Ni-induced TGF-ß signaling promotes VEGF-a secretion via integrin ß3 upregulation.

Nickel compounds are associated with lung and skin cancer incidence increase and accumulation of nickel in the body contributes to carcinogenesis. Upregulation of certain integrins in the primary tumor is associated with cancer metastasis and poor prognosis. However, the molecular mechanisms of nickel-induced cancer metastasis are still unclear. The purpose of the present study was to investigate the effects of nickel chloride (NiCl2 ) on the progression of cancer during metastasis. The results of showed that NiCl2 induces the expression of integrin ß3 mRNA and protein in a dose- and time-dependent manner. Inhibition of integrin αvß3 activation by ITGB3 ligand mimetics and GR144053, as well as downregulation of ITGB3 by lentiviral shRNA gene silencing, diminished NiCl2 -induced secretion of vascular endothelial growth factor-a (VEGF-a). Furthermore, pretreatment with type I TGF-ß receptor inhibitor, SB525334, suppressed the expression of ITGB3 at cell surface and secretion of VEGF-a in NiCl2 -treated cells. In conclusion, NiCl2 induces the expression of ITGB3 through TGF-ß signaling activation, followed by increasing VEGF-a secretion, revealing a novel role for ITGB3 in nickel compound-induced cancer metastasis and tumor angiogenesis.

Epithelial growth factor receptor tyrosine kinase inhibitors alleviate house dust mite allergen Der p2-induced IL-6 and IL-8.

Steroid-insensitive asthma-related airway inflammation is associated with the expression of epidermal growth factor receptor (EGFR) tyrosine kinase in asthmatic bronchial epithelium. Proinflammatory cytokines IL-6 and IL-8 are related to steroid-insensitive asthma. It is currently unknown how EGFR-tyrosine kinase inhibitors (EGFR-TKIs) affects house dust mite (HDM)-induced asthma in terms of inflammatory cytokines related to steroid-resistant asthma and further signaling pathway. Cytokine expressions and EGFR signaling pathway were performed by ELISA, reverse transcriptase PCR, real-time PCR, and Western blot in cell-line models. AMP-activated protein kinase (AMPK) pathway-related inhibitors were applied to confirm the association between EGFR-TKI and AMPK pathway. HDM induced IL-6 and IL-8 in a dose-dependent manner. Both Erlotinib (Tarceva) and Osimertinib (AZD-9291) reduced the levels of HDM-stimulated IL-6 and IL-8 levels in BEAS-2B cells. AZD-9291 was more effective than Erlotinib in inhibiting phospho-EGFR, and downstream phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT) and phopho-signal transducer and activator of transcription 3 (p-STAT3) pathway signaling. In addition, AMPK pathway-related inhibitor, Calcium-/calmodulin-dependent protein kinase kinase ß (CaMKKß) inhibitor, down-regulated IL-8, but EGFR-TKI had no effect on AMPK pathway. Our findings highlight EGFR-TKIs, Tarceva, and AZD-9291, attenuate HDM-induced inflammatory IL-6 and IL-8 cytokines via EGFR signaling axis pathway, but not AMPK signaling pathway.

Increased apoptosis and peripheral blood mononuclear cell suppression of bone marrow mesenchymal stem cells in severe aplastic anemia.

BACKGROUND: Although immune-mediated pathogenesis is considered an important aspect of severe aplastic anemia (SAA), its underlying mechanisms remain unclear. Mesenchymal stem cells (MSCs) are essential to the formation of specialized microenvironments in the bone marrow (BM), and MSC insufficiency can trigger the development of SAA. METHODS: To find MSC alterations in the SAA BM, we compared BM MSCs from five children with SAA and five controls. Peripheral blood mononuclear cells (PBMCs) were cocultured with MSCs to evaluate the supportive effects of MSCs on hematopoiesis. Cytometric bead array immunoassay was used to determine cytokine excretion by MSCs. The immune functions of MSCs and their conditioned medium (CM) were evaluated by PBMC proliferation assays. RESULTS: SAA MSCs were characterized by a high percentage of cells in the abnormal sub-G1 phase of the cell cycle, which suggests an increased rate of apoptosis in SAA MSCs. In comparison with control MSCs, PBMCs cocultured with SAA MSCs displayed significantly reduced PBMC proliferation (P = 0.009). Aberrant cytokine profiles were secreted by SAA MSCs, with increased concentrations of interleukin-6, interferon-γ, tumor necrosis factor-α, and interleukin-1ß in the CM. PBMC proliferation assays demonstrated additional immunosuppressive effects of SAA MSCs (P = 0.016) and their CM (P = 0.013). CONCLUSIONS: Our data revealed increased apoptosis and PBMC suppression of SAA MSCs. The alterations of MSCs may contribute to the formation of functionally abnormal microenvironments in SAA BM.

Post-inhaled corticosteroid pulmonary tuberculosis and pneumonia increases lung cancer in patients with COPD.

BACKGROUND: Inhaled corticosteroids (ICS) have been associated with decreased lung cancer risk. However, they have been associated with pulmonary infections (tuberculosis [TB] and pneumonia) in patients with chronic obstructive pulmonary disease (COPD). TB and pneumonia have increased lung cancer risk. The association between post-ICS pulmonary infections and lung cancer remains unclear. METHODS: We conducted a retrospective cohort study from 2003 to 2010 using the Taiwan National Health Insurance Research Database. Among the 1,089,955 patients with COPD, we identified 8813 new users of ICS prescribed for a period of 3 months or more and 35,252 non-ICS users who were randomly matched for sex, age and date of ICS use from 2003 to 2005. Cox proportional hazard regression was used to estimate the hazard ratio (HR) of pulmonary infections in patients with/without ICS use. RESULTS: The HRs for lung cancer in ICS users with sequential lung infections were as follows; 2.42 (95 % confidence interval [CI], 1.28-4.58) for individuals with TB, 2.37 (95 % CI, 1.01-5.54) for TB and pneumonia, and 1.17(95 % CI, 0.69-1.98) for those with pneumonia. For non-ICS users with pulmonary infections, the HRs were 1.68 (95 % CI, 0.78-3.65) for individual with TB and pneumonia, 1.42 (95 % CI, 0.89-2.26) for TB, and 0.95 (95 % CI, 0.62-1.46) for individuals with pneumonia. CONCLUSIONS: COPD patients with TB /or pneumonia who used ICS had increased risk of lung cancer. Because the overall prognosis of lung cancer remains poor, screening tests are recommended for patients with these conditions.

Post-Inhaled Corticosteroid Pulmonary Tuberculosis Increases Lung Cancer in Patients with Asthma.

PURPOSE: To evaluate the association between post-inhaled corticosteroid (ICS) pulmonary tuberculosis (TB), pneumonia and lung cancer in patients with asthma. METHODS: The study samples were collected from the National Health Insurance Database. Asthmatic patients who were first-time users of ICS between 2003 and 2005 were identified as cases. For each case, 4 control individuals were randomly matched for sex, age and date of ICS use. Cases and matched controls were followed up until the end of 2010. Cox proportional hazard regression was used to determine the hazard ratio for pulmonary infections and lung cancer risk in the ICS users and non-users. RESULTS: A total of 10,904 first-time users of ICS were matched with 43,616 controls. The hazard ratios for lung cancer were: 2.52 (95% confidence interval [CI], 1.22-5.22; p = 0.012) for individuals with post-ICS TB, 1.28 (95%CI, 0.73-2.26; p = 0.389) for post-ICS pneumonia, 2.31(95%CI, 0.84-6.38; p = 0.105) for post-ICS pneumonia+TB, 1.08 (95%CI, 0.57-2.03; p = 0.815) for TB, 0.99 (95%CI, 0.63-1.55; p = 0.970) for pneumonia, and 0.32 (95%CI, 0.05-2.32; p = 0.261) for pneumonia+ TB, respectively. CONCLUSIONS: Post-ICS TB increased lung cancer risk in patients with asthma. Because of the high mortality associated with lung cancer, screening tests are recommended for patients with post-ICS TB.

Pre-existing Pulmonary Diseases and Survival in Patients With Stage-dependent Lung Adenocarcinoma: A STROBE-compliant Article.

Asthma, chronic obstructive pulmonary disease (COPD), and pulmonary tuberculosis (TB) are common lung diseases associated with lung cancer mortality. This study evaluated sex disparities in pre-existing pulmonary diseases and stage-dependent lung adenocarcinoma survival.Patients newly diagnosed with lung adenocarcinoma between 2003 and 2008 were identified using the National Health Insurance Research Database and Cancer Registry. Cases with lung adenocarcinoma were followed until the end of 2010. Survival curves were estimated by the Kaplan-Meier method. Cox proportional-hazard regression was used to calculate the hazard ratio (HR) of pre-existing asthma, COPD, and/or TB, and to estimate all-cause mortality risk in patients with different stages of lung adenocarcinoma.A total of 14,518 cases were identified with lung adenocarcinoma. Specifically, among men, the HRs for TB were 1.69 (95% confidence interval [CI], 1.10-2.58), 1.48 (95% CI, 1.14-1.93), and 1.27 (95% CI, 1.08-1.49) for individuals with stage I + II, III, and IV diseases, respectively. The HRs for asthma were 1.41 (95% CI, 1.00-1.99) in women with stage I + II and 1.14 (95% CI, 1.04-1.26) in men with stage IV disease. For pulmonary disease combinations in men, the HRs were 1.45 (95% CI, 1.12-1.89) for asthma + COPD + TB, 1.35 (95% CI, 1.12-1.63) for COPD + TB, 1.28 (95% CI, 1.01-1.63) for TB, and 1.15 (95%CI, 1.04-1.27) for asthma + COPD, respectively. For women with stage I + II disease, the HR was 6.94 (95% CI, 2.72-17.71) for asthma + COPD + TB.Coexistence of pre-existing pulmonary diseases increased mortality risk in men with adenocarcinoma. TB is at elevated risk of mortality among men with different stages of adenocarcinoma. Asthmatic women with early-stage adenocarcinoma had increased risk of mortality.

The use of corticosteroids in patients with COPD or asthma does not decrease lung squamous cell carcinoma.

BACKGROUND: Asthma and COPD (chronic obstructive pulmonary disease) lead to persistent airway inflammation and are associated with lung cancer. The objective of the study was to assess the relationship between inhaled (ICS) and oral corticosteroid (OCS) use, and risk of lung squamous cell carcinoma (SqCC). METHODS: This study was a nested case-control study. Patients with newly diagnosed asthma or COPD between 2003 and 2010 were identified from the National Health Insurance Database. Cases were defined as patients diagnosed with SqCC after enrollment. For each case, four control individuals who were randomly matched for sex and age and date diagnosis of asthma or COPD were selected. RESULTS: From the 1,672,455 eligible participants, 793 patients with SqCC were matched with 3,172 controls. The odds ratios (ORs) of SqCC in men who received high and low-dose ICS were 2.18 (95 %CI, 1.56-3.04) and 1.77 (1.22-2.57), respectively. Similarly, the ORs were 1.46 (95 %CI, 1.16-1.84) and 1.55 (95 %CI, 1.22-1.98) for men who were placed on low and high dose OCS. However, there was no significant association between cumulative ICS and/or OCS and risk of SqCC in women. Recent dose increase in corticosteroid was significantly associated with risk of SqCC. Specifically, among men, the ORs for SqCC were 8.08 (95 %CI, 3.22-20.30) for high-dose ICS + OCS, 4.49 (95 % CI, 2.05-9.85) for high-dose ICS, and 3.54 (95 % CI, 2.50-5.01) for high-dose OCS treatments, respectively. The OR for SqCC in women who received high-dose OCS was 6.72 (95 %CI, 2.69-16.81). CONCLUSION: Corticosteroid use did not decrease SqCC in patients with asthma or COPD. Recent dose increase in corticosteroids was associated with SqCC.

The effects of pulmonary diseases on histologic types of lung cancer in both sexes: a population-based study in Taiwan.

BACKGROUND: The associations between pulmonary diseases (asthma, chronic obstructive pulmonary disease [COPD], and tuberculosis [TB]) and subsequent lung cancer risk have been reported, but few studies have investigated the association with different histologic types of lung cancer. METHODS: Patients newly diagnosed with lung cancer from 2004 to 2008 were identified from the National Health Insurance Research Database in Taiwan. Histologic types of lung cancer were further confirmed using the Taiwan Cancer Registry Database. Cox proportional hazards regression was used to calculate the hazard ratio (HR) of asthma, COPD, and TB and to estimate the risk of specific types of lung cancer. RESULTS: During the study period, 32,759 cases of lung cancer were identified from 15,219,024 insurants aged 20 years and older. In men and women, the adjusted HR estimates of squamous cell carcinoma were respectively 1.37 (95 % confidence interval [CI], 1.21-1.54) and 2.10 (95 % CI, 1.36-3.23) for TB, 1.52 (95 % CI, 1.42-1.64) and 1.50 (95 % CI, 1.21-1.85) for asthma, and 1.66 (95 % CI, 1.56-1.76) and 1.44 (95 % CI, 1.19-1.74) for COPD. Similarly, the adjusted HR estimates of adenocarcinoma were respectively 1.33 (95 % CI, 1.19-1.50) and 1.86 (95 % CI, 1.57-2.19) for TB, 1.13 (95 % CI, 1.05-1.21) and 1.18 (95 % CI, 1.09-1.28) for asthma, and 1.50 (95 % CI, 1.42-1.59) and 1.33 (95 % CI, 1.25-1.42) for COPD. The HRs of small cell carcinoma were respectively 1.24 (95 % CI, 1.01-1.52) and 2.23 (95 % CI, 1.17-4.25) for TB, 1.51 (95 % CI, 1.35-1.69) and 1.63 (95 % CI, 1.16-2.27) for asthma, and 1.39 (95 % CI, 1.26-1.53) and 1.78 (95 % CI, 1.33-2.39) for COPD. CONCLUSIONS: Asthma, COPD, and TB were associated with an increased risk of all major subtypes of lung cancer. The risk was the highest among women with TB.

The Impact of Coexisting Asthma, Chronic Obstructive Pulmonary Disease and Tuberculosis on Survival in Patients with Lung Squamous Cell Carcinoma.

BACKGROUND: Pulmonary diseases [asthma, chronic obstructive pulmonary disease (COPD), and tuberculosis (TB)] are associated with lung cancer mortality. However, the relationship between coexisting pulmonary diseases and survival in patients with lung squamous cell carcinoma (SqCC) has not been well defined. METHODS: Patients newly diagnosed with SqCC between 2003 and 2008 were identified by linking the National Health Insurance Research Database and Taiwan Cancer Registry Database. Cases with SqCC were followed up until death, loss to follow-up, or study end in 2010. Information on health status, date of death and the main causes of death was ascertained from the National Death Registry Database. Cox proportional hazard regression was used to calculate the hazard ratio (HR) of coexisting asthma, COPD and/or TB. RESULTS: During the study period, a total of 5406 cases with SqCC were enrolled. For all cause-mortality, HRs were 1.08 [95% confidence interval (CI), 0.99-1.18], 1.04 (95% CI, 0.97-1.12), and 1.14 (95% CI, 1.00-1.31) for individuals with asthma, COPD, and TB, respectively. Specifically, among men with coexisting pulmonary diseases, the HRs were 1.56 (95% CI, 1.23-1.97) and 1.11 (95% CI, 1.00-1.24) for individuals with asthma+COPD+TB and asthma+COPD, respectively. Among male patients with stage III SqCC, HRs were 3.41 (95%CI, 1.27-9.17) and 1.65 (95%CI, 1.10-2.47) for individuals with asthma+TB and asthma+COPD+TB, respectively. Among male patients with stage IV SqCC, HRs were 1.40 (95%CI, 1.00-1.97) and 1.25 (95%CI, 1.03-1.52) for individuals with asthma+ COPD+TB and asthma. Among female patients with stage I and II, HR was 0.19 (95%CI, 005-0.77) for individuals with asthma. CONCLUSIONS: Coexisting pulmonary diseases increased the risk of mortality from SqCC in male patients. For female patients with early stage SqCC, pre-existing asthma decreased mortality. These patients deserve greater attention while undergoing cancer treatment.

Impact of coexisting pulmonary diseases on survival of patients with lung adenocarcinoma: a STROBE-compliant article.

Asthma, chronic obstructive pulmonary disease (COPD), and pulmonary tuberculosis (TB) are common pulmonary diseases associated with lung cancer. Besides, smoking is more prevalent in Taiwanese men. This study evaluated gender disparities in coexisting pulmonary diseases on survival of patients with lung adenocarcinoma. Patients newly diagnosed with lung cancer between 2003 and 2008 were identified from Taiwan National Health Insurance Research Database. Cases with lung adenocarcinoma were further confirmed using the Cancer Registry Database and followed up until the end of 2010. Cox proportional hazard regression was used to calculate the hazard ratio (HR) of coexisting asthma, COPD, and/or TB to estimate all-cause mortality risk. During the study period, 13,399 cases of lung adenocarcinoma were identified. The HRs of adenocarcinoma in men and women were 1.20 (95% confidence interval [CI], 1.10-1.30) and 1.05 (95% CI, 0.95-1.16), respectively, for individuals with asthma, 1.32 (95% CI, 1.16-1.51) and 0.97 (95% CI, 0.89-1.05), respectively, for COPD, and 0.99 (95% CI, 0.93-1.06) and 1.06 (95% CI, 0.86-1.32), respectively, for individuals with TB. Specifically, among men with coexisting pulmonary diseases, the HRs were 1.63 (95% CI, 1.25-2.13), 1.31 (95% CI, 1.08-1.59), and 1.23 (95% CI, 1.11-1.36) for individuals with asthma + COPD + TB, asthma + COPD, and COPD + TB, respectively. However, there was no increase risk of mortality among women with coexisting pulmonary diseases. Coexisting pulmonary diseases are at an elevated risk of mortality among male patients with lung adenocarcinoma. Such patients deserve greater attention while undergoing cancer treatment.

The coexistence of common pulmonary diseases on the histologic type of lung cancer in both genders in Taiwan: a STROBE-compliant article.

Effects of pulmonary diseases [asthma, chronic obstructive pulmonary disease (COPD), and lung tuberculosis (TB)] on subsequent lung cancer development have been reported. However, whether patients with coexisting pulmonary diseases are at greater risk of developing various histologic types of lung cancer remains elusive. Patients newly diagnosed with lung cancer between 2004 and 2008 were identified from National Health Insurance Research Database (Taiwan). The histologic types of lung cancer were further confirmed using Taiwan Cancer Registry Database. Cox proportional hazard regression was used to calculate the hazard ratio (HR) of coexisting asthma, COPD and/or TB to estimate lung cancer risk by histologic type. During the study period, 32,759 cases of lung cancer were identified from 15,219,024 residents age 20 years and older, who were free from the disease before 2003. Coexisting pulmonary diseases showed stronger association with lung cancer than specific lung disorders. Specifically, among men, the HRs for squamous cell carcinoma (SqCC) were 3.98 (95% CI, 3.22-4.93), 2.68 (95% CI, 2.45-2.93), and 2.57 (95% CI, 2.10-3.13) for individuals with asthma+COPD+TB, asthma+COPD, and COPD+TB, respectively. Among women, the HRs for SqCC were 3.64 (95% CI, 1.88-7.05), 3.35 (95% CI, 1.59-7.07), and 2.21 (95% CI, 1.66-2.94) for individuals with TB, COPD+TB, and asthma+COPD, respectively. Adenocarcinoma HRs for men and women were 2.00 (95% CI, 1.54-2.60) and 2.82 (95% CI, 1.97-4.04) for individuals with asthma+COPD+TB, 2.28 (95% CI, 1.91-2.73) and 2.16 (95% CI, 1.57-2.95) for COPD+TB, and 1.76 (95% CI, 1.04-2.97) and 2.04 (95% CI, 1.02-4.09) for individuals with asthma+TB. Specifically, small cell carcinoma (SmCC) HRs among men were 3.65 (95% CI, 1.97-6.80), 2.20 (95% CI, 1.45-3.36), and 2.14 (95% CI, 1.86-2.47) for those with asthma+TB, asthma+COPD+TB, and asthma+ COPD, respectively. Among women, the HRs of SmCC were 8.97 (95% CI, 3.31-24.28), 3.94 (95% CI, 1.25-12.35) and 3.33 (95% CI, 2.23-4.97) for those with asthma+COPD+TB, COPD+TB, and asthma+COPD, respectively. Patients with coexistence of pulmonary diseases were more susceptible to lung cancer. Affected persons deserve greater attention while undergoing cancer screening.