High expression of IL4I1 is correlated with poor prognosis and immune infiltration in thyroid cancer.

BACKGROUND: Thyroid cancer-related deaths mostly result from metastasis. It was reported that the immunometabolism associated enzyme interleukin-4-induced-1 (IL4I1) was related to tumor metastasis. The present study was intended to investigate the effects of IL4I1 on thyroid cancer metastasis and its relationship with the prognosis. METHODS: Data from Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) were analyzed to find out the different mRNA expressions of IL4I1 between thyroid cancer and normal tissues. And Human Protein Atlas (HPA) was used to assess IL4I1 protein expression. To further differentiate thyroid cancer from normal tissues and estimate the impact of IL4I1 on the prognosis, the receiver operating characteristic curve (ROC) and Kaplan-Meier (KM) method was performed. The protein-protein interaction (PPI) network was established using STRING, and functional enrichment analyses were conducted by "clusterProfiler" package. Then, we assayed the correlation between IL4I1 and some related molecules. The relationship between IL4I1 and immune infiltration was performed using "Gene Set Variation Analysis (GSVA)" package in TCGA and tumor-immune system interaction database (TISIDB). Finally, we did in vitro experiments in order to further prove the bioeffects of IL4I1 on metastasis. RESULTS: The expression of IL4I1 mRNA and IL4I1 protein was significantly upregulated in thyroid cancer tissues. The increment of IL4I1 mRNA expression was related to high-grade malignancy, lymph node metastases and extrathyroidal extension. The ROC curve displayed the cutoff value of 0.782, with the sensitivity of 77.5% and the specificity of 77.8%. KM survival analysis showed that there was a worse PFS in patients with high IL4I1 expression than those with low IL4I1 expression (p = 0.013). Further study indicated that IL4I1 was associated with lactate, body fluid secretion, positive regulation of T cell differentiation, and cellular response to nutrients in Gene Ontology (GO) analysis. Moreover, IL4I1 was found correlated with immune infiltration. Finally, the in vitro experiments revealed the promotion of IL4I1 on cancer cell proliferation, migration and invasion. CONCLUSIONS: The increased IL4I1 expression is markedly correlated with the immune imbalance in the tumor microenvironment (TME) and predicts poor survival in thyroid cancer. This study reveals the potential clinical biomarker of poor prognosis and the target of immune therapy in thyroid cancer.

KRAS G12V mutation upregulates PD-L1 expression via TGF-ß/EMT signaling pathway in human non-small-cell lung cancer.

Although clinical data suggest remarkable promise for targeting programmed cell death protein-1 (PD-1) and ligand (PD-L1) signaling in non-small-cell lung cancer (NSCLC), it is still largely undetermined which subtype of patients will be responsive to checkpoint blockade. In the present study, we explored whether PD-L1 was regulated by mutant Kirsten rat sarcoma viral oncogene homolog (KRAS), which is frequently mutated in NSCLC and results in poor prognosis and low survival rates. We verified that PD-L1 levels were dramatically increased in KRAS mutant cell lines, particularly in NCI-H441 cells with KRAS G12V mutation. Overexpression of KRAS G12V remarkably elevated PD-L1 messenger RNA and protein levels, while suppression of KRAS G12V led to decreased PD-L1 levels in NCI-H441 cells. Consistently, higher levels of PD-L1 were observed in KRAS-mutated tissues as well as tumor tissues-derived CD4+ and CD8+ T cells using a tumor xenograft in B-NDG mice. Mechanically, both in vitro and in vivo assays found that KRAS G12V upregulated PD-L1 via regulating the progression of epithelial-to-mesenchymal transition (EMT). Moreover, pembrolizumab activated the antitumor activity and decreased tumor growth with KRAS G12V mutated NSCLC. This study demonstrates that KRAS G12V mutation could induce PD-L1 expression and promote immune escape via transforming growth factor-ß/EMT signaling pathway in KRAS-mutant NSCLC, providing a potential therapeutic approach for NSCLC harboring KRAS mutations.

Probability of cancer in high-risk patients predicted by the protein-based lung cancer biomarker panel in China: LCBP study.

BACKGROUND: The authors built a model for lung cancer diagnosis previously based on the blood biomarkers progastrin-releasing peptide (ProGRP), carcinoembryonic antigen (CEA), squamous cell carcinoma antigen (SCC), and cytokeratin 19 fragment (CYFRA21-1). In the current study, they examined whether modification of the model to include relevant clinical information, risk factors, and low-dose chest computed tomography screening would improve the performance of the biomarker panel in large cohorts of Chinese adults. METHODS: The current study was a large-scale multicenter study (ClinicalTrials.gov identifier NCT01928836) performed in a Chinese population. A total of 715 participants were enrolled from 5 regional centers in Beijing, Henan, Nanjing, Shanghai, and Chongqing between October 2012 and February 2014. Serum biomarkers ProGRP, CEA, SCC, and CYFRA21-1 were analyzed on the ARCHITECT i2000SR. Relevant clinical information was collected and used to develop a patient risk model and a nodule risk model. RESULTS: The resulting patient risk model had an area under the receiver operating characteristic (ROC) curve of 0.7037 in the training data set and 0.7190 in the validation data set. The resulting nodule risk model had an area under the ROC curve of 0.9151 in the training data set and 0.5836 in the validation data set. Moreover, the nodule risk model had a relatively higher area under the ROC curve (0.9151 vs 0.8360; P = 0.001) compared with the American College of Chest Physician model in patients with lung nodules. CONCLUSIONS: Both the patient risk model and the nodule risk model, developed for the early diagnosis of lung cancer, demonstrated excellent discrimination, allowing for the stratification of patients with different levels of lung cancer risk. These new models are applicable in high-risk Chinese populations. Cancer 2018;124:262-70. © 2017 American Cancer Society.

Posttranslational modifications of FOXO1 regulate epidermal growth factor receptor tyrosine kinase inhibitor resistance for non-small cell lung cancer cells.

Epidermal growth factor receptor tyrosine kinase inhibitors (TKIs) are effective clinical therapies for advanced non-small cell lung cancer (NSCLC) patients, while resistance to TKIs remains a serious problem in clinical practice. Recently, it has been proposed that targeting mTOR could overcome TKI resistance in NSCLC cells. Forkhead box class O1 (FOXO1) has emerged as an important rheostat that modulates the activity of Akt and mTOR signaling pathway. However, the role of FOXO1 and related regulatory mechanism in TKI resistance in NSCLC remain largely unknown. Here, we find that mTOR-AKT-FOXO1 signaling cascade is deregulated in TKI-resistant NSCLC cells and that FOXO1 was highly phosphorylated and lowly acetylated upon erlotinib treatment. Combination of mTOR or PI3K inhibitor and erlotinib overcomes TKI resistance to inhibit cell growth and induce apoptosis in TKI-resistant NSCLC cells. Furthermore, the phosphorylation and acetylation of FOXO1 are reversely modulated by mTORC2-AKT signaling pathway. FOXO1 mutation analyses reveal that FOXO1 acetylation inhibits cell proliferation and promotes NSCLC cell apoptosis, while the phosphorylation of FOXO1 plays opposite roles in NSCLC cells. Importantly, increasing FOXO1 acetylation by a HDAC inhibitor, depsipeptide, overcomes TKI resistance to effectively induce TKI-resistant NSCLC cell apoptosis. Together, FOXO1 plays dual roles in TKI resistance through posttranslational modifications in NSCLC and this study provides a possible strategy for treatment of TKI-resistant NSCLC patients.

Hsa_circ_0003288 facilitates tumor progression by targeting miR-145 in non-small cell lung cancer cells.

Circular RNA (circRNA) has been shown to participate in various tumors, including lung cancer. In the present study, we explored the expression and functional relevance of hsa_circ_0003288 in human non-small cell lung cancer (NSCLC). We verified that hsa_circ_0003288 expression was upregulated in lung cancer tissues and cell lines. Overexpression of hsa_circ_0003288 dramatically promoted lung cancer cell proliferation, colony formation, inhibited apoptosis, and increased cell migration and invasion in vitro. Xenograft experiments showed that hsa_circ_0003288 overexpression accelerated tumor growth in vivo. Mechanistically, hsa_circ_0003288 negatively regulated miR-145 to exert the oncogenic role in lung cancer. Overexpression of miR-145 decreased cell proliferation, induced apoptosis, and suppressed migration and invasion in lung cancer. Additionally, miR-145 co-transfection abolished the oncogenic role of hsa_circ_0003288. Collectively, these findings identified a novel regulatory role of hsa_circ_0003288/miR-145 axis in the progression of NSCLC.

Associations between the use of ß-adrenoceptor acting drugs and the risk of dementia in older population.

Objective: Age-related decline within the noradrenergic system is associated with reduced cognition. The ß-adrenoceptors are widely expressed in the brain as well as in the peripheral. Medications targeting ß-adrenoceptor activity have been widely used in older adults. The aim of this study was to explore the associations between ß-adrenoceptor acting drugs and the risk of dementia in the older population. Methods: The subjects' information was collected from the electronic medical record (EMR) database. A propensity score matching strategy was conducted to select control participants for users of ß2-agonists or ß-antagonists. Logistic regression analysis was performed to estimate the risk of dementia with the use of ß2-agonists or ß-antagonists. Results: A total of 1,429 participants in the EMR database were included in the study. The use of ß2-agonists was strongly associated with a decreased risk of dementia [OR = 0.324, 95% confidence interval (CI): 0.149-0.707, P = 0.005]. This decreased risk showed a statistically significant inverse time-dependent pattern (P trend = 0.014). However, the use of non-selective ß-antagonists significantly correlated with an increased dementia risk (OR = 1.961, 95% CI: 1.144-3.359, P = 0.014), although no time-dependent manner was found (P trend = 0.220). There was no association between selective ß1-antagonists usage and dementia risk (OR = 1.114, P = 0.625). Conclusion: The use of ß-adrenoceptor acting drugs seems to be associated with the risk of dementia. Pharmacological interventions modulating ß2-adrenoceptor activity might be a potential target in therapeutics for dementia.

A detrimental mutation on USP40 unlocks the tumorigenesis in a rare case of lung cancer.

Lung adenocarcinoma (LUAD) is the most common histologic subtype of lung cancer. Previous research has shown heterogeneity in lung cancer, with the parallel existence of multiple subclones characterized by their own specific mutational landscape. The aim of our study was to gain insight into the evolutionary pattern of lung cancer by investigating the genomic heterogeneity between a nodule and its distant tumor. Luckily, we obtained nodule and tumor samples derived from surgery and a blood sample from a single patient. The samples are very unique, for tissues with the same genetic background from nodules to malignant tumors are rarely available and require precise micro-cutting. In this study, we performed whole-genome sequencing of these two samples, to identify novel candidate driver genes associated with LUAD. The nodule and tumor were found to have common significant ubiquitin-specific protease 40 (USP40) mutations, indicating an important driver role for the gene. Moreover, we also observed the two novel candidate driver genes ASCL5 and CAPNS1 in the LUAD sample. In summary, we pinpoint the predominant mutations in LUAD by WES, highlighting the substantial genetic alterations contributing to LUAD tumorigenesis. This may provide a better understanding of the clonal evolution during tumor development.

Characteristics of circulating tumor cells in organ metastases, prognosis, and T lymphocyte mediated immune response.

Circulating tumor cells (CTCs) possess profound influence on tumor metastases and disease progression. This study aimed to investigate the correlation of CTCs with clinical characteristics and T-cell immunity, and to explore whether CTCs and the subpopulations can serve as an independent prognostic factor in advanced non-small cell lung cancer (NSCLC). A prospective study was conducted in late stages of NSCLC patients. The levels of overall CTCs and the three subpopulation CTCs were enumerated using the CanPatrol™ CTC enrichment system. The information about the patients which included the clinical characteristics, survival status at the 200th day postdiagnosis, and the levels of T cells was collected. Mann-Whitney U test, Kruskal-Wallis H test, Cox regression, and Spearman's rank correlation coefficient were the statistical methods used in this study. We detected CTCs in 27 of the 31 eligible patients; the level of epithelial-mesenchymal circulating tumor cells (EMCTCs) was higher than that of epithelial circulating tumor cells and that of mesenchymal circulating tumor cells (MCTCs) in the majority of NSCLC patients. Organ metastases were positively associated with the levels of overall CTCs, EMCTCs, and MCTCs (P<0.05). EMCTCs and MCTCs were associated with worse clinical outcomes. Additionally, the levels of EMCTCs were negatively associated with the levels of CD3+ T cells (P=0.01) and CD8+ T cells (P=0.04). In conclusion, the levels of CTCs were positively associated with organ metastases, particularly bone metastases, but were negatively associated with T-cell levels. The levels of EMCTCs and MCTCs had negative prognostic value.

Rituximab effectively reverses Tyrosine kinase inhibitors (TKIs) resistance through inhibiting the accumulation of rictor on mitochondria-associated ER-membrane (MAM).

Tyrosine kinase inhibitors (TKIs), a novel group of target-specific anti lung cancer drugs, have recently been found to resistant to some NSCLC cells which have the T790M EGFR mutation. However, recent investigations on the therapies of resistance to EGFR-TKIs are very limited. Therefore, it is important to develop more effective therapies to reverse EGFR-TKIs resistance. In our present study, erlotinib was used as the TKIs drug and the effects of the erlotinib on cell growth were evaluated. Cell viability and concentration dependent studies were performed using HCI-H1975 and HCI-H1299 cells alone with erlotinib, respectively. Further combined with rituximab, the results showed that erlotinib and rituximab were significantly inhibited the cell growth. Furthermore, the combination of erlotinib and rituximab greatly decreased the expression of p-mTOR and p-EGFR. Additional results from western blotting and immunofluorescence assays demonstrated that the accumulation of rictor was also decreased on MAM. Thus, all these results suggested that EGFR-TKIs combined with CD20 mono-antibody significantly decrease the cell growth of H1975 cells and H1299, with T790M EGFR mutation, and inhibit the localization of the key mTOR pathway proteins to MAM. So, it may be a promising strategy for overcoming EGFR TKI resistance in NSCLC patients.

Significance of NLDA, the commixed index of inflammation, immune responses, hemostasis, and nutrition, for predicting metastatic non-small cell lung cancer prognosis and metastases.

PURPOSE: This study aimed to take a comprehensive review of the hematological indexes and discover a novel, comprehensive, and economical index for prognostic prediction. RESULTS: The predictive prognostic model revealed that an elevated value of NLDA (NLDA = neutrophil count/lymphocyte count × D-dimer count/albumin) was an independent risk factor for one-year adverse prognosis (hazard ratio = 3.038; 95% confidence interval [CI], 1.959-4.712; P < 0.001). The C-indexes of internal and external validation in nomogram were 0.738 (95% CI, 0.686-0.79) and 0.731 (95% CI, 0.631-0.831), respectively. The areas under the curves of the NLDA values in retrospective and prospective studies were 0.700 (95% CI, 0.631-0.769; P < 0.001) and 0.692 (95% CI, 0.535-0.822; P = 0.005), respectively. The cut-off value of NLDA was 0.15. NLDA was positively associated with M stage (P = 0.032), organ metastasis counts (P = 0.006), liver metastases (P = 0.019), and vertebrae metastases (P = 0.013). MATERIALS AND METHODS: This was a retrospective and prospective study. The clinicopathological characteristics and hematological parameters of stage IV non-small cell lung cancer patients were analyzed retrospectively and prospectively to establish a valid predictive prognostic model. The primary endpoint was the 1-year overall survival. The predictive prognostic model was established and validated by Cox Regression and nomogram. The cut-off and predictive prognostic values of the novel indexes were calculated through the receiver operating characteristic curves. The chi-square test was used to explore the correlation between the new prognostic hematological index and metastatic characteristics. CONCLUSIONS: In this study, NLDA, a new, comprehensive and economic parameter, was found to be an independent adverse prognostic factor for stage IV non-small cell lung cancer patients, and was positively associated with organ metastases.

Pulmonary enteric adenocarcinoma with pancreatic metastasis: A case report.

Pulmonary enteric adenocarcinoma is a markedly rare pathological type of lung adenocarcinoma. As the pancreas is a relatively uncommon site for metastasis, the present case is even more unusual. A 62-year-old male was admitted to hospital following the identification of masses in the left chest wall, right abdominal wall and right upper limb, but with no respiratory symptoms. Computed tomography (CT) of the chest revealed a lump in the lung and a mass in the left chest wall, and 18F-fluorodeoxyglucose (18F-FDG) uptake by the lumps was increased. An enhanced abdominal CT revealed a hypodense and homogeneous mass on the head of the pancreas, which was slightly enhanced compared with normal pancreatic tissue. In addition, the 18F-FDG uptake of the lesion was increased and the standardized uptake value (SUV) delayed was not evidently decreased compared with SUVearly. A number of other abnormal metabolic lesions were also identified using positron emission tomography/CT, whereas no abnormal 18F-FDG uptake was identified in the gastrointestinal organ. Furthermore, rectocolonoscopy was performed to exclude diagnosis of metastatic colorectal adenocarcinoma. The hematoxylin- and eosin-stained smears of the masses in the right lung and left chest demonstrated an enteric pattern, which shared morphological and immunohistochemical (IHC) features with those of colorectal adenocarcinoma. The IHC detection revealed that the lesions in the right lung were positive for cytokeratin 7 (CK7), and negative for CK20 and thyroid transcription factor 1 (TTF-1), and the expression of caudal type homeobox 2 (CDX2) was weakly positive; the masses in the left chest wall were positive for CK7, negative for TTF-1, and CK20 and CDX2 were weakly expressed.

[Pulmonary sclerosing hemangioma: report of 15 cases and review of the literature].

OBJECTIVE: To improve the understanding of pulmonary sclerosing hemangioma (PSH). METHODS: The clinical data of 15 cases of PSH were analyzed, and the literature was reviewed. The etiology, clinical manifestations, differential diagnosis, treatment and outcome of PSH were described. RESULTS: The etiology and histological origin of PSH were unclear. Most cases were asymptomatic or only with mild symptoms. The radiology of PSH often showed isolated nodule with distinct margin in the lung field. The characteristics of its pathological manifestation were as follows: (1) background of cell gathering or mucin matrix with scattered white blood cells; (2) proliferation of hemangioma with sclerosis of vessel wall; (3) papillary proliferation of small vessels intruding into the air space; (4) existence of hemorrhage or sclerosis zone. Immunohistological studies had not defined the correct histological origin of PSH. A pre-operation diagnosis of PSH was difficult. Thirteen cases had been misdiagnosed as malignancy. The outcome of the disease was good when early surgical resection was performed. CONCLUSIONS: PSH is an uncommon disease, and can be easily misdiagnosed. More attention should be paid to its clinical features and management.

RAF1-MEK1-ERK/AKT axis may confer NSCLC cell lines resistance to erlotinib.

The fact that advanced NSCLC patients with wild type (wt) EGFR can benefit from erlotinib therapy makes it critical to find out biomarkers for effective selection of patients and improving the therapy effects. In present study, 3 NSCLC cell lines (U1752, Calu-6 and NCI-H292) with wt EGFR and different sensitivities to erlotinib were used for microarray analysis. The differential basal gene expression between 2 NSCLC cell lines was analyzed, about 353 genes were expression-altered with higher than 2-fold changes between Calu-6 and U1752. And Ingenuity Pathway Analysis (IPA) showed that these genes were mainly enriched in regulation of epithelial-mesenchymal transition (EMT) pathway, Wnt-ß catenin signaling, Tec kinase signaling and some types of cancer-related signaling. More interestingly, RAF1 (c-raf), MAP2K1 (MEK1), SNAI and downstream signaling molecules ERK and AKT were predicted to be activated in erlotinib-resistant cell line by IPA. Subsequent immunoblotting experiments showed that the phosphorylation of ERK and AKT were exactly increased stepwise from erlotinib sensitive cell line to erlotinib resistant cell lines. Collectively, activation of RAF1-MEK1-ERK/AKT axis may determine the resistance of NSCLC cell lines bearing wt EGFR to erlotinib. Our work provides potential biomarkers and therapeutic targets for NSCLC patients harboring wt EGFR.