed at the centimetre or micrometre scale. Moreover, the capability of generating and combining different internal porosities enables the OM microfluidics to be used for pore-size based applications, as demonstrated by separation of biomolecular mixtures.


Subject(s)
Microfluidics , Printing, Three-Dimensional , Color , Lab-On-A-Chip Devices , Porosity
5.
Acta Pharm Sin B ; 12(2): 787-800, 2022 Feb.
Article in English | MEDLINE | ID: mdl-35256947

ABSTRACT

The bile acid-responsive G-protein-coupled receptor TGR5 is expressed in monocytes and macrophages, and plays a critical role in regulating inflammatory response. Our previous work has shown its role in promoting the progression of non-small cell lung cancer (NSCLC), yet the mechanism remains unclear. Here, using Tgr5-knockout mice, we show that TGR5 is required for M2 polarization of tumor-associated macrophages (TAMs) and suppresses antitumor immunity in NSCLC via involving TAMs-mediated CD8+ T cell suppression. Mechanistically, we demonstrate that TGR5 promotes TAMs into protumorigenic M2-like phenotypes via activating cAMP-STAT3/STAT6 signaling. Induction of cAMP production restores M2-like phenotypes in TGR5-deficient macrophages. In NSCLC tissues from human patients, the expression of TGR5 is associated with the infiltration of TAMs. The co-expression of TGR5 and high TAMs infiltration are associated with the prognosis and overall survival of NSCLC patients. Together, this study provides molecular mechanisms for the protumor function of TGR5 in NSCLC, highlighting its potential as a target for TAMs-centric immunotherapy in NSCLC.

6.
Acta Pharmacol Sin ; 43(1): 64-75, 2022 Jan.
Article in English | MEDLINE | ID: mdl-33742107

ABSTRACT

Coronavirus disease 2019 (COVID-19) broke out in December 2019. Due its high morbility and mortality, it is necessary to summarize the clinical characteristics of COVID-19 patients to provide more theoretical basis for future treatment. In the current study, we conducted a retrospective analysis of the clinical characteristics of COVID-19 patients and explored the risk factors for the severity of illness. A total of 101 COVID-19 patients hospitalized in Leishenshan Hospital (Wuhan, China) was classified into three sub-types: moderate (n = 47), severe (n = 36), and critical (n = 18); their clinical data were collected from the Electronic Medical Record. We showed that among the 101 COVID-19 patients, the median age was 62 years (IQR 51-74); 50 (49.5%) patients were accompanied by hypertension, while 25 (24.8%) and 22 (21.8%) patients suffered from diabetes and heart diseases, respectively, with complications. All patients were from Wuhan who had a definite history of exposure to the epidemic area. Multivariate logistic regression analysis revealed that older age, diabetes, chronic liver disease, percentage of neutrophils (N%) > 75%, CRP > 4 mg/L, D-dimer > 0.55 mg/L, IL-2R > 710 U/mL, IL-8 > 62 pg/mL, and IL-10 > 9.1 pg/mL were independent variables associated with severe COVID-19. In conclusion, we have identified the independent risk factors for the severity of COVID-19 pneumonia, including older age, diabetes, chronic liver disease, higher levels of N%, CRP, D-dimer, IL-2R, IL-8, and IL-10, providing evidence for more accurate risk prediction.


Subject(s)
COVID-19/pathology , Aged , COVID-19/metabolism , China , Female , Hospitalization , Humans , Interleukin-10/metabolism , Male , Middle Aged , Neutrophils/metabolism , Neutrophils/pathology , Retrospective Studies , Risk Factors , Severity of Illness Index
7.
Expert Rev Respir Med ; 15(12): 1551-1561, 2021 12.
Article in English | MEDLINE | ID: mdl-34689661

ABSTRACT

INTRODUCTION: Interstitial lung abnormalities (ILAs), which refer to mild or subtle nongravity-dependent interstitial changes, may be neglected by some clinicians due to many reasons, such as lack of diagnostic criteria for ILAs and absence of available treatments and surveillance strategies. However, without intervention, some ILAs may progress to interstitial lung disease (ILD). This review summarizes our current knowledge of this condition and ways of diagnosing it together with current management. We hope that this will lead to better recognition of ILAs. AREAS COVERED: We reviewed the literature on PubMed between 2008 and 2020 focusing on prevalence, etiology, symptoms, diagnostic biomarkers, clinical associations, and management of ILAs. EXPERT OPINION: Timely diagnosis with close monitoring of ILAs and appropriate intervention should be recognized as the management approach to ILAs. Research into ILAs should continue to improve its management.


Subject(s)
Lung Diseases, Interstitial , Humans , Lung , Lung Diseases, Interstitial/diagnosis , Lung Diseases, Interstitial/epidemiology , Lung Diseases, Interstitial/therapy
8.
Int Immunopharmacol ; 97: 107697, 2021 Aug.
Article in English | MEDLINE | ID: mdl-33933847

ABSTRACT

BACKGROUND: Toward the end of December 2019, a novel type of coronavirus (2019-nCoV) broke out in Wuhan, China. Here, the hematological characteristics of patients with severe and critical 2019-nCoV pneumonia in intensive care unit (ICU) were investigated, which may provide the necessary basis for its diagnosis and treatment. METHODS: We collected data on patients with confirmed 2019-nCoV pneumonia in the ICU of Leishenshan Hospital in Wuhan from February 25 to April 2, 2020. Real-time reverse-transcription polymerase chain reaction was used to confirm the presence of 2019-nCoV, and various hematological characteristics were analyzed. RESULTS: All patients tested positive for 2019-nCoV using nasopharyngeal swabs or sputum after admission, and interstitial pneumonia findings were noted on chest computed tomography. Sex, age and comorbidities were not significantly different between the severe and critical groups. In terms of prognosis, the survival rate of patients in the severe group reached 100%, whereas that of patients in the critical group was only 13.33% after positive treatment. Furthermore, lymphocyte percentage, blood urea nitrogen, calcium, D-dimer, myohemoglobin, procalcitonin, and IL-6 levels were high-risk factors for disease progression in critical patients. Finally, lymphocyte percentage and blood urea nitrogen, calcium, myohemoglobin, and IL-6 levels were closely associated with patient prognosis. CONCLUSIONS: 2019-nCoV pneumonia should be considered a systemic disease. Patients with more complications were more likely to develop critical disease. Lymphocyte percentage and blood urea nitrogen, calcium, myohemoglobin, and IL-6 levels can be monitored to prevent progression critical disease.


Subject(s)
COVID-19/blood , COVID-19/diagnosis , Intensive Care Units , Adult , Aged , Blood Urea Nitrogen , COVID-19/mortality , Calcium/blood , Female , Fibrin Fibrinogen Degradation Products/metabolism , Hemoglobins/metabolism , Humans , Interleukin-6/blood , Logistic Models , Lymphocytes/metabolism , Male , Middle Aged , Procalcitonin/blood , Prognosis , Retrospective Studies , Risk Factors
9.
Sci Rep ; 10(1): 3436, 2020 02 26.
Article in English | MEDLINE | ID: mdl-32103127

ABSTRACT

Dual-energy spectral computed tomography (DESCT) is based on fast switching between high and low voltages from view to view to obtain dual-energy imaging data, and it can generate monochromatic image sets, iodine-based material decomposition images and spectral CT curves. Quantitative spectral CT parameters may be valuable for reflecting Ki-67 expression and EGFR mutation status in non-small-cell lung cancer (NSCLC). We investigated the associations among the quantitative parameters generated in DESCT and Ki-67 expression and EGFR mutation in NSCLC. We studied sixty-five NSCLC patients with preoperative DESCT scans, and their specimens underwent Ki-67 and EGFR evaluations. Statistical analyses were performed to identify the spectral CT parameters for the diagnosis of Ki-67 expression and EGFR mutation status. We found that tumour grade and the slope of the spectral CT curve in the venous phase were the independent factors influencing the Ki-67 expression level, and the area under the curve (AUC) of the slope of the spectral CT curve in the venous phase in the receiver operating characteristic analysis for distinguishing different Ki-67 expression levels was 0.901. Smoking status and the normalized iodine concentration in the venous phase were independent factors influencing EGFR mutation, and the AUC of the two-factor combination for predicting the presence of EGFR mutation was 0.807. These results show that spectral CT parameters may be useful for predicting Ki-67 expression and the presence of EGFR mutation in NSCLC.


Subject(s)
Carcinoma, Non-Small-Cell Lung/diagnosis , Ki-67 Antigen/metabolism , Lung Neoplasms/diagnosis , Aged , Area Under Curve , Carcinoma, Non-Small-Cell Lung/diagnostic imaging , Carcinoma, Non-Small-Cell Lung/metabolism , Diagnosis, Differential , ErbB Receptors/genetics , ErbB Receptors/metabolism , Female , Humans , Iodine/chemistry , Iodine/metabolism , Logistic Models , Lung Neoplasms/diagnostic imaging , Lung Neoplasms/metabolism , Male , Middle Aged , Mutation , ROC Curve , Smoking , Tomography, X-Ray Computed
10.
Oncol Lett ; 18(2): 1278-1286, 2019 Aug.
Article in English | MEDLINE | ID: mdl-31423188

ABSTRACT

Despite the clinical requirement for early diagnosis, the early events in lung cancer and their mechanisms are not fully understood. Pituitary tumor transforming gene 1 binding factor (PTTG1IP) is a tumor-associated gene; however, to the best of our knowledge, its association with lung cancer has not been reported. The present study analyzed PTTG1IP expression in early-stage non-small cell lung cancer (NSCLC) samples and investigated its epigenetic regulatory mechanisms. The results revealed that the mRNA level of PTTG1IP in NSCLC tissues was significantly downregulated by 43% compared with that in adjacent tissues. In addition, overexpression of this gene significantly inhibited cell proliferation. According to data from The Cancer Genome Atlas, a significant negative correlation was identified between the PTTG1IP gene methylation level and expression level in lung adenocarcinoma and lung squamous cell carcinoma cases. Reduced representation bisulfite sequencing (RRBS) analysis of six paired early-stage NSCLC tissue samples indicated that the CpG island shore of the PTTG1IP promoter is hypermethylated in lung cancer tissues, which was further validated in 12 paired early-stage NSCLC samples via bisulfite amplicon sequencing. Following treatment with 5-aza-2'-deoxycytidine to reduce DNA methylation in the promoter region, the PTTG1IP mRNA level increased, indicating that the PTTG1IP promoter DNA methylation level negatively regulates PTTG1IP transcription. In conclusion, in early-stage NSCLC, the PTTG1IP gene is regulated by DNA methylation in its promoter region, which may participate in the development and progression of lung cancer.

11.
Nature ; 570(7761): 363-367, 2019 06.
Article in English | MEDLINE | ID: mdl-31217598

ABSTRACT

The formation of microscopic cavities and microfibrils at stress hotspots in polymers is typically undesirable and is a contributor to material failure. This type of stress crazing is accelerated by solvents that are typically weak enough not to dissolve the polymer substantially, but which permeate and plasticize the polymer to facilitate the cavity and microfibril formation process1-3. Here we show that microfibril and cavity formation in polymer films can be controlled and harnessed using standing-wave optics to design a periodic stress field within the film4. We can then develop the periodic stress field with a weak solvent to create alternating layers of cavity and microfibril-filled polymers, in a process that we call organized stress microfibrillation. These multi-layered porous structures show structural colour across the full visible spectrum, and the colour can be tuned by varying the temperature and solvent conditions under which the films are developed. By further use of standard lithographic and masking tools, the organized stress microfibrillation process becomes an inkless, large-scale colour printing process generating images at resolutions of up to 14,000 dots per inch on a number of flexible and transparent formats5,6.

12.
Cancer Immunol Res ; 7(6): 990-1000, 2019 06.
Article in English | MEDLINE | ID: mdl-30975694

ABSTRACT

The farnesoid X receptor (FXR) regulates inflammation and immune responses in a subset of immune-mediated diseases. We previously reported that FXR expression promotes tumor cell proliferation in non-small cell lung cancer (NSCLC). Here we study the relevance of FXR to the immune microenvironment of NSCLC. We found an inverse correlation between FXR and PD-L1 expression in a cohort of 408 NSCLC specimens; from this, we identified a subgroup of FXRhighPD-L1low patients. We showed that FXR downregulates PD-L1 via transrepression and other mechanisms in NSCLC. Cocultured with FXRhighPD-L1low NSCLC cell lines, effector function and proliferation of CD8+ T cell in vitro are repressed. We also detected downregulation of PD-L1 in FXR-overexpressing Lewis lung carcinoma (LLC) mouse syngeneic models, indicating an FXRhighPD-L1low subtype in which FXR suppresses tumor-infiltrating immune cells. Anti-PD-1 therapy was effective against FXRhighPD-L1low mouse LLC tumors. Altogether, our findings demonstrate an immunosuppressive role for FXR in the FXRhighPD-L1low NSCLC subtype and provide translational insights into therapeutic response in PD-L1low NSCLC patients treated with anti-PD-1. We recommend FXRhighPD-L1low as a biomarker to predict responsiveness to anti-PD-1 immunotherapy.


Subject(s)
B7-H1 Antigen/metabolism , Carcinoma, Non-Small-Cell Lung/etiology , Carcinoma, Non-Small-Cell Lung/metabolism , Fragile X Mental Retardation Protein/metabolism , Lung Neoplasms/etiology , Lung Neoplasms/metabolism , Programmed Cell Death 1 Receptor/metabolism , Receptors, Cytoplasmic and Nuclear/genetics , Animals , Antineoplastic Agents, Immunological/pharmacology , Antineoplastic Agents, Immunological/therapeutic use , B7-H1 Antigen/genetics , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/pathology , Cell Line, Tumor , Disease Models, Animal , Female , Gene Expression Regulation, Neoplastic , Humans , Immunohistochemistry , Immunophenotyping , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Lymphocytes, Tumor-Infiltrating/drug effects , Lymphocytes, Tumor-Infiltrating/immunology , Lymphocytes, Tumor-Infiltrating/metabolism , Mice , Molecular Targeted Therapy , Receptors, Cytoplasmic and Nuclear/metabolism , Tumor Microenvironment/immunology , Xenograft Model Antitumor Assays
13.
Cancer Lett ; 412: 194-207, 2018 01 01.
Article in English | MEDLINE | ID: mdl-29074425

ABSTRACT

Mounting evidence suggests that an emerging G protein-coupled receptor, TGR5, plays a crucial role ranging from metabolic diseases to cancers. However, the biological functions of TGR5 in non-small cell lung cancer (NSCLC) remain elusive. We found that TGR5 was aberrantly expressed in NSCLC and positively correlated with an advanced clinical stage in NSCLC patients. We further discovered that TGR5 knockdown prevented JAK2 and STAT3 phosphorylation and repressed the expression of STAT3 target genes, thus inhibiting cell proliferation, migration and invasion in NSCLC. Moreover, the promotive effects of TGR5 were significantly reversed by a JAK2 inhibitor or STAT3 knockdown. Additionally, we demonstrated a positive correlation between TGR5 and p-STAT3 expression in NSCLC tissue samples. Patients with both high TGR5 and p-STAT3 expression had the worst prognosis. In addition, the serum levels of deoxycholic acid (DCA), ursodeoxycholic acid (UDCA) and chenodeoxycholic acid (CDCA) in NSCLC patients were much higher than those in the healthy controls and the patients with higher serum DCA levels had stronger TGR5 expression simultaneously. Moreover, DCA markedly promoted NSCLC cell migration and invasion through a TGR5-dependent way. Taken together, these results indicate that TGR5 drives cell growth and migration through JAK2/STAT3 signaling pathway in NSCLC.


Subject(s)
Carcinoma, Non-Small-Cell Lung/pathology , Janus Kinase 2/physiology , Lung Neoplasms/pathology , Receptors, G-Protein-Coupled/physiology , STAT3 Transcription Factor/physiology , Signal Transduction/physiology , Adult , Aged , Animals , Cell Cycle Checkpoints , Cell Line, Tumor , Cell Movement , Cell Proliferation , Female , Humans , Male , Mice , Mice, Inbred BALB C , Middle Aged
14.
Sci Rep ; 7(1): 591, 2017 04 04.
Article in English | MEDLINE | ID: mdl-28377627

ABSTRACT

Farnesoid X receptor (FXR), a nuclear receptor for maintaining bile acid homeostasis, has been recognized as a tumor suppressor in enterohepatic tissues. However, its expression and functional role in non-small cell lung cancer (NSCLC) remain unclear. We report that FXR is significantly increased in NSCLC and that it predicts poor clinical outcomes in NSCLC patients. FXR knockdown in NSCLC cells inhibited in vitro cell proliferation, blocked xenograft growth in nude mice, and delayed the G1/S transition of the cell cycle, whereas ectopic overexpression of FXR promoted NSCLC cell proliferation. Mechanistic analysis demonstrated that FXR could directly bind to an inverted repeat-0 sequence in the CCND1 promoter and activate its transcription. Cyclin D1 overexpression rescued NSCLC cells from the delayed G1/S transition and the impaired cell proliferation induced by FXR knockdown. Importantly, a positive correlation between the expression of FXR and cyclin D1 was confirmed in NSCLC samples, and patients with high expression of both FXR and cyclin D1 had the worst prognosis. In summary, our results suggest that FXR has oncogenic potential in NSCLC development, providing mechanistic insights that could be exploited for both prognostic and therapeutic purposes.


Subject(s)
Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/metabolism , Cyclin D1/genetics , Fragile X Mental Retardation Protein/metabolism , Lung Neoplasms/genetics , Lung Neoplasms/metabolism , Oncogene Proteins/metabolism , Trans-Activators/metabolism , Adult , Aged , Carcinoma, Non-Small-Cell Lung/mortality , Carcinoma, Non-Small-Cell Lung/pathology , Cell Cycle Checkpoints/genetics , Cyclin D1/metabolism , Female , Gene Expression Regulation, Neoplastic , Humans , Kaplan-Meier Estimate , Lung Neoplasms/mortality , Lung Neoplasms/pathology , Male , Middle Aged , Neoplasm Grading , Neoplasm Metastasis , Neoplasm Staging , Prognosis , Promoter Regions, Genetic , Proportional Hazards Models , Protein Binding , Proto-Oncogene Mas , Transcriptional Activation
15.
J Pharmacol Exp Ther ; 359(1): 54-61, 2016 10.
Article in English | MEDLINE | ID: mdl-27432893

ABSTRACT

Metastasis accounts for the majority of cancer-related deaths. Transforming growth factor ß (TGF-ß) is believed to promote late-stage cancer progression and metastasis by inducing epithelial-mesenchymal transition (EMT). We previously reported that MS80, a novel oligosaccharide sulfate, inhibits TGF-ß1-induced pulmonary fibrosis by binding TGF-ß1. In our study MS80 effectively inhibited TGF-ß/Smad signaling in lung cancer cells, breast cancer cells, and model cell lines. In addition, MS80 inhibited TGF-ß1-induced EMT, motility, and invasion in vitro. Moreover, MS80 significantly inhibited lung metastasis in orthotopic 4T1 xenografts. Notably, the MS80 treatment significantly increased the infiltration of CD8(+) T cells and decreased the infiltration of regulatory T cells in primary tumors and spleens in mice bearing 4T1 xenografts. Therefore, MS80 is a novel and promising candidate for treating metastatic malignancies by targeting TGF-ß1-induced EMT and mediating immunosuppression.


Subject(s)
Epithelial-Mesenchymal Transition/drug effects , Oligosaccharides/pharmacology , Transforming Growth Factor beta1/antagonists & inhibitors , Transforming Growth Factor beta1/pharmacology , Animals , Apoptosis/drug effects , CD8-Positive T-Lymphocytes/drug effects , CD8-Positive T-Lymphocytes/immunology , Cell Line, Tumor , Cell Movement/drug effects , Cell Transformation, Neoplastic , Female , Humans , Mice , Neoplasm Invasiveness , Neoplasm Metastasis , Signal Transduction/drug effects , Smad Proteins/metabolism
16.
J Thorac Dis ; 8(6): E393-8, 2016 Jun.
Article in English | MEDLINE | ID: mdl-27293865

ABSTRACT

Pulmonary migratory infiltrates (PMI) are observed in a few diseases. We report here a case of PMI attributed to Mycoplasma pneumonia (Mp) infection. The patient's past medical history was characterized by fleeting and/or relapses of patchy opacification or infiltrates of parenchyma throughout the whole lung field except for left lower lobe radiographically. Serological assays revealed an elevation of IgG antibody specific to Mp and its fourfold increase in convalescent serum. Histopathological findings showed polypoid plugs of fibroblastic tissue filling and obliterating small air ways and interstitial infiltrates of mononuclear inflammatory cells in the vicinal alveolar septa. The patient was treated with azithromycin which resulted in a dramatic improvement clinically and imageologically. In spite of the increasing incidence of Mp, the possible unusual imaging manifestation and underlying mechanism haven't attracted enough attention. To our knowledge, there are rare reports of such cases.

17.
Oncol Rep ; 36(2): 1016-22, 2016 Aug.
Article in English | MEDLINE | ID: mdl-27349500

ABSTRACT

Statins are the most effective drugs used in the reduction of intracellular synthesis of cholesterol. Numerous studies have confirmed that statins reduce the risk of multiple types of cancers. Statin use in cancer patients is associated with reduced cancer-related mortality. Epithelial-to-mesenchymal transition (EMT), a complicated process programmed by multiple genes, is an important mechanism of cancer metastasis. We explored the effect and mechanism of atorvastatin on the EMT process in A549 cells by establishing an EMT model in vitro induced by TGF-ß1, and evaluated the effects of atorvastatin on the lower signaling pathway of TGF-ß1 stimulation. Our results showed that atorvastatin partially inhibited the EMT process, and inhibited cell migration and actin filament remodeling. Transcriptional upregulation of ZEB1 and protein sphingosine kinase 1 (SphK1) induced by TGF-ß1 was also suppressed. SphK1 plasmid transient transfection strengthened the EMT process induced by TGF-ß1 in the presence of atorvastatin. Our experiments confirmed that atorvastatin can partially inhibit the EMT process of non-small cell lung cancer cells induced by TGF-ß1 by attenuating the upregulation of SphK1.


Subject(s)
Atorvastatin/pharmacology , Epithelial-Mesenchymal Transition/drug effects , Lung Neoplasms/drug therapy , Phosphotransferases (Alcohol Group Acceptor)/genetics , Transforming Growth Factor beta1/genetics , Up-Regulation/drug effects , A549 Cells , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Cell Line, Tumor , Cell Movement/genetics , Epithelial-Mesenchymal Transition/genetics , Humans , Lung Neoplasms/genetics , Signal Transduction/drug effects , Signal Transduction/genetics , Transcription, Genetic/drug effects , Transcription, Genetic/genetics , Transcriptional Activation/drug effects , Transcriptional Activation/genetics , Up-Regulation/genetics , Zinc Finger E-box-Binding Homeobox 1/genetics
18.
Respirology ; 21(6): 1075-80, 2016 08.
Article in English | MEDLINE | ID: mdl-27185272

ABSTRACT

BACKGROUND AND OBJECTIVE: The roles of bile acid microaspiration and bile acid-activated farnesoid X receptor (FXR) in the pathogenesis of idiopathic pulmonary fibrosis (IPF) remain unclear. We hypothesized that bile acids activate alveolar epithelial cells (AECs) and lung fibroblasts, which may be regulated by FXR activation. METHODS: Human AECs and normal or IPF-derived lung fibroblast cells were incubated with the three major bile acids: lithocholic acid (LCA), deoxycholic acid (DCA) and chenodeoxycholic acid (CDCA). The AECs injury indices, epithelial-mesenchymal transition (EMT) and lung fibroblast activation were evaluated. FXR expression in IPF lungs and the roles of FXR and FXR-independent pathways in bile acid-induced profibrotic effects were also investigated. RESULTS: LCA, DCA and CDCA reduced cell viability and increased intracellular reactive oxygen species (ROS) production in A549 cells. They all induced EMT, as shown by enhanced α-SMA and vimentin and decreased E-cadherin levels. LCA directly induced differentiation of lung fibroblasts to myofibroblasts. All three bile acids promoted cellular migration but not proliferation of lung fibroblasts. FXR expression was upregulated in IPF lungs, and inhibition of FXR restrained the bile acid-induced EMT and lung fibroblast activation. Differentiation and proliferation were enhanced in lung fibroblasts exposed to conditioned medium from bile acid-stimulated A549 cells, which contained increased levels of profibrotic factors. TGF-ß/Smad3 signaling was also involved in the bile acid-induced EMT and lung fibroblast differentiation. CONCLUSION: Bile acid microaspiration may promote the development of pulmonary fibrosis by inducing activation of AECs and lung fibroblasts via FXR-dependent and independent pathways.


Subject(s)
Alveolar Epithelial Cells/metabolism , Bile Acids and Salts/metabolism , Fibroblasts/physiology , Gastroesophageal Reflux/complications , Idiopathic Pulmonary Fibrosis , Receptors, Cytoplasmic and Nuclear/metabolism , Cell Culture Techniques , Cell Movement/physiology , Epithelial-Mesenchymal Transition , Humans , Idiopathic Pulmonary Fibrosis/etiology , Idiopathic Pulmonary Fibrosis/metabolism , Idiopathic Pulmonary Fibrosis/pathology , Reactive Oxygen Species/metabolism , Respiratory Aspiration/complications , Signal Transduction , Transforming Growth Factor beta
19.
J Thorac Dis ; 8(11): 3063-3074, 2016 Nov.
Article in English | MEDLINE | ID: mdl-28066584

ABSTRACT

BACKGROUND: Epithelial-mesenchymal transition (EMT) and cyclooxygenase-2 (COX-2) contribute to airway remodelling and inflammation in chronic obstructive pulmonary disease (COPD). Recent data suggest that the farnesoid X receptor (FXR), a nuclear receptor traditionally considered as bile acid-activated receptor, is also expressed in non-classical bile acids target tissues with novel functions beyond regulating bile acid homeostasis. This study aimed to investigate the potential role of FXR in the development of COPD, as well as factors that affect FXR expression. METHODS: Expression of FXR, EMT biomarkers and COX-2 was examined by immunohistochemistry in lung tissues from non-smokers, smokers, and smokers with COPD. The role of FXR in TGF-ß1-induced EMT and COX-2 expression in human bronchial epithelial (HBE) cells was evaluated in vitro. Factors regulating FXR expression were assessed in cultured HBE cells and a cigarette smoke-induced rat model of COPD. RESULTS: Expression of FXR, EMT markers and COX-2 was significantly elevated in small airway epithelium of COPD patients compared with controls. The staining scores of FXR in small airway epithelium were negatively related with FEV1% of predicted of smokers without and with COPD. FXR agonist GW4064 remarkably enhanced and FXR antagonist Z-Guggulsterone significantly inhibited EMT changes in TGF-ß1-treated HBE cells. Both chenodeoxycholic acid (CDCA) and GW4064 increased COX-2 expression in HBE cells, whereas Z-Guggulsterone dramatically restrained CDCA-induced COX-2 expression. Finally, FXR expression is induced by IL-4 and IL-13 in HBE cells, as well as by cigarette smoke exposure in a rat model of COPD. CONCLUSIONS: Overexpression of FXR in small airway may contribute to airway remodelling and inflammation in COPD by regulating EMT and COX-2 expression.

20.
J Basic Microbiol ; 55(5): 671-8, 2015 May.
Article in English | MEDLINE | ID: mdl-25112215

ABSTRACT

The aim of this study was to evaluate the effects of quorum sensing (QS) systems in Pseudomonas aeruginosa (P. aeruginosa) on the expression of ampC gene induced by antibiotics. An in vitro dynamic model of P. aeruginosa biofilms was established in a silicon tube in once-flowthrough system at 37 °C. Biofilm generation was identified by argentation. Biofilm morphology of standard P. aeruginosa strain (PAO-1) and QS systems deficient strains (PDO100, rhlI deficient strain; PAO-JP1, lasI deficient strain; and PAO-MW1, rhlI and lasI deficient strain) were observed by optical microscope. The expression of ampC in PAO1, PAO1 with QS inhibitor (furanone C-30) and the QS deficient strains before and after induced by antibiotics were quantified by real-time quantitative PCR. The biofilms of PAO-1 and PDO100 were much thicker and denser than that of PAO-JP1 and PAO-MW1. Being induced by antibiotics, the expression of ampC in PAO1 and PDO100 was significantly higher than that in PAO-MW1 and PAO-JP1. With the effect of furanone C-30, the expression of ampC in PAO1 induced by antibiotics was reduced in a dose-dependent manner. QS system, especially the las system, plays an important role in both biofilm formation and antimicrobials induced ampC expression and furanone C-30 is a potent inhibitor for P. aeruginosa QS system.


Subject(s)
Anti-Bacterial Agents/metabolism , Bacterial Proteins/biosynthesis , Biofilms/drug effects , Pseudomonas aeruginosa/drug effects , Pseudomonas aeruginosa/physiology , Quorum Sensing , beta-Lactamases/biosynthesis , beta-Lactams/metabolism , Bacteriological Techniques , Biofilms/growth & development , Ceftazidime/metabolism , Gene Deletion , Gene Expression Profiling , Gene Expression Regulation, Bacterial/drug effects , Imipenem/metabolism , Microscopy , Pseudomonas aeruginosa/enzymology , Real-Time Polymerase Chain Reaction , Temperature
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