Proteogenomic characterization of small cell lung cancer identifies biological insights and subtype-specific therapeutic strategies.

We performed comprehensive proteogenomic characterization of small cell lung cancer (SCLC) using paired tumors and adjacent lung tissues from 112 treatment-naive patients who underwent surgical resection. Integrated multi-omics analysis illustrated cancer biology downstream of genetic aberrations and highlighted oncogenic roles of FAT1 mutation, RB1 deletion, and chromosome 5q loss. Two prognostic biomarkers, HMGB3 and CASP10, were identified. Overexpression of HMGB3 promoted SCLC cell migration via transcriptional regulation of cell junction-related genes. Immune landscape characterization revealed an association between ZFHX3 mutation and high immune infiltration and underscored a potential immunosuppressive role of elevated DNA damage response activity via inhibition of the cGAS-STING pathway. Multi-omics clustering identified four subtypes with subtype-specific therapeutic vulnerabilities. Cell line and patient-derived xenograft-based drug tests validated the specific therapeutic responses predicted by multi-omics subtyping. This study provides a valuable resource as well as insights to better understand SCLC biology and improve clinical practice.

Whole-exome and targeted gene sequencing of large-cell lung carcinoma reveals recurrent mutations in the PI3K pathway.

BACKGROUND: Large cell lung carcinoma (LCLC) is an exceptionally aggressive disease with a poor prognosis. At present, little is known about the molecular pathology of LCLC. METHODS: Ultra-deep sequencing of cancer-related genes and exome sequencing were used to detect the LCLC mutational in 118 tumor-normal pairs. The cell function test was employed to confirm the potential carcinogenic mutation of PI3K pathway. RESULTS: The mutation pattern is determined by the predominance of A > C mutations. Genes with a significant non-silent mutation frequency (FDR) < 0.05) include TP53 (47.5%), EGFR (13.6%) and PTEN (12.1%). Moreover, PI3K signaling (including EGFR, FGRG4, ITGA1, ITGA5, and ITGA2B) is the most mutated pathway, influencing 61.9% (73/118) of the LCLC samples. The cell function test confirmed that the potential carcinogenic mutation of PI3K pathway had a more malignant cell function phenotype. Multivariate analysis further revealed that patients with the PI3K signaling pathway mutations have a poor prognosis (P = 0.007). CONCLUSIONS: These results initially identified frequent mutation of PI3K signaling pathways in LCLC and indicate potential targets for the treatment of this fatal type of LCLC.

The predictive value of inflammatory biomarkers for major pathological response in non-small cell lung cancer patients receiving neoadjuvant chemoimmunotherapy and its association with the immune-related tumor microenvironment: a multi-center study.

BACKGROUND: Inflammatory biomarkers in the peripheral blood have been established as predictors for immunotherapeutic efficacy in advanced non-small cell lung cancer (NSCLC). Whether they can also predict major pathological response (MPR) in neoadjuvant setting remains unclear. METHODS: In this multi-center retrospective study, 122 and 92 stage I-IIIB NSCLC patients from six hospitals who received neoadjuvant chemoimmunotherapy followed by surgery were included in the discovery and external validation cohort, respectively. Baseline and on-treatment neutrophil-to-lymphocyte ratio (NLR), derived NLR (dNLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR) and systemic immune-inflammation index (SII) were calculated and associated with MPR. Furthermore, resected tumor samples from 37 patients were collected for RNA-sequencing to investigate the immune-related tumor microenvironment. RESULTS: In both the discovery and validation cohorts, the on-treatment NLR, dNLR, PLR, and SII levels were significantly lower in the patients with MPR versus non-MPR. On-treatment SII remained an independent predictor of MPR in multivariate logistic regression analysis. The area under the curve (AUC) of on-treatment SII for predicting MPR was 0.75 (95%CI, 0.67-0.84) in the discovery cohort. Moreover, the predictive value was further improved by combining the on-treatment SII and radiological tumor regression data, demonstrating an AUC of 0.82 (95%CI, 0.74-0.90). The predictive accuracy was validated in the external cohort. Compared with the SII-high group, patients with SII-Low were associated with the activated B cell receptor signaling pathway and a higher intratumoral immune cell infiltration level. CONCLUSIONS: On-treatment SII was independently associated with MPR in NSCLC patients receiving neoadjuvant chemoimmunotherapy. Further prospective studies are warranted.

Frequent EGFR exon 20 insertion in the so-called peripheral-type squamous cell neoplasm of uncertain malignant potential: a variant of bronchiolar adenoma or under-recognised entity?

INTRODUCTION: Herein we describe a series of rare peripheral pulmonary neoplasms temporarily termed "peripheral type squamous cell neoplasm of uncertain malignant potential (PSCN-UMP)" and investigate their relationship to bronchiolar adenoma (BA) and squamous cell carcinoma (SCC). MATERIALS AND METHODS: The histologic and immunohistochemical features of 10 PSCN-UMPs and six BAs were compared. Whole exome sequencing (WES) and bioinformatics analysis were performed to further compare the genetic features of PSCN-UMPs, BAs, and NSCLCs. RESULTS: All PSCN-UMPs were peripherally located and histologically characterised by the lepidic, nested, and papillary proliferation of relatively bland squamous cells, accompanied by entrapped hyperplastic reactive pneumocytes. The basal squamous cells coexpressed TTF1 and squamous markers. Both cellular components exhibited bland morphology and a low proliferative activity. The six BAs met the morphologic and immunophenotypic features of proximal-type BA. Genetically, driver mutations, including frequent EGFR exon 20 insertions, were found in PSCN-UMPs, while the KRAS mutation, BRAF mutation, and ERC1::RET fusion were detected in BAs. PSCN-UMPs also shared some alterations with BAs in mutational signatures, while copy number variants (CNV) were enriched in MET and NKX2-1 in PSCN-UMP and MCL1, MECOM, SGK1, and PRKAR1A in BA. CONCLUSION: PSCN-UMPs exhibited the proliferation of bland squamous cells accompanied by entrapped pneumocytes and frequent EGFR exon 20 insertions, which showed distinct features from BAs and SCCs. Recognition of this specific entity will help to expand the morphologic and molecular spectrum of peripheral lung squamous neoplasms.

Major pathological response exhibited distinct prognostic significance for lung adenocarcinoma post different modalities of neoadjuvant therapy.

AIMS: For non-small-cell lung cancer (NSCLC) patients receiving neoadjuvant therapy, the major pathological response (MPR) is defined as the percentage of residual viable tumour cells (%RVT) in the tumour bed of no more than 10%. It has been proposed as a predictor of survival in neoadjuvant therapy-treated cohorts. Nonetheless, the significance of %RVT in the pathological assessment of lung adenocarcinoma cohorts remains undetermined. METHODS AND RESULTS: Overall, 152 lung adenocarcinoma patients were included in this retrospective study, among whom 67 received neoadjuvant targeted therapy and 85 received neoadjuvant chemotherapy. Clinicopathological characteristics, neoadjuvant treatment response and survival status were investigated. The routinely adopted standard for MPR (%RVT ≤ 10%) failed to differentiate prognosis in the lung adenocarcinoma population. For the neoadjuvant chemotherapy cohort, the optimal %RVT cut-off value of RFS was 60%. However, this cut-off value was clinically insignificant in the neoadjuvant targeted-therapy cohort. Hence, for these patients, we built a nomogram model including high-grade patterns and ypN stage to predict disease recurrence, demonstrating high efficacy (a bootstrap-corrected C-index of 0.731). CONCLUSIONS: %RVT served as a strong indicator of the prognosis of lung adenocarcinoma in patients receiving neoadjuvant chemotherapy but not neoadjuvant targeted therapy. Residual high-grade pathological patterns might substitute MPR in prognostic evaluation of lung adenocarcinoma post-targeted therapy.

Clinical utility of [18F]FDG PET/CT in the assessment of mediastinal lymph node disease after neoadjuvant chemoimmunotherapy for non-small cell lung cancer.

OBJECTIVES: The performance of positron emission tomography/computed tomography (PET/CT) for the prediction of ypN2 disease in non-small cell lung cancer (NSCLC) after neoadjuvant chemoimmunotherapy has not been reported. This multicenter study investigated the utility of PET/CT to assess ypN2 disease in these patients. METHODS: A total of 181 consecutive patients (chemoimmunotherapy = 86, chemotherapy = 95) at four institutions were enrolled in this study. Every patient received a PET/CT scan prior to surgery and complete resection with systematic nodal dissection. The diagnostic performance was evaluated through area under the curve (AUC). Kaplan-Meier method and Cox analysis were performed to identify the risk factors affecting recurrences. RESULTS: The sensitivity, specificity, and accuracy of PET/CT for ypN2 diseases were 0.667, 0.835, and 0.779, respectively. Therefore, the AUC was 0.751. Compared with the false positive cases, the mean value of max standardized uptake value (SUVmax) (6.024 vs. 2.672, p < 0.001) of N2 nodes was significantly higher in true positive patients. Moreover, the SUVmax of true positive (7.671 vs. 5.976, p = 0.365) and false (2.433 vs. 2.339, p = 0.990) positive cases were similar between chemoimmunotherapy and chemotherapy, respectively. Survival analysis proved that pathologic N (ypN) 2 patients could be stratified by PET/CT-N2(+ vs. -) for both chemoimmunotherapy (p = 0.023) and chemotherapy (p = 0.010). CONCLUSIONS: PET/CT is an accurate and non-invasive test for mediastinal restaging of NSCLC patients who receive neoadjuvant chemoimmunotherapy. The ypN2 patients with PET/CT-N2( +) are identified as an independent prognostic factor compared with PET/CT-N2(-). CLINICAL RELEVANCE STATEMENT: Imaging with 18F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) plays an integral role during disease diagnosis, staging, and therapeutic response assessments in patients with NSCLC. PET/CT could be an effective non-invasive tool for predicting ypN2 diseases after neoadjuvant chemoimmunotherapy. KEY POINTS: • PET/CT could serve as an effective non-invasive tool for predicting ypN2 diseases. • The ypN2 patients with PET/CT-N2( +) were a strong and independent prognostic factor. • The application of PET/CT for restaging should be encouraged in clinical practice.

Liquid biopsy in lung cancer: significance in diagnostics, prediction, and treatment monitoring.

Primary lung cancer is one of the most common malignant tumors in China. Approximately 60% of lung cancer patients have distant metastasis at the initial diagnosis, so it is necessary to find new tumor markers for early diagnosis and individualized treatment. Tumor markers contribute to the early diagnosis of lung cancer and play important roles in early detection and treatment, as well as in precision medicine, efficacy monitoring, and prognosis prediction. The pathological diagnosis of lung cancer in small biopsy specimens determines whether there are tumor cells in the biopsy and tumor type. Because biopsy is traumatic and the compliance of patients with multiple biopsies is poor, liquid biopsy has become a hot research direction. Liquid biopsies are advantageous because they are nontraumatic, easy to obtain, reflect the overall state of the tumor, and allow for real-time monitoring. At present, liquid biopsies mainly include circulating tumor cells, circulating tumor DNA, exosomes, microRNA, circulating RNA, tumor platelets, and tumor endothelial cells. This review introduces the research progress and clinical application prospect of liquid biopsy technology for lung cancer.

Deep convolutional neural network-based classification of cancer cells on cytological pleural effusion images.

Lung cancer is one of the leading causes of cancer-related death worldwide. Cytology plays an important role in the initial evaluation and diagnosis of patients with lung cancer. However, due to the subjectivity of cytopathologists and the region-dependent diagnostic levels, the low consistency of liquid-based cytological diagnosis results in certain proportions of misdiagnoses and missed diagnoses. In this study, we performed a weakly supervised deep learning method for the classification of benign and malignant cells in lung cytological images through a deep convolutional neural network (DCNN). A total of 404 cases of lung cancer cells in effusion cytology specimens from Shanghai Pulmonary Hospital were investigated, in which 266, 78, and 60 cases were used as the training, validation and test sets, respectively. The proposed method was evaluated on 60 whole-slide images (WSIs) of lung cancer pleural effusion specimens. This study showed that the method had an accuracy, sensitivity, and specificity respectively of 91.67%, 87.50% and 94.44% in classifying malignant and benign lesions (or normal). The area under the receiver operating characteristic (ROC) curve (AUC) was 0.9526 (95% confidence interval (CI): 0.9019-9.9909). In contrast, the average accuracies of senior and junior cytopathologists were 98.34% and 83.34%, respectively. The proposed deep learning method will be useful and may assist pathologists with different levels of experience in the diagnosis of cancer cells on cytological pleural effusion images in the future.

Prognostic and predictive value of the newly proposed grading system of invasive pulmonary adenocarcinoma in Chinese patients: a retrospective multicohort study.

Our aim was to validate and analyze the prognostic impact of the novel International Association for the Study of Lung Cancer (IASLC) Pathology Committee grading system for invasive pulmonary adenocarcinomas (IPAs) in Chinese patients and to evaluate its utility in predicting a survival benefit from adjuvant chemotherapy (ACT). In this multicenter, retrospective, cohort study, we included 926 Chinese patients with completely resected stage I IPAs and classified them into three groups (Grade 1, n = 119; Grade 2, n = 431; Grade 3, n = 376) according to the new grading system proposed by the IASLC. Recurrence-free survival (RFS) and overall survival (OS) were estimated by the Kaplan-Meier method, and prognostic factors were assessed using univariable and multivariable Cox proportional hazards models. All included cohorts were well stratified in terms of RFS and OS by the novel grading system. Furthermore, the proposed grading system was found to be independently associated with recurrence and death in the multivariable analysis. Among patients with stage IB IPA (N = 490), the proposed grading system identified patients who could benefit from ACT but who were undergraded by the adenocarcinoma (ADC) classification. The novel grading system not only demonstrated prognostic significance in stage I IPA in a multicenter Chinese cohort but also offered clinical value for directing therapeutic decisions regarding adjuvant chemotherapy.

Comparative profiling of single-cell transcriptome reveals heterogeneity of tumor microenvironment between solid and acinar lung adenocarcinoma.

BACKGROUND: The diversity of histologic composition reflects the inter- and intra-tumor heterogeneity of lung adenocarcinomas (LUADs) macroscopically. Insights into the oncological characteristics and tumor microenvironment (TME) of different histologic subtypes of LUAD at the single-cell level can help identify potential therapeutic vulnerabilities and combinational approaches to improve the survival of LUAD patients. METHODS: Through comparative profiling of cell communities defined by scRNA-seq data, we characterized the TME of LUAD samples of distinct histologic subtypes, with relevant results further confirmed in multiple bulk transcriptomic, proteomic datasets and an independent immunohistochemical validation cohort. RESULTS: We find that the hypoxic and acidic situation is the worst in the TME of solid LUADs compared to other histologic subtypes. Besides, the tumor metabolic preferences vary across histologic subtypes and may correspondingly impinge on the metabolism and function of immune cells. Remarkably, tumor cells from solid LUADs upregulate energy and substance metabolic activities, particularly the folate-mediated one-carbon metabolism and the key gene MTHFD2, which could serve as a potential therapeutic target. Additionally, ubiquitination modifications may also be involved in the progression of histologic patterns. Immunologically, solid LUADs are characterized by a predominance of exhausted T cells and immunosuppressive myeloid cells, where the hypoxic, acidified and nutrient-deprived TME has a non-negligible impact. Discrepancies in stromal cell function, evidenced by varying degrees of stromal remodeling and fibrosis, may also contribute to the specific immune phenotype of solid LUADs. CONCLUSIONS: Overall, our research proposes several potential entry points to improve the immunosuppressive TME of solid LUADs, thereby synergistically potentiating their immunotherapeutic efficacy, and may provide precise therapeutic strategies for LUAD patients of distinct histologic subtype constitution.

Identification of filigree pattern increases the diagnostic accuracy of micropapillary pattern on frozen section for lung adenocarcinoma.

AIMS: The presence of micropapillary (MIP) in early-stage lung adenocarcinoma is associated with a poorer prognosis, especially in patients undergoing sublobectomy. However, data on the sensitivity of frozen section (FS) evaluation of MIP is still limited. We included the concept of a filigree pattern on FS to assess its effect on the diagnostic sensitivity and specificity of MIP, and to verify its prognostic value in stage T1 lung adenocarcinoma. METHODS: A panel of five pathologists evaluated 125 patients with T1 lung adenocarcinoma from January to February 2014 as a study cohort, and 151 patients from January to February 2020 as a validation cohort. The diagnostic accuracy of the filigree and classical micropapillary (cMIP) pattern on FS was investigated. RESULTS: The diagnostic sensitivity of the MIP pattern on FS increased from 43.2% to 65.3% and 56.8% to 81.1% in the study cohort and validation cohort, respectively, and both with good specificity. Filigree not only increased the sensitivity of identifying MIP when there was an absence of cMIP, but also increased the sensitivity when the presence of a minor amount of cMIP. The almost perfect agreement among five pathologists was reached on cMIP and substantial agreement was reached on the filigree in the two cohorts. Moreover, the cMIP and filigree were both correlated with poorer recurrence-free survival (pcMIP = 0.003; pfiligree = 0.032) and overall survival (pcMIP = 0.004; pfiligree = 0.005). CONCLUSIONS: The identification of a filigree may improve the diagnostic sensitivity of the MIP pattern on FS. FS was feasible for the detection of filigree and cMIP patterns in stage T1 lung adenocarcinomas.

The diagnostic value of transbronchial lung cryobiopsy combined with rapid on-site evaluation in diffuse lung diseases: a prospective and self-controlled study.

BACKGROUND: The etiology of interstitial lung diseases (ILDs) is varied. Early diagnosis and a specific pathological type could significantly improve the prognosis. Mostly, it is difficult to make the etiology diagnosis of ILD through traditional biopsy methods. It will be of great significance to explore an effective biopsy method. METHODS: The prospective study was designed to evaluate the diagnostic value of transbronchial lung cryobiopsy (TBCB) combined with rapid on-site evaluation (ROSE), compared with conventional transbronchial lung biopsy (TBLB), in a large sample of ILD patients. All patients enrolled will undergo both TBLB and TBCB procedures. The study will observe the differences in the diagnostic efficiency of pathological typing and incidence of operation-related complications between TBCB and TBLB. Besides, it will analyze the relationship between the time of biopsy and the incidence of complications, the relationship between freezing time, size of specimen, and complications. And it will evaluate the consistency of pathological, clinical, and radiology. DISCUSSION: It may be the first time that ROSE technique will be used in the diagnosis of ILD. The results of this study will clarify the value of TBCB in the diagnosis of ILD and confirm its safety and effectiveness, which is expected to significantly improve the efficiency of diagnosis in ILD patients. TRAIL REGISTRATION: The trial was registered on the Chinese Clinical Trial Registry website ( http://www.chictr.org.cn/showproj.aspx?proj=57834 ) (Registration number: ChiCTR2000035492).

Excimer laser atherectomy combined with drug-coated balloon versus drug-eluting balloon angioplasty for the treatment of infrapopliteal arterial revascularization in ischemic diabetic foot: 24-month outcomes.

There are few studies on excimer laser (308 nm) atherectomy in the treatment of infrapopliteal artery disease. The purpose of this retrospective clinical study was to assess the efficacy and safety of excimer laser atherectomy (ELA) in combination with adjuvant drug-coated balloon angioplasty (DCB) compared to DCB for infrapopliteal arterial revascularization in patients with ischemic diabetic foot. From September 2018 to February 2019, a total of 79 patients with diabetic foot were treated for infrapopliteal arterial revascularization at Tianjin First Central Hospital (Tianjin, China). In this project, 35 patients were treated with ELA combined with DCB angioplasty, and 44 patients were treated with DCB angioplasty. The patients' baseline characteristics were similar between the 2 groups. The primary efficacy endpoints through 24 months were clinically driven target lesion revascularization (CD-TLR), wound healing rate, major amputation rate, and target vessel patency rate. The primary safety endpoint through 24 months was all-cause mortality. The primary efficacy results at 24 months of ELA + DCB versus DCB were CD-TLR of 14.3% versus 34.1% (p = 0.044), wound healing rate of 88.6% versus 65.9% (p = 0.019), target vessel patency rate of 80.0% versus 52.3% (p = 0.010), and major amputations rate of 5.7% versus 22.7% (p = 0.036). The safety signal at 24 months of all-cause mortality rate was 2.9% for ELA + DCB group and 4.5% for DCB group (p = 0.957). ELA combined with DCB angioplasty is more effective than DCB in the treatment of infrapopliteal artery disease in patients with ischemic diabetic foot, which can improve the wound healing rate and target vessel patency rate. There was no statistical difference in the safety results between the two groups.

microRNA-320b suppresses HNF4G and IGF2BP2 expression to inhibit angiogenesis and tumor growth of lung cancer.

We examined the effect of microRNA-320b (miR-320b) on tumor growth and angiogenesis in lung cancer and also determined its downstream molecular mechanisms. Lung cancer tissues and adjacent non-cancerous tissues were collected from 66 patients with lung cancer. miR-320b expression was experimentally determined to be expressed at low level in cancer tissues. The results of gain-of-function experiments suggested that miR-320b overexpression suppressed cancer cell invasion, tube formation, tumor volume and angiogenesis in xenografted nude mice. Hepatocyte nuclear factor 4 gamma (HNF4G) was identified as a target of miR-320b based on in silico analysis. Dual-luciferase reporter gene assays further identified the binding relationship between HNF4G and miR-320b. Lung cancer tissues exhibited increased expression of HNF4G and insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2). Meanwhile, HNF4G knockdown suppressed IGF2BP2 expression, thereby repressing cancer cell invasion and tube formation. Furthermore, IGF2BP2 modified m6A to increase the expression of thymidine kinase 1 (TK1), thus promoting angiogenesis. In nude mice, restoration of TK1 reversed the suppressive effect of miR-320b overexpression on tumor growth rate and CD31 expression. In conclusion, miR-320b suppresses lung cancer growth and angiogenesis by inhibiting HNF4G, IGF2BP2 and TK1.

miR-30 Family Reduction Maintains Self-Renewal and Promotes Tumorigenesis in NSCLC-Initiating Cells by Targeting Oncogene TM4SF1.

Increasing evidence indicates that tumor-initiating cells (TICs) are responsible for the occurrence, development, recurrence, and development of the drug resistance of cancer. MicroRNA (miRNA) plays a significant functional role by directly regulating targets of TIC-triggered non-small-cell lung cancer (NSCLC), but little is known about the function of the miR-30 family in TICs. In this study, we found the miR-30 family to be downregulated during the spheroid formation of NSCLC cells, and patients with lower miR-30a/c expression had shorter overall survival (OS) and progression-free survival (PFS). Moreover, transmembrane 4 super family member 1 (TM4SF1) was confirmed to be a direct target of miR-30a/c. Concomitant low expression of miR-30a/c and high expression of TM4SF1 correlated with a shorter median OS and PFS in NSCLC patients. miR-30a/c significantly inhibited stem-like characteristics in vitro and in vivo via suppression of its target gene TM4SF1, and then it inhibited the activity of the mTOR/AKT-signaling pathway. Thus, our data provide the first evidence that TM4SF1 is a direct target of miR-30a/c and miR-30a/c inhibits the stemness and proliferation of NSCLC cells by targeting TM4SF1, suggesting that miR-30a/c and TM4SF1 may be useful as tumor biomarkers for the diagnosis and treatment of NSCLC patients.

Element-based prognostics of occupational pneumoconiosis using micro-proton-induced X-ray emission analysis.

Pneumoconiosis is an occupational disease accompanied by long-term lung impairment, for which prediction of prognosis is poorly understood because of the complexity of the inhaled particles. Micro-proton-induced X-ray emission (micro-PIXE) analysis, which is advantageous for high-sensitivity, two-dimensional element mapping of lung tissues, was used to investigate element-based predictive factors of prognosis in Chinese patients with welder's and coal miner's pneumoconiosis. Chest radiographs and lung function tests showed that most of the coal miners deteriorated, whereas symptoms in some welders were alleviated after 5 yr, as determined by comparing percent vital capacity (%VC) and forced expiratory volume in the 1st second over forced vital capacity (FEV1.0/FVC) to values taken at the initial diagnosis. Micro-PIXE analysis suggested that the most abundant particulates in welder's pneumoconiosis were Fe, Mn, and Ti (metallic oxide),which were accompanied by particulates containing Si, Al, and Ca (aluminum silicate) or only Si (SiO2); the most abundant particulates in coal miner's pneumoconiosis were composed of C, Si, Al, K, and Ti, which were accompanied by particulates containing Ca or Fe. Particulates containing Al, Si, S, K, Ca, and Ti (orthoclase and anorthite) were correlated with severity of fibrosis. Multivariable linear regression suggested that long-term FEV1.0/FVC decrease was independently associated with Si and smoking index, whereas %VC decrease was associated with Si and Ti. A risk index comprised of these factors was developed to predict the prognosis of pneumoconiosis. Micro-PIXE analysis is feasible for the evaluation of elemental composition and dust exposure, especially for patients whose exposure is mixed or uncertain.

Serum deprivation response inhibits breast cancer progression by blocking transforming growth factor-ß signaling.

Serum deprivation response (SDPR), a key substrate for protein kinase C, play a critical role in inducing membrane curvature and participate in the formation of caveolae. However, the function of SDPR in cancer development and progression is still not clear. Here, we found that SDPR is downregulated in human breast cancer. Overexpression of SDPR suppresses cell proliferation and invasion in MDA-MB-231 cells, while depletion of SDPR promotes cell proliferation and invasion in MCF10A cells. Subsequently, SDPR depletion induces epithelial-mesenchymal transition (EMT)-like phenotype. Finally, knockdown of SDPR activates transforming growth factor-ß (TGF-ß) signaling by upregulation of TGF-ß1 expression. In conclusion, our results showed that SDPR inhibits breast cancer progression by blocking TGF-ß signaling. Serum deprivation response suppresses cell proliferation and invasion in breast cancer cells. SDPR depletion induces epithelial-mesenchymal transition by activation of TGF-ß signaling.

Critical role of miR-155/FoxO1/ROS axis in the regulation of non-small cell lung carcinomas.

Lung cancer is the leading cause of cancer-related deaths in the world, and non-small cell lung carcinomas (NSCLC) account for 85 % of lung cancer cases. Despite enormous achievement in the treatment of NSCLC, the molecular mechanisms underlying the pathogenesis are largely unknown. The current study was designed to evaluate the role of miR-155 in NSCLC cell proliferation and to explore the possible molecular mechanisms. We found that miR-155 expression was increased in NSCLC tissues and cell lines. The increase of miR-155 significantly increased A549 cell proliferation, decreased S phase cell population and increased G2/M phase cell population. Decrease of miR-155 expression markedly inhibited cell proliferation, increased S phase cell population, and decreased G2/M phase cell population. Increase of miR-155 significantly decreased forkhead box protein O1 (FoxO1) 3'UTR luciferase activity and expression and decrease of miR-155 notably increased FoxO1 expression. Overexpression of FoxO1 significantly inhibited miR-155-exerted increase of cell proliferation and G2/M cell population. Downregulation of FoxO1 by siRNAs significantly promoted cell proliferation, decreased S phase cell numbers, and increased G2/M cell population. Downregulation of FoxO1 markedly increased ROS level, as reflected by increased DHE staining. Moreover, when N-acetylcysteine was present, increase of cell proliferation induced by downregulation of FoxO1, and upregulation of miR-155 was significantly inhibited. In conclusion, we found that miR-155 promoted NSCLC cell proliferation through inhibition of FoxO1 and the subsequent increase of ROS generation. Our findings highlight miR-155/FoxO1/ROS axis as a novel therapeutic target for the inhibition of NSCLC growth.