Malignant pleural effusions (MPE) commonly result from malignant tumors and represent advanced-stage cancers. Thus, in clinical practice, early recognition of MPE is valuable. However, the current ...diagnosis of MPE is based on pleural fluid cytology or histologic analysis of pleural biopsies with a low diagnostic rate. This research aimed to assess the diagnostic ability of eight previously identified Non-Small Cell Lung Cancer (NSCLC)-associated genes for MPE. In the study, eighty-two individuals with pleural effusion were recruited. There were thirty-three patients with MPE and forty-nine patients with benign transudate. mRNA was isolated from the pleural effusion and amplified by Quantitative real-time PCR. The logistic models were further applied to evaluate the diagnostic performance of those genes. Four significant MPE-associated genes were discovered in our study, including Dual-specificity phosphatase 6 (DUSP6), MDM2 proto-oncogene (MDM2), Ring finger protein 4 (RNF4), and WEE1 G2 Checkpoint Kinase (WEE1). Pleural effusion with higher expression levels of MDM2 and WEE1 and lower expression levels of RNF4 and DUSP6 had a higher possibility of being MPE. The four-gene model had an excellent performance distinguishing MPE and benign pleural effusion, especially for pathologically negative effusions. Therefore, the gene combination is a suitable candidate for MPE screening in patients with pleural effusion. We also identified three survival-associated genes, WEE1, Neurofibromin 1 (NF1), and DNA polymerase delta interacting protein 2 (POLDIP2), which could predict the overall survival of patients with MPE.
Hypoxia preconditioning has been proven to be an effective method to enhance the therapeutic action of mesenchymal stem cells (MSCs). However, the beneficial effects of hypoxic MSCs in ...ischemia/reperfusion (I/R) lung injury have yet to be investigated. In this study, we hypothesized that the administration of hypoxic MSCs would have a positive therapeutic impact on I/R lung injury at molecular, cellular, and functional levels.
I/R lung injury was induced in isolated and perfused rat lungs. Hypoxic MSCs were administered in perfusate at a low (2.5×105 cells) and high (1×106 cells) dose. Rats ventilated with a low tidal volume of 6 ml/kg served as controls. Hemodynamics, lung injury indices, inflammatory responses and activation of apoptotic pathways were determined.
I/R induced permeability pulmonary edema with capillary leakage and increased levels of reactive oxygen species (ROS), pro-inflammatory cytokines, adhesion molecules, cytosolic cytochrome C, and activated MAPK, NF-κB, and apoptotic pathways. The administration of a low dose of hypoxic MSCs effectively attenuated I/R pathologic lung injury score by inhibiting inflammatory responses associated with the generation of ROS and anti-apoptosis effect, however this effect was not observed with a high dose of hypoxic MSCs. Mechanistically, a low dose of hypoxic MSCs down-regulated P38 MAPK and NF-κB signaling but upregulated glutathione, prostaglandin E2, IL-10, mitochondrial cytochrome C and Bcl-2. MSCs infused at a low dose migrated into interstitial and alveolar spaces and bronchial trees, while MSCs infused at a high dose aggregated in the microcirculation and induced pulmonary embolism.
Hypoxic MSCs can quickly migrate into extravascular lung tissue and adhere to other inflammatory or structure cells and attenuate I/R lung injury through anti-oxidant, anti-inflammatory and anti-apoptotic mechanisms. However, the dose of MSCs needs to be optimized to prevent pulmonary embolism and thrombosis.
The echogenic swirling pattern has a role in predicting malignant pleural effusion (MPE). However, its predictive ability is suboptimal, and its clinical utility remains to be defined. The aim of ...this study was to assess the diagnostic potential of the echogenic swirling pattern combined with pleural carcinoembryonic antigen (CEA) and routine laboratory tests of pleural effusion in MPE. The 80 consecutive patients with underlying malignancy and pleural effusions were recruited. All patients underwent one diagnostic thoracentesis with a cytologic examination of pleural fluid. Our study showed that the sensitivity of echogenic swirling patterns in MPE diagnosis was 67.7%, specificity was 72.2%, positive predictive value (PPV) was 89.4%, and negative predictive value (NPV) was 39.4%. Both CEA and lactate dehydrogenase (LDH) had acceptable sensitivity (71.0% and 60.7%) and specificity (72.2% and 77.8%). Combining the echogenic swirling pattern, pleural CEA, and pleural LDH, the highest sensitivity (95.2%) with a good PPV (86.8) was reached. In this clinical study, we found that combining the echogenic swirling pattern, pleural CEA, and pleural LDH had a higher sensitivity and a high positive predictive value for the diagnosis of MPE. This combination is a potentially suitable method for MPE screening in cancer patients with pleural effusions.
Recent evidence has suggested that synovial inflammation and macrophage polarization were involved in the pathogenesis of osteoarthritis (OA). Additionally, high-molecular-weight hyaluronic acid ...(HMW-HA) was often used clinically to treat OA. GRP78, an endoplasmic reticulum (ER) stress chaperone, was suggested to contribute to the hyperplasia of synovial cells in OA. However, it was still unclear whether HMW-HA affected macrophage polarization through GRP78. Therefore, we aimed to identify the effect of HMW-HA in primary synovial cells and macrophage polarization and to investigate the role of GRP78 signaling. We used IL-1β to treat primary synoviocytes to mimic OA, and then treated them with HMW-HA. We also collected conditioned medium (CM) to culture THP-1 macrophages and examine the changes in the phenotype. IL-1β increased the expression of GRP78, NF-κB (p65 phosphorylation), IL-6, and PGE2 in primary synoviocytes, accompanied by an increased macrophage M1/M2 polarization. GRP78 knockdown significantly reversed the expression of IL-1β-induced GRP78-related downstream molecules and macrophage polarization. HMW-HA with GRP78 knockdown had additive effects in an IL-1β culture. Finally, the synovial fluid from OA patients revealed significantly decreased IL-6 and PGE2 levels after the HMW-HA treatment. Our study elucidated a new form of signal transduction for HMW-HA-mediated protection against synovial inflammation and macrophage polarization and highlighted the involvement of the GRP78-NF-κB signaling pathway.
Tuberculosis (TB) and sarcoidosis are both granulomatous diseases with potential interassociations. However, much uncertainty remains; thus, the present study aimed to clarify the association between ...these diseases.
We established two cohorts in this retrospective longitudinal cohort study using data obtained from the Taiwan National Health Insurance Database from 2000 to 2015. One cohort, which comprised 31 221 patients with TB and 62 442 age-, sex- and index year-matched controls, was used to analyse the risk of sarcoidosis; the other cohort comprised 2442 patients with sarcoidosis and 9688 controls and was used to assess the risk of TB. A Cox proportional hazards model adjusted for potential confounders was used in each cohort.
Patients with TB showed an 8.09-fold higher risk of developing sarcoidosis than non-TB subjects (95% CI = 3.66-17.90), whereas patients with sarcoidosis showed a 1.85-fold higher risk of developing TB than non-sarcoidosis subjects (95% CI = 1.36-2.50). The TB subtype analysis revealed the highest risk of developing sarcoidosis in patients with extrapulmonary TB, and the highest risk of developing extrapulmonary TB was observed in patients with sarcoidosis compared with non-sarcoidosis subjects. Patients with TB showed a higher risk of developing sarcoidosis throughout the follow-up period, but patients with sarcoidosis only showed a higher risk of developing TB within the first year.
TB is a risk factor for developing sarcoidosis. The results of this bidirectional cohort study also highlight the clinical difficulty of diagnosing sarcoidosis and TB.
Osimertinib has demonstrated efficacy in patients with epidermal growth factor receptor (EGFR) T790M-positive non-small cell lung cancer (NSCLC) in clinical trials. However, real-world data on its ...effectiveness remain scarce. Taiwanese patients with T790M-positive locally advanced or metastatic NSCLC and progressive disease following treatment with at least one EGFR tyrosine kinase inhibitor (TKI) were enrolled from the osimertinib early access program. Of the 419 patients (mean age, 63 years; female, 67%), 53% were heavily pretreated (≥ third-line 3L), making osimertinib a fourth-line (4L) intervention. The median progression-free survival (PFS) was 10.5 months (95% confidence interval CI: 8.95-11.41); the 18-month PFS rate was 26.5%. The median overall survival (OS) was 19.0 months (95% CI: 16.30-20.95); the 24-month OS rate was 40.9%. The objective response rate was 32.46%, and the disease control rate was 86.38%. The median time to treatment discontinuation of osimertinib monotherapy was 11.9 months (95% CI: 10.49-13.11). Subgroup analyses of median PFS and OS in the chemotherapy combination group vs. the osimertinib monotherapy group yielded no difference. Central nervous system (CNS) metastasis, number of prior lines of therapy, and types of initial EGFR-TKIs did not significantly impact outcomes. The median PFS values were 9.0 (95% CI: 5.18-11.34) and 10.9 (95% CI: 9.18-11.90) months with and without CNS metastasis, respectively, and 10.8 (95% CI: 8.59-12.69), 13.6 (95% CI: 10.89-16.3), and 9.2 (95% CI: 7.8-10.62) months for second-line (2L), 3L, and ≥4L therapy, respectively. In patients who received osimertinib as 2L therapy, the median PFS values in response to prior afatinib, erlotinib and gefitinib treatment were 11.2 (95% CI: 4.85-4.79), 10.5 (95% CI: 8.59-20.26) and 8.7 (95% CI: 7.21-16.79) months, respectively. Overall, real-world data from Taiwan support the clinical benefits of osimertinib in EGFR T790M -positive NSCLC.
Sonographic septation is associated with prolonged hospitalization and increased mortality in patients diagnosed with empyema. However, it is unknown whether sonographic septation is associated with ...complicated parapneumonic effusion (CPPE) or the need for invasive procedures among patients with pneumonia. In this retrospective study, we included 180 patients with non-purulent neutrophilic exudative pleural effusion secondary to pulmonary infections such as pneumonia and lung abscess. We performed univariate and multivariate logistic regression analyses, including baseline clinical characteristics, values from blood samples, and sonographic echogenicity, to identify variables correlated with CPPE and the need for invasive procedures. Seventy of the 180 included patients (38.89%) displayed sonographic septation. Multivariate logistic regression analysis identified that sonographic septation (adjusted OR (AOR)=3.38 (95% CI 1.64 to 6.98), p=0.001) and younger age (AOR=2.63 (95% CI 1.24 to 5.58), p=0.012) were independently associated with CPPE. With regard to treatment strategy, sonographic septation (AOR 9.06 (95% CI 3.71 to 22.11), p<0.001) and total serum protein level (AOR=1.80 (95% CI 1.13 to 2.86), p=0.013) were independently associated with the need for subsequent invasive procedures in patients with CPPE using multivariate logistic regression analysis. Sonographic septation is a useful predictor of CPPE and may imply the need for early invasive procedures.
Epigenetic modification is considered a major mechanism of the inactivation of tumor suppressor genes that finally contributes to carcinogenesis. LIM homeobox transcription factor 1α (
) is one of ...the LIM-homeobox-containing genes that is a critical regulator of growth and differentiation. Recently,
was shown to be hypermethylated and functioned as a tumor suppressor in cervical cancer, ovarian cancer, and gastric cancer. However, its role in lung cancer has not yet been clarified. In this study, we used public databases, methylation-specific PCR (MSP), reverse transcription PCR (RT-PCR), and bisulfite genomic sequencing to show that
was downregulated or silenced due to promoter hypermethylation in lung cancers. Treatment of lung cancer cells with the demethylating agent 5-aza-2'-deoxycytidine restored
expression. In the lung cancer cell lines H23 and H1299, overexpression of LMX1A did not affect cell proliferation but suppressed colony formation and invasion. These suppressive effects were reversed after inhibition of LMX1A expression in an inducible expression system in H23 cells. The quantitative RT-PCR (qRT-PCR) data showed that LMX1A could modulate epithelial mesenchymal transition (EMT) through
) and
(
. NanoString gene expression analysis revealed that all aberrantly expressed genes were associated with processes related to cancer progression, including angiogenesis, extracellular matrix (ECM) remodeling, EMT, cancer metastasis, and hypoxia-related gene expression. Taken together, these data demonstrated that LMX1A is inactivated through promoter hypermethylation and functions as a tumor suppressor. Furthermore, LMX1A inhibits non-small cell lung cancer (NSCLC) cell invasion partly through modulation of EMT, angiogenesis, and ECM remodeling.
According to several studies, tuberculosis (TB) may be involved in the pathogenesis of cardiovascular disease. However, the relationship between TB and peripheral arterial disease (PAD) has not been ...studied. The aim of this study was to investigate whether patients with TB exhibit an increased risk of developing PAD.
The data assessed in this national population-based cohort study were obtained from the Taiwan National Health Insurance Database from 2000 to 2010. Patients with newly diagnosed TB were selected using the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes. The non-TB cohort was randomly frequency-matched to the TB cohort at a ratio of 2:1 according to age, sex and index year. Cox's proportional hazards regression models were used to analyse the risk of PAD.
We enrolled 14 350 patients with TB and 28 700 controls in this study. The risk of PAD was 3.93-fold higher in the patients with TB than in the non-TB controls after adjusting for age, sex, co-morbidities and socio-economic status. Based on the subgroup analysis, the TB cohort exhibited an increased risk of developing PAD compared with the non-TB cohort, regardless of age, sex, co-morbidities and socio-economic status. Patients with TB had a higher risk of developing PAD than healthy control subjects after 1 year of follow-up.
Patients with TB have a significantly higher risk of developing PAD than patients without TB. TB should be considered when evaluating a patient's risk of developing PAD.
Lung cancer has the highest number of deaths globally. About 75% of nonsmall cell lung cancer (NSCLC) cases are diagnosed at an advanced stage. Despite significant therapeutic progress, the prognosis ...remains poor. For patients who have undergone conventional treatment followed by disease progression, palliative care generally remains the only option. As reported in recent years, cellular immunotherapies play an important role in treating lung cancer and may be an option for terminal-stage disease. We applied a novel management approach with immune killer cells therapy to treat a patient with NSCLC with liver metastases. The carcinoembryonic antigen returned to normal level during the treatment period, and the follow-up abdominal computed tomography at 3 months after completion of the therapy displayed no residual metastatic liver tumors.
PDF
