Candida albicans elicits protective allergic responses via platelet mediated T helper 2 and T helper 17 cell polarization.

Fungal airway infection (airway mycosis) is an important cause of allergic airway diseases such as asthma, but the mechanisms by which fungi trigger asthmatic reactions are poorly understood. Here, we leverage wild-type and mutant Candida albicans to determine how this common fungus elicits characteristic Th2 and Th17 cell-dependent allergic airway disease in mice. We demonstrate that rather than proteinases that are essential virulence factors for molds, C. albicans instead promoted allergic airway disease through the peptide toxin candidalysin. Candidalysin activated platelets through the Von Willebrand factor (VWF) receptor GP1bα to release the Wnt antagonist Dickkopf-1 (Dkk-1) to drive Th2 and Th17 cell responses that correlated with reduced lung fungal burdens. Platelets simultaneously precluded lethal pulmonary hemorrhage resulting from fungal lung invasion. Thus, in addition to hemostasis, platelets promoted protection against C. albicans airway mycosis through an antifungal pathway involving candidalysin, GP1bα, and Dkk-1 that promotes Th2 and Th17 responses.

Neopterin in patients with COPD, asthma, and ACO: association with endothelial and lung functions.

BACKGROUND AND OBJECTIVE: Endothelial dysfunction has been widely recognized in chronic airway diseases, including chronic obstructive pulmonary disease (COPD) and asthma; however, it remains unclear in asthma-COPD overlap (ACO). Neopterin (NP), a metabolite of guanosine triphosphate, is a novel biomarker for identifying the increased risk of adverse cardiovascular events. This study aims to investigate the association of NP with endothelial dysfunction and impaired lung function in COPD, asthma, and ACO patients. METHODS: A total of 77 subjects were prospectively recruited. All the participants underwent lung function test, endothelial function evaluation, including pulse wave velocity (PWV) and flow-mediated dilation (FMD), and blood sample detection. Moreover, the effect of NP on endothelial cells (ECs) in anoxic environments was assessed in vitro. RESULTS: Endothelial function was significantly decreased in the COPD and ACO patients compared with that in the healthy controls (P < 0.05). Forced expiratory volume in 1 s (FEV1) was negatively correlated with PWV and positively correlated with FMD (P < 0.05). NP was significantly increased in patients with chronic respiratory diseases compared with that in the control group, with COPD being the highest, followed by asthma, and ACO as the last (P < 0.05). The plasma level of NP exhibited negative correlations with FEV1 and positive correlations with PWV (P < 0.05). In vitro, a high level of NP increased the reactive oxygen species (ROS) and decreased the mitochondrial membrane potential (ΔΨm) of ECs dose-dependently in a hypoxic environment (P < 0.05). CONCLUSION: NP was related to disease severity of chronic airway diseases and involved in the pathogenesis of endothelial dysfunction. A high NP level may contribute to endothelial dysfunction by increasing the oxidative stress of ECs dose-dependently in a hypoxic environment. Our findings may provide a novel evaluation and therapeutic target for endothelial dysfunction related to chronic airway diseases.

Eosinophilic bronchiectasis increases length and cost of hospitalization: a retrospective analysis in a hospital of southern China from 2012 to 2020.

BACKGROUND: The concept of eosinophilic bronchiectasis has received clinical attention recently, but the association between blood eosinophil count (BEC) and hospital characteristics has rarely been reported yet. We aim to investigate the clinical impact of BEC on patients with acute bronchiectasis exacerbation. METHODS: A total of 1332 adult patients diagnosed with acute exacerbation of bronchiectasis from January 2012 to December 2020 were included in this retrospective study. A propensity-matched analysis was performed by matching age, sex and comorbidities in patients with high eosinophil count (≥ 300 cell/µL) and low eosinophil count (< 300 cell/µL). Clinical characteristics, length of hospital stay (LOS), hospitalization cost and inflammatory markers were compared between the two groups. RESULTS: Eosinophilic bronchiectasis occurred in approximately 11.7% of all patients. 156 propensity score-matched pairs were identified with and without high eosinophil count. Eosinophilic bronchiectasis presented with a longer LOS [9.0 (6.0-12.5) vs. 5.0 (4.0-6.0) days, p < 0.0001] and more hospitalization cost [15,011(9,753-27,404) vs. 9,109(6,402-12,287) RMB, p < 0.0001] compared to those in non-eosinophilic bronchiectasis. The median white blood cell (WBC), lymphocyte, platelet (PLT) and C-reactive protein (CRP) levels in eosinophilic bronchiectasis were significantly increased. Multivariate logistic regression analysis confirmed that the high levels of eosinophil count (OR = 13.95, p < 0.0001), worse FEV1% predicted (OR = 7.80, p = 0.0003) and PLT (OR = 1.01, p = 0.035) were independent prognostic factors for length of hospital (LOS) greater than 7 days. CONCLUSION: Eosinophilic bronchiectasis patients had longer length of hospital stay and more hospitalization cost compared to those in non-eosinophilic bronchiectasis group, which might be associated with the stronger inflammatory reaction.

Association of immune-related adverse events with COVID-19 pneumonia in lung cancer patients receiving immune checkpoint inhibitors: a cross-sectional study in China.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are commonly used to treat lung cancer patients, but their use can lead to immune-related adverse events (irAEs), which pose a challenge for treatment strategies. The impact of irAEs on the incidence of COVID-19 pneumonia in lung cancer patients during the ongoing COVID-19 pandemic is unclear. This study aims to investigate the association between irAEs and COVID-19 pneumonia in lung cancer patients receiving ICIs. METHODS: We conducted a cross-sectional study of lung cancer patients who received ICIs and were infected with COVID-19 due to the Omicron variant between December 2022 and February 2023 in China. We collected data on irAEs and COVID-19 outcomes. Logistic regression analyses were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between irAEs and the incidence of COVID-19 pneumonia. RESULTS: A total of 193 patients were enrolled, with 72 patients (37.30%) in the irAEs group and 121 patients (62.70%) in the non-irAEs group. Twenty-six patients (13.47%) developed COVID-19 pneumonia and 6 patients (3.11%) progressed to severe cases after COVID-19 infection. Multivariate logistic regression showed that the lung cancer patients who experienced irAEs was significantly associated with a higher incidence rate of COVID-19 pneumonia (OR = 9.56, 95%CI: 2.21-41.33; P = 0.0025). CONCLUSION: Our study suggests that lung cancer patients receiving ICIs and experiencing irAEs may have a higher risk of developing COVID-19 pneumonia due to the Omicron variant. Therefore, close monitoring of these patients during the COVID-19 pandemic is necessary to mitigate this risk.

Simultaneous evaluation of the fractional exhaled nitric oxide and blood eosinophil count of T2-high endotype in patients with non-cystic fibrosis bronchiectasis.

OBJECTIVE: Recently, a type 2 inflammation (T2) high endotype in bronchiectasis was identified. The fraction of exhaled nitric oxide (FeNO) and blood eosinophil count (BEC) are recognized as representative biomarkers of T2 inflammation. Herein, we investigate the clinical characteristics of T2-high endotype in non-cystic fibrosis bronchiectasis patients classified by FeNO and BEC. METHODS: This retrospective study included 164 bronchiectasis patients treated in the First Affiliated Hospital of Sun Yat-sen University from December 2017 to July 2022. Clinical characteristics were analyzed after classifying patients into four groups according to T2 inflammation biomarkers (FeNO ≥25 ppb; BEC ≥200/µL). RESULTS: Among the 164 bronchiectasis patients, 35.3% (58/164) presented with high FeNO, 30.5% (50/164) presented with high BEC, and 10.4% (17/164) had high FeNO and BEC. Patients with high FeNO and low BEC presented with better lung function, fewer affected lobes, and lower dyspnea prevalence compared with the three other groups. Moreover, decreased FeNO, instead of decreased BEC, is revealed to be an independent predictor for disease severity and airflow obstruction in bronchiectasis. CONCLUSIONS: Simultaneous evaluation of FeNO and BEC proposed different endotypes of bronchiectasis established that patients with low BEC and high FeNO had better lung function, fewer affected lobes, lower dyspnea prevalence, and less disease severity. This result will contribute to a more comprehensive assessment of the disease severity and lead to more precise treatment of T2 inflammation in bronchiectasis patients.

Increased expression of IL1-RL1 is associated with type 2 and type 1 immune pathways in asthma.

BACKGROUND: Asthma is a common chronic airway disease in the world. The purpose of this study was to explore the expression of IL1-RL1 in sputum and its correlation with Th1 and Th2 cytokines in asthma. METHODS: We recruited 132 subjects, detected IL1-RL1 protein level in sputum supernatant by ELISA, and analyzed the correlation between the expression level of IL1-RL1 and fraction of exhaled nitric oxide (FeNO), IgE, peripheral blood eosinophil count (EOS#), and Th2 cytokines (IL-4, IL-5, IL-10, IL-13, IL-33 and TSLP) and Th1 cytokines (IFN-γ, IL-2, IL-8). The diagnostic value of IL1-RL1 was evaluated by ROC curve. The expression of IL1-RL1 was further confirmed by BEAS-2B cell in vitro. RESULTS: Compared with the healthy control group, the expression of IL1-RL1 in sputum supernatant, sputum cells and serum of patients with asthma increased. The AUC of ROC curve of IL1-RL1 in sputum supernatant and serum were 0.6840 (p = 0.0034), and 0.7009 (p = 0.0233), respectively. IL1-RL1 was positively correlated with FeNO, IgE, EOS#, Th2 cytokines (IL-4, IL-5, IL-10, IL-13, IL-33 and TSLP) and Th1 cytokines (IFN-γ, IL-2, IL-8) in induced sputum supernatant. Four weeks after inhaled glucocorticoids (ICS) treatment, the expression of IL1-RL1 in sputum supernatant and serum was increased. In vitro, the expression of IL1-RL1 in BEAS-2B was increased after stimulated by IL-4 or IL-13 for 24 h. CONCLUSION: The expression of IL1-RL1 in sputum supernatant, sputum cells and serum of patients with asthma was increased, and was positively correlated with some inflammatory markers in patients with asthma. IL1-RL1 may be used as a potential biomarker for the diagnosis and treatment of asthma.

Potential benefit of osismertinib plus bevacizumab in leptomeningeal metastasis with EGFR mutant non-small-cell lung cancer.

BACKGROUND: EGFR-mutant non-small cell lung cancer (NSCLC) is prone to leptomeningeal metastasis (LM) after Tyrosine kinase inhibitors (TKIs) treatment. Our previous study suggested that osimertinib plus bevacizumab was safe and effective in LM from EGFR-mutant NSCLC. This study aimed to compare the efficacy of osimertinib plus bevacizumab with osimertinib in EGFR-mutant NSCLC patients with LM. METHODS: We retrospectively reviewed the data from 27 LM patients with EGFR-mutant NSCLC who received osimertinib with or without bevacizumab at the Second Affiliated Hospital of Nanchang University. Next, we investigated the antitumor efficacy of osimertinib plus bevacizumab in an LM xenograft model using the H1975 (EGFR exon20 T790M and exon21 L858R) cell line. We examined the ability of osimertinib plus bevacizumab compared with osimertinib to penetrate the blood-brain barrier (BBB) and explored the potential mechanism. RESULTS: Our retrospective study observed the improved survival of LM patients in osimertinib plus bevacizumab group. The median overall survival (OS) of the patients who received osimertinib and bevacizumab (n = 16) compared with osimertinib group (n = 11) was 18.0 months versus 13.7 months (log-rank test, p = 0.046, HR = 2.867, 95% CI 1.007-8.162). The median intracranial Progression-free Survival (iPFS) was 10.6 months versus 5.5 months (log-rank test, p = 0.037, HR = 3.401, 95% CI 1.079-10.720). In the LM xenograft model with H1975 cells, the combined treatment significantly increased the effective intracranial concentration of osimertinib, modulated the level of E-cadherin and downregulated the levels of EGFR and downstream signaling pathways including p-AKT and reduced tumor microvessel density (TMD), indicated that combined osimertinib with bevacizumab may exhibit a synergistic effect in EGFR-mutant LM model possibly by modulating the level of E-cadherin. CONCLUSIONS: Our findings indicate the potential benefit of osimertinib plus bevacizumab in LM with EGFR-mutant NSCLC, and more larger sample size research are still needed.

Effect of EGFR amplification on the prognosis of EGFR-mutated advanced non-small-cell lung cancer patients: a prospective observational study.

BACKGROUND: Epidermal growth factor receptor (EGFR) amplification refers to the copy number increase of EGFR gene, and is often identified as a "bypass" way of Epidermal growth factor receptor Tyrosine kinase inhibitors (EGFR-TKI) resistance. We aimed to explore the effect of EGFR amplification on EGFR mutation treatment-naive advanced non-squamous non-small cell lung cancer (NSCLC) patients. METHODS: We conducted a prospective observational study in single center, enrolling advanced non-squamous NSCLC patients receiving Tyrosine kinase inhibitors (TKIs) between March 3, 2019, and February 1, 2022. Next-generation sequencing (NGS) was used to detect genetic alterations in tumor tissue samples. Progression-free survival (PFS) curves were performed using the Kaplan-Meier method. Univariate and multivariate analyses were used to evaluate factors affecting the efficacy of TKIs. RESULTS: A total of 117 treatment-naive advanced NSCLC patients were identified in this study. EGFR amplification was found in 22 of 117 (18.8%) patients with EGFR mutations. Of 22 patients with EGFR amplification, 10 patients harbored EGFR 19 del, 11 patients with 21-L858R. The median follow-up time was 22.47 months. The median PFS of the patients with or without EGFR amplification was 8.25 months and 10.67 months, respectively (log-rank test, P = 0.63). In multivariate analysis, EGFR amplification was not an independent prognosis factor for the patients receiving first-line TKIs [HR = 1.38, 95%CI (0.73-2.58), P = 0.321]. Subgroup analysis revealed that EGFR amplification is a risk factor for progression in the brain metastasis population. [HR = 2.28, 95%CI (1.01, 5.14), P = 0.047]. CONCLUSION: EGFR amplification is not an independent prognosis factor for PFS in advanced non-squamous NSCLC patients receiving first-line TKIs. However, it is an independent risk factor for PFS in the brain metastasis population.

Elevated CEACAM5 Levels in Patients with Asthma.

INTRODUCTION: Asthma is a common chronic respiratory disease. This study aimed to explore the expression level of carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) in induced sputum supernatant, induced sputum cells, and serum of asthma patients. METHODS: The protein levels of CEACAM5 in induced sputum supernatant and serum were detected by enzyme-linked immunosorbent assay. The expression of CEACAM5 in induced sputum cells was detected by quantitative reverse transcription polymerase chain reaction (qRT-PCR). We analyzed the correlations between CEACAM5 expression and the clinical characteristics (FeNO and IgE) of asthma. The receiver operating characteristic (ROC) curve was used to analyze the diagnostic value of CEACAM5 in asthma. The expression level of CEACAM5 in 16HBE and BEAS-2B cells was detected by qRT-PCR. RESULTS: The expression of CEACAM5 in induced sputum supernatant, induced sputum cells, and serum of asthma patients was significantly upregulated. Asthma patients with high CEACAM5 expression in induced sputum supernatant had higher levels of FeNO, IgE, and IL-13. The expression levels of CEACAM5 in induced sputum supernatant and induced sputum cells were positively correlated with FeNO and IgE. The ROC curve showed that CEACAM5 had a good diagnostic value in asthma. CEACAM5 expression was upregulated in BEAS-2B and 16HBE cells after IL-4 or IL-13 stimulation for 48 h. CONCLUSION: The expression levels of CEACAM5 in induced sputum supernatant, induced sputum cells, and serum of asthma patients were significantly increased. CEACAM5 may be involved in eosinophilic inflammation of asthma and may be used as a diagnostic biomarker and therapeutic target of asthma.

Exploration of induced sputum BIRC3 levels and clinical implications in asthma.

BACKGROUND: Baculoviral IAP repeat-containing 3 (BIRC3) which encodes a member of the IAP family of proteins upregulated in the asthma expression profile dataset. However, there was few research on studying the clinical implication of BIRC3 in asthma. OBJECTIVE: To validate BIRC3 expression and its clinical implications in induced sputum of asthma. METHODS: Based on the GSE76262 (118 asthma cases and 21 healthy controls) dataset, differentially expressed genes were screened using R software. Subsequently, BIRC3 mRNA and protein were clinically verified in induced sputum samples through quantitative real-time polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA). Besides, the correlations between BIRC3 expression and asthmatic eosinophilic/allergic inflammation indicators (FeNO, IgE, and EOS%), pulmonary function (FEV1, FEV1% pred, FVC% pred, and FEV1/FVC), and inflammatory cytokines (IL-4, IL-5, IL-13, IL-25, IL-10, IL-33, and TSLP) were analyzed. Finally, BIRC3 mRNA was detected in human primary bronchial epithelial cells stimulated by cytokines (IL-4 or IL-13). RESULTS: BIRC3 was screened as a candidate gene in the GSE76262, which was highly expressed in asthma. Highly expressed BIRC3 was positively correlated with eosinophilic and allergic indicators, including FeNO, blood eosinophil, and serum IgE. Moreover, BIRC3 protein was positively associated with inflammation cytokines, like IL-4, IL-5, IL-13, IL-25, IL-10, IL-33, and TSLP, while negatively correlated with FEV1, FEV1%pred, FVC% pred, and FEV1/FVC. Furthermore, the expression of BIRC3 could be induced in primary bronchial epithelial cells treated by cytokines IL-4 or IL-13. CONCLUSIONS: BIRC3 significantly increased in induced sputum of asthma and positively correlated with airway eosinophilic and peripheral blood allergic inflammation, type 2 cytokines, and airway obstruction. Increased BIRC3 might be involved in the pathogenesis of asthma by affecting the eosinophilic and allergic inflammation.

The impact of novel anchored barbed suture for capsular closure on hospital length of stay after total knee arthroplasty: a retrospective cohort study.

OBJECTIVE: The aim was to evaluate whether using novel anchored barded suture for capsular closure can further shorten the length of stay following primary total knee arthroplasty (TKA) within existed enhanced recovery after surgery (ERAS) protocol in osteoarthritis patients. METHODS: A retrospective cohort study was conducted among osteoarthritis patients aged 18 to 80 years without major comorbidities who underwent primary unilateral TKA between January 2018 and December 2019 was conducted. The capsular closure techniques, interventions for ERAS, operation time and length of stay were collected via hospital electronic information system. Propensity-score matching was used to compensate for the difference in interventions for ERAS and patient characteristics. Subgroup comparison of patients treated under normal ERAS protocol was performed. RESULTS: Included were 315 patients with capsular closure by barded suture and 397 patients with interrupted capsular closure by traditional suture. Patients' characteristics and interventions for ERAS were balanced after propensity-score matching. The average postoperative length of stay in barded suture group was shorter than the compared group (2.10 ± 0.57 vs. 2.33 ± 0.80 days, p = 0.004), and with a significantly higher proportion of patients discharging within 2 days post procedure (88.0% vs. 70.7%, p < 0.001). The operation time for patients with barded suture closure was shorter compared to interrupted closure technique (100.90 ± 16.59 vs. 105.52 ± 18.47 min, p = 0.004). Subgroup analysis of patients treated under different levels ERAS protocol showed comparable results. CONCLUSION: The use of barded suture for capsular closure was associated with shorter length of stay after TKA compared to traditional suture, suggesting that barded suturing technique could be one effective intervention for ERAS.

Efficacy of osimertinib for preventing leptomeningeal metastasis derived from advanced EGFR-mutated non-small cell lung cancer: a propensity-matched retrospective study.

BACKGROUND: Leptomeningeal metastasis (LM) is a severe complication of advanced non-small cell lung cancer (NSCLC). This retrospective study aimed to investigate the potential use of osimertinib for preventing LM in patients with advanced epidermal growth factor receptor (EGFR)-mutated NSCLC. METHODS: Patients with advanced NSCLC harboring EGFR mutations who underwent tyrosine kinase inhibitors (TKIs) therapy for at least 8 weeks between September 2016 and September 2019 were eligible for this study. All included patients were divided into two groups based on whether they received osimertinib, the osimertinib group (patients treated with osimertinib) and the control group (patients not treated with osimertinib). Propensity score matching (PSM, ratio of 1:1) was used to account for differences in baseline characteristics. The cumulative incidence of LM and the overall survival (OS) were evaluated. RESULTS: A total of 304 patients were included in the study population. Among them, 116 patients received osimertinib, and 188 did not. A total of 112 patients remained in each group after PSM, and the baseline characteristics were not significantly different between the two cohorts. LM developed in 11 patients (9.82%) in the osimertinib group and 24 patients (21.42%) in the control group (hazard ratio [HR] 0.38, 95% confidence interval [CI] 0.19-0.79, p = 0.009). Multivariate analysis indicated that osimertinib was an independent, statistically significant predictor for determining the risk for LM, with an HR of 0.33 (p = 0.042). At present, the OS rate data are too immature for statistical analysis. CONCLUSION: Real-world data demonstrate that osimertinib can significantly reduce the incidence of LM in patients with advanced NSCLC harboring common EGFR mutations. Given this result, osimertinib should be encouraged in clinical practice for specific patient populations.

Efficacy and acquired resistance for EGFR-TKI plus thoracic SBRT in patients with advanced EGFR-mutant non-small-cell lung cancer: a propensity-matched retrospective study.

BACKGROUND: This retrospective study aimed to evaluate the efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) with stereotactic body radiation therapy (SBRT) and to elucidate potential mechanisms of acquired resistance. METHODS: Patients with advanced NSCLC harboring positive EGFR mutations after initial TKI therapy for at least 8 weeks were eligible for SBRT between August 2016 and August 2019. Eligible patients were treated with thoracic SBRT, and TKI was continued after SBRT until it was considered ineffective. The control group was treated with TKIs monotherapy. Propensity score matching (PSM, ratio of 1:2) was used to account for differences in baseline characteristics. Overall survival (OS), progression-free survival (PFS), treatment safety and resistance mechanisms were evaluated. RESULTS: Three hundred eight patients were included in the study population. Among them, 262 patients received TKIs alone, and 46 patients received TKIs with SBRT. Baseline characteristics were not significantly different between the two cohorts after PSM. The median PFS was 19.4 months in the TKIs +SBRT group compared to 13.7 months in the TKIs group (p = 0.034). An influence on OS has not yet been shown (p = 0.557). Of the 135 patients evaluated after PSM, 28 and 71 patients in the TKIs and TKIs +SBRT cohorts, respectively, had plasma cell-free DNA (cfDNA) next-generation sequencing (NGS) performed at baseline and disease progression. In the TKIs +SBRT cohort, the NGS results showed that T790M mutations were detected in 64.3% (18/28) of patients. Patients in the TKIs cohort exhibited fewer T790M-positive mutations (40.8%, p = 0.035) compared to patients in the TKIs +SBRT cohort. CONCLUSION: Real world data prove that TKIs plus thoracic SBRT significantly extend PFS with tolerable toxicity. The mutation ratio of T790M was increased in the TKIs +SBRT group compared to the TKIs only group. Further randomized studies are warranted.

Selective cleavage of fibrinogen by diverse proteinases initiates innate allergic and antifungal immunity through CD11b.

Proteinases are essential drivers of allergic airway disease and innate antifungal immunity in part through their ability cleave the clotting factor fibrinogen (FBG) into fibrinogen cleavage products (FCPs) that signal through Toll-like receptor 4 (TLR4). However, the mechanism by which FCPs engage TLR4 remains unknown. Here, we show that the proteinases from Aspergillus melleus (PAM) and other allergenic organisms rapidly hydrolyze FBG to yield relatively few FCPs that drive distinct antifungal mechanisms through TLR4. Functional FCPs, termed cryptokines, were characterized by rapid loss of the FBG α chain with substantial preservation of the ß and γ chains, including a γ chain sequence (Fibγ390-396) that binds the integrin Mac-1 (CD11b/CD18). PAM-derived cryptokines could be generated from multiple FBG domains, and the ability of cryptokines to induce fungistasis in vitro and innate allergic airway disease in vivo strongly depended on both Mac-1 and the Mac-1-binding domain of FBG (Fibγ390-396). Our findings illustrate the essential concept of proteinase-activated immune responses and for the first time link Mac-1, cryptokines, and TLR4 to innate antifungal immunity and allergic airway disease.

Derlin-1 exhibits oncogenic activities and indicates an unfavorable prognosis in breast cancer.

Derlin-1 is involved in the elimination of misfolded proteins and has been implicated in the progression of human cancers. However, its prognostic value and biological function in breast cancer remain unknown. Here, we show that Derlin-1 is overexpressed in breast cancer and exhibits oncogenic activities via interaction with UBE2C. Increased expression of Derlin-1 is correlated with lymph node metastasis, advanced clinical stage, and unfavorable overall survival in two cohorts containing over 1,000 patients. Multivariate analyses by the Cox regression model suggest Derlin-1 is an independent factor for poor prognosis. In vitro experiments demonstrate that Derlin-1 expression is transcriptionally upregulated by c-Myc. Ectopic expression of Derlin-1 promotes breast cancer cell proliferation and migration, whereas the knockdown of Derlin-1 results in the opposite phenotypes. Mechanistically, Derlin-1 directly binds to UBE2C to increase the phosphorylation of AKT and ERK. The treatment of UBE2C siRNA markedly attenuates Derlin-1-mediated cell growth and migration. Collectively, our data suggest Derlin-1 is a potential prognostic factor and functions as an oncogene in breast cancer.

Positive association between heart dosimetry parameters and a novel cardiac biomarker, solubleST-2, in thoracic cancer chest radiation.

BACKGROUND: Early screening and diagnosis of radiation-induced heart disease (RIHD) is difficult in patients with chest radiation exposure. sST-2 is involved in myocardial stress or injury. We evaluated the relationship between heart dose parameters and sST-2 changes in chest malignant tumor patients who received chest radiation. METHODS: We prospectively collected thoracic malignancy cancer patients who had received chest radiotherapy. Heart dosimetry parameters were extracted from the treatment planning system. sST-2 was measured at baseline, the middle stage, and after radiotherapy (recorded as pre-ST-2, mid-ST-2, and post-ST-2). sST-2 change rate was calculated. Scatter plots showed the relationship between cardiac dose parameters and ST-2 change rate. Multiple regression was used to analyze the relationship between cardiac dose parameters and ST-2 change rate. RESULTS: Totally, 60 patients were enrolled. The mean V5 , V10 , V20 , V30 , V40 , and MHD was 60.93 ± 27.79%, 51.43 ± 25.44%, 39.17 ± 21.75%, 28.07 ± 17.15%,18.66 ± 12.18%, and 18.60 ± 8.63 Gy, respectively. The median M-LAD was 11.31 (IQR 3.33-18.76) Gy. The mean pre-ST-2, mid-ST-2, and post-ST-2 was 5.1 ± 3.8, 6.4 ± 3.9, and 7.6 ± 4.4, respectively. sST-2 was elevated with thoracic irradiation (P < .001). Multivariate linear regression analyses showed that V5 , V10 , V20 , and MHD were independently and positively associated with ST-2 change rate (ß = .04, .04, .04, and .10, respectively, all P < .05). CONCLUSION: Serum sST-2 levels were elevated over time during radiotherapy. V5 , V10 , V20 and MHD were independently and positively associated with the elevated ST-2 change rate.

Optimal location of subtrochanteric osteotomy in total hip arthroplasty for crowe type IV developmental dysplasia of hip.

BACKGROUND: When reconstructing a hip with developmental dysplasia and high dislocation, sub-trochanteric shortening osteotomy is typically needed for placing the acetabular component in the appropriate anatomical position. However, the procedure can result in complications such as non-union of the osteotomy. We evaluated the contact area and the coincidence rate between the proximal and distal fragments at different femoral osteotomy levels and lengths. We then determined the optimal location of subtrochanteric femoral shortening transverse osteotomy in patients with unilateral Crowe type IV developmental dysplasia of the hip (DDH). The consistency between the proximal and distal segments was assessed as a possible predictive indicator of the union at the osteotomy site. METHODS: We retrospectively reviewed 57 patients with unilateral Crowe type IV DDH who underwent X-ray imaging of both hip joints. We labelled the inner and outer diameters of the circular ring as N (mm) and M (mm), respectively. We defined the overlapped area between the proximal and distal ring as contact area S (mm2), and the ratio of contact area to distal ring area as coincidence rate R. RESULTS: N varied from 9.8-15.2 mm and M varied from 20.7-24 mm, both demonstrated a decreasing trend in the proximal to distal direction. At osteotomy lengths ranging from 0.5-2 cm, there were no differences in S between the different levels of osteotomy in each group. At osteotomy lengths ≤2.5 cm, a significant higher coincidence rate was noted from 2 cm below the lesser trochanter to other positions below the level. At osteotomy lengths from 3 to 5.5 cm, a significantly higher coincidence rate was observed from the level of 1.5 cm below the lesser trochanter to other positions below the level. CONCLUSIONS: Our findings suggest that femoral shortening transverse osteotomy at the optimal subtrochanteric level can predictably increase the contact area and coincidence rate, which may contribute to the union at the osteotomy site. Considering the stability of the prostheses, it appears appropriate that osteotomy location should be shifted slightly distally. TRIAL REGISTRATION: Retrospectively registered.

Orthodontic compressive force modulates Ets-1/Tks5 pathway to promote the formation of circumferential invadopodia and the fusion of osteoclast precursors.

During orthodontic treatment a mechanical force is applied to the teeth. However, it remains unclear how mechanical force promotes the maturation and fusion of osteoclast precursors into osteoclasts. In this study, we aimed to explore the mechanism by which orthodontic compressive force promotes osteoclast maturation. We used a RAW264.7 macrophage-like cell line derived from Balb/c mice as the experimental model. We found that compressive force promoted the maturation of osteoclasts based on tartrate-resistant acid phosphatase staining and the formation of invadopodia based on immunstaining of Tks5 and F-actin. Moreover, we found that compressive force upregulated the expression of Ets-1 and Tks5 and promoted the activation of Ets-1 in RAW264.7 cells. Furthermore, we identified Tks5 as a transcription target of Ets-1 in RAW264.7 cells and demonstrated that Ets-1 mediates the effects of compressive force on Tks5 upregulation, invadopodia formation and cell fusion in osteoclasts. In conclusion, Ets-1 is upregulated by compressive force and it is essential to transducing the mechanical signal to promote invadopodia formation and osteoclast fusion. Our findings provide novel insight into the mechanism underlying osteoclast maturation and fusion during orthodontic treatment.

Spatial dimming scheme for optical OFDM based visible light communication.

A new dimming control scheme termed spatial dimming orthogonal frequency division multiplexing (SD-OFDM) is proposed for multiple-input and multiple output OFDM based visible light communication. The basic idea of SD-OFDM is that the illumination can be represented by the number of glared light emitting diodes (LEDs) in an LED lamp. As the biasing level of LEDs does not adjust to represent the required illumination level, the proposed scheme can significantly mitigate the clipping noise compared to analogue dimming schemes. Furthermore, unlike digital dimming schemes that control illumination levels by setting different duty cycles of pulse width modulation, the proposed scheme is always in the "on-state" for varied illumination levels. Both analytical and simulation results indicate that the proposed scheme is an efficient and feasible dimmable scheme.