Effects of methylation and transcription factor YY1 on ID2 expression in non-small cell lung carcinoma cells.

The inhibitor of DNA-binding 2 (ID2) plays a major role in tumor dedifferentiation in non-small cell lung cancer (NSCLC). Studies have indicated an inverse correlation between ID2 expression and NSCLC cell invasiveness. However, the mechanisms through which ID2 activation is regulated are currently unclear. We overexpressed ID2 in H1299 cells and extensively characterized their cellular behaviors. By employing a serial deletion approach combined with a reporter assay, we pinpointed the basal promoter region of ID2. We also examined the DNA methylation status of the ID2 promoter to elucidate the epigenetic mechanisms driving ID2 regulation. Our results revealed that ID2 overexpression effectively inhibited the migration, invasion, proliferation, and colony formation abilities of H1299 cells. The region from -243 to +202 played a major role in driving the transcriptional activity of ID2. Sequence analysis results indicated that the transcription factor Yin Yang 1 (YY1) might be crucial in the regulation of ID2 expression. The ectopically expressed YY1 activated both the expression levels of ID2 and the transcriptional activity of the ID2 promoter, potentially contributing to its repressive activity on cancer cell growth. Furthermore, site-directed mutagenesis and chromatin immunoprecipitation assays revealed that YY1 may target the -120 and -76 sites of the ID2 promoter, thereby activating its transcriptional activity. The ID2 promoter regions were also fully methylated in CL1-5 cells, and the methylation level was correlated with the expression levels of the ID2 promoter. Moreover, the YY1-induced suppression of colony formation was counteracted by ID2 knockdown, which suggests that YY1 represses cell colony growth through the regulation of ID2. Our results indicate that YY1 plays a role in transactivating ID2 expression and might also contribute to the repression of colony growth through the regulation of ID2.

Antibodies against Small Ubiquitin-like Modifier Activating Enzyme May Be a Protective Factor from Rapid Progressive Interstitial Lung Disease in Patients Bearing Antibodies against Melanoma Differentiation Associated Gene 5.

Background: Anti-MDA5 antibody-bearing (anti-MDA5+)-dermatomyositis (DM) or polymyositis (PM) is notorious for causing rapidly progressive interstitial lung disease (RPILD) and/or cancers with high mortality rate. However, anti-MDA5 antibodies (Abs) are also found in other connective tissue diseases and their link with RPILD, especially with regard to the mortality rate, are unknown. Methods: We retrospectively recruited 71 patients bearing anti-MDA5-Abs in serum, stratified them in terms of a presence or absence of RPILD, and evaluated their clinical features, laboratory findings, associated myositis antibodies, concurrent connective tissue disease (CTD) as well as newly developed malignancies. Results: In total, 39 (55%) patients presented with DM/PM, but 32 (45%) did not. In total, 22 of the former and 11 of the latter developed RPILD eventually, accounting for a total of 46% of all MDA-5 bearing patients. On the other hand, 15 of all 71 (21.1%) patients had cancers. Among the 32 patients who did not have DM/PM, 27 (38.0% of all 71) had other CTDs, indicating that only 5 (7.0% of 71) patients did not have CTDs. Senility (odds ratio (OR) = 1.816, p = 0.032), presence of anti-Ro-52 antibody (OR = 1.676, p = 0.018), elevated C-reactive protein (CRP, OR = 4.354, p < 0.001) and carcinoembryonic antigen (CEA, OR = 2.625, p = 0.005) posed risks for RPILD. High lactose dehydrogenase (LDH, p = 0.009), CRP (p = 0.001) and CEA (p = 0.001), ferritin (p ≤ 0.001) and low albumin (p ≤ 0.001) were significantly associated with mortality. Anti-SAE antibodies were negatively correlated with RPILD as analyzed by univariate (OR = 0.245, p = 0.017) and multivariate (OR = 0.058, p = 0.036) regressions, indicating that they may be a protective factor in relation to RPILD (OR = 0.543, p = 0.008) or fatality (OR = 0.707, p = 0.012), which was also demonstrated in subgroup analyses. Conclusions: In contrast to various risk factors for RPILD or mortality, anti-SAE antibodies might conversely be a protective factor in anti-MDA5+ patients.

Survival Analysis in Patients with Lung Cancer and Subsequent Primary Cancer: A Nationwide Cancer Registry Study.

With improved survival in patients with cancer, the risk of developing multiple primary malignancies (MPMs) has increased. We aimed to characterize MPMs involving lung cancer and compare these characteristics between patients with single lung cancer and those with lung cancer and subsequent primary cancer (known as lung cancer first [LCF]). Methods: This retrospective study was conducted based on Taiwan Cancer Database from Taiwan's National Health Insurance Registry Database. Patients with lung cancer (n = 72,219) from 1 January 2011 to 31 December 2015, were included in this study, and their medical records were traced back to 1 January 2002, and followed until 31 December 2019. Results: MPMs occurred in 10,577 (14.65%) patients with lung cancer, and LCF and other cancer first (OCF) accounted for 35.55% and 64.45% of these patients, with a mean age at lung cancer diagnosis of 65.18 and 68.92 years, respectively. The median interval between primary malignancies in the OCF group was significantly longer than that in the LCF group (3.26 vs. 0.11 years, p < 0.001). Patients in the single lung cancer group were significantly older than those in the LCF group (67.12 vs. 65.18 years, p < 0.001). The mean survival time of patients with LCF was longer than that of patients with single lung cancer. Following initial lung cancer, the three most common second primary malignancies were lung, colon, and breast cancers. For patients with advanced lung cancer, survival in patients with mutant epidermal growth factor receptor (EGFR) was longer than that in patients with undetected EGFR. In stage 3 and 4 patients with EGFR mutations, the LCF group showed better survival than the single lung cancer group. Conversely, in stage 1 patients with mutant EGFR, the LCF group exhibited worse survival than the single lung cancer group. Conclusions: Survival in patients with MPMs depends on baseline characteristics and treatments. Our findings may contribute to the development of precision medicine for improving personalized treatment and survival as well as the reduction of medical costs.

Treating with Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitors (TKIs) Accompanying Lower Incidence of Second Primary Cancers.

Lung cancer survivors are at risk of developing second primary cancers (SPCs). Although some risk factors for the development of SPCs have been addressed, their impacts have not been clarified. This study, based on Taiwan's National Health Insurance Research Database (NHIRD), a nationwide database, was designed to investigate the risk factors for SPCs in patients with initial lung cancer and identify the impacts of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment on the development of SPCs. In this study, 37,954 individuals were included, of whom 2819 had SPCs. These patients were further divided into the second primary lung cancers (SPLC) and second primary extrapulmonary cancer (SPEC) groups. Among the patients with lung cancer without SPCs, those aged <65 years accounted for 53.15%. Patients aged ≥65 years accounted for 40.18% and 53.24% in the SPLC and SPEC groups, respectively. Females accounted for 50.3% of patients without SPC, 54% of the SPLC group, and 44.3% of the SPEC group. Univariate and multivariate Cox proportional hazard models showed increased hazard ratios for smoking, hypertension, and diabetes mellitus, and lower HRs for surgery, chemotherapy, radiotherapy, and TKIs. Patients undergoing surgery, chemotherapy, and radiotherapy were associated with a lower risk of SPCs. Treatment with EGFR TKIs was a significant and independent factor associated with lower incidence of SPCs. This study may encourage researchers to establish predictive models based on our results to assess the risk factors for SPCs, and therefore, early screening and intervention could be applied, and the SPCs-related mortality and relevant medical costs could be reduced.

Characteristics and local risk factors of community-acquired and health-care-associated Staphylococcus aureus pneumonia.

This study aims at identifying characteristics, risk factors and mortality of community-acquired (CAP) and health-care-associated pneumonia (HCAP) by Staphylococcus aureus (S. aureus). We retrieved adults with S. aureus CAP or HCAP diagnosed by blood or pleural effusion culture in 2.6 years, and compared with those of Streptococcus pneumoniae (S. pneumoniae) CAP or HCAP diagnosed by blood or respiratory culture, or urine antigen. We found 18 patients with CAP and 9 HCAP due to S. aureus (female 33%, 66.6 ± 12.4 years-old), and 48 patients with CAP and 15 HCAP due to S pneumoniae (female 41%, 69.5 ± 17.5 years). Diabetes mellitus (52% vs. 24%, p = 0.019), hemodialysis (11% vs. 0%, p = 0.046), skin lesions (44% vs. 0%, p < 0.001), cavitary nodules (37% vs. 1.6%, p < 0.001) and pleural effusions (48% vs. 18%, p = 0.007) were more common in staphylococcal than pneumococcal group. Three patients with staphylococcal pneumonia had acute myocardial infarction. Pneumonia severity index (139 ± 52 vs. 109 ± 43, p = 0.005) and 30-day mortality (41% vs. 9.5%, p = 0.001) were higher in staphylococcal group. Multivariate analysis showed underlying disease (especially cancer and cirrhosis), risk class 4/5, altered mentality, shock and bilateral pneumonia were risk factors for 30-day mortality.