Optimizing treatment administration strategies using negative mNGS results in corticosteroid-sensitive diffuse parenchymal lung diseases.

Timely adjustments of antibiotic and corticosteroid treatments are vital for patients with diffuse parenchymal lung diseases (DPLDs). In this study, 41 DPLD patients with negative metagenomic next-generation sequencing (mNGS) results who were responsive to corticosteroids were enrolled. Among these patients, about 26.8% suffered from drug-induced DPLD, while 9.8% presented autoimmune-related DPLD. Following the report of the negative mNGS results, in 34 patients with complete antibiotics administration profiles, 79.4% (27/34) patients discontinued antibiotics after receiving negative mNGS results. Moreover, 70.7% (29/41) patients began or increased the administration of corticosteroid upon receipt of negative mNGS results. In the microbiota analysis, Staphylococcus and Stenotrophomonas showed higher detection rates in patients with oxygenation index (OI) below 300, while Escherichia and Stenotrophomonas had higher abundance in patients with pleural effusion. In summary, our findings demonstrated the clinical significance of mNGS in assisting the antibiotic and corticosteroid treatment adjustments in corticosteroid-responsive DPLD. Lung microbiota may imply the severity of the disease.

Identification of Hedyotis diffusa Willd-specific mRNA-miRNA-lncRNA network in rheumatoid arthritis based on network pharmacology, bioinformatics analysis, and experimental verification.

Hedyotis diffusa Willd (HDW) possesses heat-clearing, detoxification, anti-cancer, and anti-inflammatory properties. However, its effects on rheumatoid arthritis (RA) remain under-researched. In this study, we identified potential targets of HDW and collected differentially expressed genes of RA from the GEO dataset GSE77298, leading to the construction of a drug-component-target-disease regulatory network. The intersecting genes underwent GO and KEGG analysis. A PPI protein interaction network was established in the STRING database. Through LASSO, RF, and SVM-RFE algorithms, we identified the core gene MMP9. Subsequent analyses, including ROC, GSEA enrichment, and immune cell infiltration, correlated core genes with RA. mRNA-miRNA-lncRNA regulatory networks were predicted using databases like TargetScan, miRTarBase, miRWalk, starBase, lncBase, and the GEO dataset GSE122616. Experimental verification in RA-FLS cells confirmed HDW's regulatory impact on core genes and their ceRNA expression. We obtained 11 main active ingredients of HDW and 180 corresponding targets, 2150 RA-related genes, and 36 drug-disease intersection targets. The PPI network diagram and three machine learning methods screened to obtain MMP9, and further analysis showed that MMP9 had high diagnostic significance and was significantly correlated with the main infiltrated immune cells, and the molecular docking verification also showed that MMP9 and the main active components of HDW were well combined. Next, we predicted 6 miRNAs and 314 lncRNAs acting on MMP9, and two ceRNA regulatory axes were obtained according to the screening. Cellular assays indicated HDW inhibits RA-FLS cell proliferation and MMP9 protein expression dose-dependently, suggesting HDW might influence RA's progression by regulating the MMP9/miR-204-5p/MIAT axis. This innovative analytical thinking provides guidance and reference for the future research on the ceRNA mechanism of traditional Chinese medicine in the treatment of RA.

Bavachinin Ameliorates Rheumatoid Arthritis Inflammation via PPARG/PI3K/AKT Signaling Pathway.

Bavachinin (BVC) is a natural small molecule from the Chinese herb Fructus Psoraleae. It exhibits numerous pharmacological effects, including anti-cancer, anti-inflammation, anti-oxidation, anti-bacterial, anti-viral, and immunomodulatory properties. BVC may serve as a novel drug candidate for the treatment of rheumatoid arthritis (RA). Nevertheless, the effects and mechanisms of BVC against RA are still unknown. BVC targets were selected by Swiss Target Prediction and the PharmMapper database. RA-related targets were collected from the GeneCards, OMIM, DrugBank, TTD, and DisGeNET databases. PPI network construction and enrichment analysis were conducted by taking the intersection target of BVC targets and RA-related targets. Hub targets were further screened using Cytoscape and molecular docking. MH7A cell lines and collagen-induced arthritis (CIA) mice were used to confirm the preventive effect of BVC on RA and its potential mechanism. Fifty-six RA-related targets of BVC were identified through databases. These genes were primarily enriched in PI3K/AKT signaling pathway according to KEGG enrichment analysis. Molecular docking analysis suggested that BVC had the highest binding energy with PPARG. The qPCR and western blotting results showed that BVC promoted the expression of PPARG at both the mRNA level and protein level. Western blotting indicated that BVC might affect MH7A cell functions through the PI3K/AKT pathway. Furthermore, treatment with BVC inhibited the proliferation, migration, and production of inflammatory cytokines in MH7A cells and induced cell apoptosis to a certain extent. In vivo, BVC alleviated joint injury and inflammatory response in CIA mice. This study revealed that BVC may inhibit the proliferation, migration, and production of inflammatory cytokines in MH7A cells, as well as cell apoptosis through the PPARG/PI3K/AKT signaling pathway. These findings provide a theoretical foundation for RA therapy.

Clinicopathological characteristics and cancer-specific prognosis of primary pulmonary lymphoepithelioma-like carcinoma: a population study of the US SEER database and a Chinese hospital.

Introduction: Primary pulmonary lymphoepithelioma-like carcinoma (PPLELC) is a rare histological type of non-small cell lung cancer (NSCLC), which accounts for less than 1% of NSCLC. Currently, there is no well-recognized treatment guideline for PPLELC. Methods: We identified PPLELC patients from the Surveillance, Epidemiology, and End Results (SEER) dataset between 2000 and 2015 (n = 72) as well as from our medical center between 2014 and 2020 (n = 16). All diagnoses were confirmed by pathological testing, and the clinicopathological characteristics of patients were retrieved and summarized. Survival analyses were conducted using the Kaplan-Meier analysis and log-rank tests. Multivariate survival analysis was performed with the Cox regression hazards model. Results: The median age at diagnosis of the PPLELC cohort was 64 years, ranging from 15 to 86 years. The percentages of patients with TNM stages I, II, III, and IV were 52.3%, 10.2%, 20.5%, and 17.0%, respectively. Among the 88 cases, lesion resection was performed in 69 cases (78.4%), 16 cases (18.1%) received beam radiation, and 40 cases (45.5%) underwent chemotherapy. In the SEER dataset of lung cancer, the percentage of PPLELC in the Asian race (0.528‰) was almost 10 times higher than that in the white (0.065‰) and black (0.056‰) races. Patients with TNM stage III-IV exhibited a worse prognosis than those with TNM stage I-II (p = 0.008), with a 5-year cancer-specific survival (CSS) rate of 81.8% for TNM stage I-II and 56.2% for TNM stage III-IV. Specifically, the N stage and M stage were the leading prognostic factors, not the T stage and tumor size. Moreover, patients who underwent surgery had significantly better outcomes than those who did not (p = 0.014). Additional multivariate analysis indicated that the TNM stage was an independent prognosis factor for CSS (HR, 3.31; 95% CI, 1.08-10.14). Conclusion: PPLELC is a rare tumor with Asian susceptibility. Although the prognosis of PPLELC is better than that of other subtypes of NSCLC, it remains unsatisfactory for advanced-stage disease. The current treatment options for PPLELC include surgical resection, chemotherapy, radiotherapy, and immune therapy. Among these options, patients with surgical resection have better survival rates in this study. However, large-scale clinical research trials will be necessary to develop effective treatment guidelines for PPLELC.

Network pharmacology and experimental validation to identify the potential mechanism of Hedyotis diffusa Willd against rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic, systemic, autoimmune disease that may lead to joint damage, deformity, and disability, if not treated effectively. Hedyotis diffusa Willd (HDW) and its main components have been widely used to treat a variety of tumors and inflammatory diseases. The present study utilized a network pharmacology approach, microarray data analysis and molecular docking to predict the key active ingredients and mechanisms of HDW against RA. Eleven active ingredients in HDW and 180 potential anti-RA targets were identified. The ingredients-targets-RA network showed that stigmasterol, beta-sitosterol, quercetin, kaempferol, and 2-methoxy-3-methyl-9,10-anthraquinone were key components for RA treatment. KEGG pathway results revealed that the 180 potential targets were inflammatory-related pathways with predominant enrichment of the AGE-RAGE, TNF, IL17, and PI3K-Akt signaling pathways. Screened through the PPI network and with Cytoscape software, RELA, TNF, IL6, TP53, MAPK1, AKT1, IL10, and ESR1 were identified as the hub targets in the HDW for RA treatment. Molecular docking was used to identify the binding of 5 key components and the 8 related-RA hub targets. Moreover, the results of network pharmacology were verified by vitro experiments. HDW inhibits cell proliferation in MH7A cells in a dose and time-dependent manner. RT-qPCR and WB results suggest that HDW may affect hub targets through PI3K/AKT signaling pathway, thereby exerting anti-RA effect. This study provides evidence for a clinical effect of HDW on RA and a research basis for further investigation into the active ingredients and mechanisms of HDW against RA.

Causes of death and conditional survival estimates of long-term lung cancer survivors.

Introduction: Lung cancer ranks the leading cause of cancer-related death worldwide. This retrospective cohort study was designed to determine time-dependent death hazards of diverse causes and conditional survival of lung cancer. Methods: We collected 816,436 lung cancer cases during 2000-2015 in the SEER database, after exclusion, 612,100 cases were enrolled for data analyses. Cancer-specific survival, overall survival and dynamic death hazard were assessed in this study. Additionally, based on the FDA approval time of Nivolumab in 2015, we evaluated the effect of immunotherapy on metastatic patients' survival by comparing cases in 2016-2018 (immunotherapy era, n=7135) and those in 2013-2016 (non-immunotherapy era, n=42061). Results: Of the 612,100 patients, 285,705 were women, the mean (SD) age was 68.3 (11.0) years old. 252,558 patients were characterized as lung adenocarcinoma, 133,302 cases were lung squamous cell carcinoma, and only 78,700 cases were small cell lung carcinomas. TNM stage was I in 140,518 cases, II in 38,225 cases, III in 159,095 cases, and IV in 274,262 patients. 164,394 cases underwent surgical intervention. The 5-y overall survival and cancer-specific survival were 54.2% and 73.8%, respectively. The 5-y conditional survival rate of cancer-specific survival is improved in a time-dependent pattern, while conditional overall survival tends to be steady after 5-y follow-up. Except from age, hazard disparities of other risk factors (such as stage and surgery) diminished over time according to the conditional survival curves. After 8 years since diagnosis, mortality hazard from other causes became higher than that from lung cancer. This critical time point was earlier in elder patients while was postponed in patients with advanced stages. Moreover, both cancer-specific survival and overall survival of metastatic patients in immunotherapy era were significantly better than those in non-immunotherapy era (P<0.001), indicating that immunotherapeutic intervention indeed bring remarkable benefits to advanced lung cancer patients. Conclusions: Our findings expand on previous studies by demonstrating that non-lung-cancer related death risk becomes more and more predominant over the course of follow-up, and we establish a personalized web-based calculator to determine this critical time point for long-term survivors. We also confirmed the survival benefit of advanced lung cancer patients in immunotherapy era.

Multiple stents for tracheobronchomalacia caused by hydrochloric acid inhalation: a case report.

Tracheobronchomalacia (TBM) is a rare disease characterized by excessive collapsibility of the central airways during expiration. Potential consequences and treatment courses of the aspiration of erosive agents are seldom reported. To our knowledge, this is the first report of TBM caused by hydrochloric acid inhalation, which was successfully treated by multiple airway stents insertion. A 45-year-old female presented with dyspnea and pharynx discomfort after falling into a hydrochloric acid pool. The patient was successfully treated with multiple stents insertion. In 15 months after the stents insertion, the clinical symptoms have been rapidly improved. Inhaled chemical damage may lead to TBM, while multiple airway stents insertion showed a good therapeutic effect for such special TBM.

Alpha-momorcharin regulates cytokine expression and induces apoptosis in monocytes.

Background and aim: Alpha-momorcharin (α-MMC) is a type I ribosome-inactivating protein (RIP) that is purified from Momordica charantia. Despite its strong antitumor activities, α-MMC exerts the undesirable immunotoxicity effects of hypersensitivity or immunosuppression. Since α-MMC is a plant protein, its application in vivo can easily induce hypersensitivity, but its immunosuppressive mechanism is still unclear. Materials and methods: The toxicity of α-MMC to peripheral blood cells and the cytokine expression in peripheral blood mononuclear cells (PBMCs) and spleen immune cells were measured in rats. For further confirmation, experiments were performed in vitro with the mononuclear cell line THP-1, B lymphocyte cell line WIL2-S and T lymphocyte cell line Jurkat. Results: High doses of α-MMC (3.0 mg/kg) resulted in weight loss in rats, a decreased percentage of monocytes, and increased percentages of eosinophils and basophils. Both high-dose and low-dose (1.0 mg/kg) α-MMC inhibited cytokine expression in PBMCs and increased cytokine expression in spleen T cells. In in vitro, α-MMC mainly acted on THP-1 cells, with effects including high dose-induced apoptosis and low dose-induced regulation of inhibitory cytokine expression. Conclusions: The action of α-MMC on immune cells mainly affects monocytes, thereby eliciting its immunosuppressive effect. Its mode of action is to guide functional immunosuppressive regulation at low doses and induce apoptosis at high doses. As the monocytes would be recruited into tumor tissues and are polarized into tumor-associated macrophages, the selective cytotoxicity and cytokine release regulation of α-MMC in monocytes may be an important mechanism of its antitumor effects.

LRP1 receptor-mediated immunosuppression of α-MMC on monocytes.

Alpha-MMC is a type I ribosome-inactivating protein purified from bitter gourd that has strong anti-tumour and antiviral activity. Alpha-MMC also has immunosuppressive effects, but the mechanism of these immunosuppressive effects remains unclear. It is reported that the binding of α-MMC to its specific cell membrane LRP1 receptor is key to its biological effects. In this study, we investigated the effect of α-MMC on cytotoxicity and cytokine release regulation in three immune cells, human monocyte THP-1 cells, B-lymphocyte WIL2 cells and T-lymphocyte H9 cells, and explored the correlation between this effect and LRP1 receptor distribution on these three cell types. We demonstrate that α-MMC has a significant effect of apoptosis induction and cytokine release in THP-1 cells but has no effect on WIL2-S and H9 cells. Specifically, at a non-cytotoxic dose (80 µg/ml), α-MMC regulates THP-1 cells by inhibiting IL-1ß, IL-2, IL-8, IL-9, IL-12, MIP-1α/ß, MCP-1 and TNF-α expression and enhancing IL-1ra and RANTES expression, resulting in the inhibition of cellular immune function. Subsequent experiments showed that the cytokine expression regulated by α-MMC can be blocked by silencing the LRP1 receptor of α-MMC. Further research indicated that phosphorylation of 9 signalling proteins of the MAPK pathway was significantly regulated by α-MMC and was blocked by LRP1 silencing. We conclude that the regulation of cytokine expression induced by α-MMC in monocyte THP-1 cells is mediated by the LRP1 receptor, likely via the MAPK signalling pathway. Our results suggest that the inhibition effect on monocytes/macrophages mediates the immunosuppressive function of α-MMC. Due to the selective cytotoxicity and cytokine release regulation of α-MMC in monocytes/macrophages, α-MMC may be used for killing Tumour-Associated Macrophages (M2 subtypes) or inhibiting their cytokine release in the tumour microenvironment.

Multiple intercostal neurilemmomas in a Chinese woman.

Neurilemmomas are rare tumors of neural crest cell origin that occur most commonly in the head and neck region. Intercostal neurilemmomas are extremely rare and are mostly seen as solitary tumors in the posterior mediastinum. Only one case report of multiple intercostal neurilemmomas has been documented previously. In this article, we report a case of multiple intercostal neurilemmomas in a 54-year-old woman who had initially presented with progressive dull left chest pain over a 1-year period. A computed tomography scan revealed three tumors in the left thoracic cavity which were distributed as a string of beads along the third intercostal nerve. Histological and immunohistochemical testing confirmed a diagnosis of neurilemmomas. The patient underwent successful radical excision of the tumors through a thoracotomy approach, and her postoperative course was uneventful. Following the operation, she had no evidence of recurrences.

Chemosynthesis and characterization of site-specific N-terminally PEGylated Alpha-momorcharin as apotential agent.

Alpha-momorcharin (α-MC), a type I ribosome-inactivating protein (RIP) isolated from Momordica charantia seeds, has been extensively studied for its antitumor, antiviral and antifungal activities. However, as an exogenous protein, problems associated with short half-life and strong immunogenicity have limited its clinical application. Poly (ethylene glycol) (PEG), as a polyether compound, is a well established and efficient modifier to develop it as a potential agent. Nevertheless, conventional PEGylation is not site-controlled and the conjugates are often not homogenous due to the generation of multi-PEGylated derivatives. To obtain a homogenous mono-PEGylated α-MC, the PEGylation was carried out by coupling a 20 kDa mPEG-butyraldehyde (mPEG-ALD) with α-MC. The product was separated and purified by MacroCap SP chromatography. Results from SDS-PAGE and MALDI-TOF MS revealed that the PEGylated α-MC consisted of one molecule mPEG and α-MC. Edman degradation confirmed that the N-terminal residue of α-MC was successfully coupled with mPEG-ALD. The mono-PEGylated α-MC possessed an extremely similar secondary structure to native α-MC through spectral analyses. In addition, it also showed low immunogenicity by double immunodiffusion and preserved moderate antitumor activity to three kinds of tumor cell lines in vitro. Finally, trypsin resistance was also considerably improved.

Preablation neutrophil-to-lymphocyte ratio as an independent prognostic factor in locally advanced hepatocellular carcinoma patients following radiofrequency ablation.

BACKGROUND AND AIMS: Neutrophil-to-lymphocyte ratio (NLR), as an inflammation-based marker, plays critical roles in hepatocellular carcinoma (HCC). This study was aimed to investigate the prognostic value of preablation NLR in locally advanced HCC patients following radiofrequency ablation (RFA) and to determine an optimal cutoff value for NLR. MATERIALS AND METHODS: From September 2008 to May 2017, 402 locally advanced HCC patients treated with RFA were retrospectively evaluated. Several prognostic factors including NLR was assessed with univariate and multivariate analysis. The optimal cutoff value of NLR was determined with a maximally selected log-rank test. Other prognostic factors influenced the overall survival (OS) were also evaluated. RESULTS: Based on the univariate analysis of 16 prognostic factors for OS, the type of hepatitis, a-fetoprotein (AFP), NLR, alanine aminotransferase, aspartate aminotransferase, and serum albumin were identified as independent prognostic factors; and based on multivariate analysis of 6 prognostic factors for OS, AFP, and NLR were identified (P < 0.05). A NLR of 2.2 was determined to be the optimal cutoff value (area under the curve = 0.855, P < 0.001). In a comparison between the high NLR group and the low NLR group, there was a difference of 7 months in the median OS (24 vs. 31 months, P < 0.001). CONCLUSIONS: Preablation NLR was a valuable predictor in locally advanced HCC patients treated with RFA. NLR ≥2.2 indicated a poor prognosis. These findings suggested that preablation NLR may be a convenient, easily-obtained, low cost, and reliable biomarker with prognostic potential for HCC patients.

Predictive and prognostic value of serum periostin in advanced non-small cell lung cancer patients receiving chemotherapy.

Periostin is an extracellular matrix protein involved in tumorigenesis and metastasis. However, the role of serum periostin as a surrogate marker for treatment efficacy is still unknown. In 122 advanced non-small cell lung cancer cases, 37 patients with benign lung disease and 40 healthy controls, serum periostin was measured by enzyme-linked immunosorbent assays. The associations of serum periostin levels with the clinic-pathological parameters, chemotherapy response, and clinical outcomes of non-small cell lung cancer patients were analyzed. Serum periostin levels were significantly higher in non-small cell lung cancer patients, and it was related significantly to bone metastasis ( p = 0.021). Serum periostin of 65 non-small cell lung cancer patients were detected before and after two cycles of chemotherapy. The patients with and without periostin response had significant difference in objective response to chemotherapy ( p = 0.001). For the 122 non-small cell lung cancer patients, the median progression-free survival was 5 months. In a multivariate analysis, performance status (hazard ratio, 1.71; 95% confidence interval, 1.10-2.67), baseline periostin (hazard ratio, 1.01; 95% confidence interval, 1.00-1.01), and periostin response (hazard ratio, 0.50; 95% confidence interval, 0.29-0.86) were significantly correlated with prognosis. In conclusion, serum periostin was elevated in advanced non-small cell lung cancer patients. Baseline periostin and periostin responses appeared to be reliable surrogate markers to predict chemotherapy response and survival in patients with advanced non-small cell lung cancer.

The role of microRNA-93 regulating angiopoietin2 in the formation of malignant pleural effusion.

The biological roles of miRNAs in the development of malignant pleural effusion (MPE) are unclear. In this study, the miRNA microarray analysis was performed in two different prognosis groups of lung adenocarcinoma patients. Expression profiles of miRNAs in MPEs were identified. With the help of quantification PCR, we confirmed the expression differences of miRNAs and further analyzed their biological functions and relative target genes in vitro. The target gene of miR-93 was estimated by online database, and also, the protein was tested. The target gene and the binding sites of specific miRNA were estimated by online database. The combining capacity of binding sites was verified by luciferase reporter gene assay, and the target gene protein was tested by western blot. We detected 107 miRNAs with expression differences (n = 10) and confirmed significant expression differences in miR-93 and miR-146a in two groups of patients (n = 84). By manipulating miR-93 expression of human lymphatic endothelial cells (HLEC) and human umbilical vein endothelial cells (HUVEC), we discovered that high expression of miR-93 inhibited migration, proliferation, and angiogenesis. And also, miR-93 increased not only apoptosis, but also G1 phase cell block. By using luciferase reporter gene assay and western blot, we confirmed that angiopoietin2 (Ang2) was the target of miR-93. The data showed that miR-93 has an inhibiting effect on pleural effusion. By targeting Ang2, miR-93 regulates angiogenesis and lymphangiogenesis and plays a role in pathogenetic mechanism of MPE. MiR-93/Ang2 may shed light on potential new targets in cancer treatment.

PU.1 serves a critical role in the innate defense against Aspergillus fumigatus via dendritic cell-associated C-type lectin receptor-1 and toll-like receptors-2 and 4 in THP-1-derived macrophages.

Aspergillus fumigatus (A. fumigatus) is one of the most common fungal pathogens of invasive pulmonary aspergillosis (IPA), which may be life threatening in immunocompromised individuals. The dendritic cell-associated C-type lectin receptor (Dectin-1), toll­like receptor (TLR)-2 and TLR-4 are major pattern recognition receptors in alveolar macrophages that recognize A. fumigatus components. The PU.1 transcription factor is known to be important for the transcriptional control of these three receptors in mature macrophages. The present study investigated whether alterations of PU.1 expression may affect the innate defense against A. fumigatus in the human monocyte THP­1 cell line. THP-1-derived macrophages were transduced with PU.1 adenoviral vectors and transfected with PU.1 small interfering RNA, and the mRNA and protein expression levels of Dectin­1, TLR­2 and TLR­4 were measured. In addition, the levels of tumor necrosis factor (TNF)­α and interleukin (IL)­1ß were ascertained, and fungal phagocytosis and killing were assessed. The results demonstrated that overexpression of PU.1 by recombinant adenoviral vectors resulted in a significant upregulation of Dectin­1, TLR­2 and TLR­4 at the transcriptional and translational levels. In response to A. fumigatus stimulation, PU.1 overexpression increased TNF­α and IL­1ß production. In addition, Dectin­1, TLR­2 and TLR­4 upregulation may have enhanced the phagocytosis and killing ability of THP­1­derived macrophages. As expected, silencing of PU.1 led to downregulation of Dectin­1, TLR­2, TLR­4 and the expression of pro­inflammatory cytokines, as well as decreased phagocytosis and the killing ability of THP1­derived macrophages. In conclusion, the results indicate that PU.1 may be a critical factor for the innate defense against A. fumigatus, and may therefore be a potential target for the prophylaxis and treatment of IPA.

Efficacy and safety of recombinant human tumor necrosis factor application for the treatment of malignant pleural effusion caused by lung cancer.

Malignant pleural effusion (MPE) signifies a poor prognosis for patients with lung cancer. For treating physicians, the primary goals are to achieve sufficient control of MPE and minimize invasive intervention. Recombinant human mutant tumor necrosis factor-alpha (rhu-TNF) has been used in the treatment of MPE. The aim of our research was to evaluate the efficacy and safety of rhu-TNF application via ultrasound-guided chest tube for the treatment of MPE. rhu-TNF was administered as a single dose to 102 patients with MPE caused by lung cancer, and dexamethasone (Dxm, 5 mg) was administered 30 minutes before rhu-TNF in 35 randomly selected patients in order test its ability to prevent side effects. The primary endpoint was the efficacy of the rhu-TNF treatment (disease response rate) and side effects (pain, fever, and flu-like symptoms), evaluated four weeks after instillation. The disease response rate of rhu-TNF treatment was 81.37%. Side effects included 13 (12.75%) patients complaining of flu-like symptoms, 15 (14.71%) with fever/chill, and 14 (13.73%) with chest pain. A significantly higher efficacy was observed for treatment with 3 MU versus 2 MU of rhu-TNF (P = 0.036), while the adverse effects were similar. There was no significant association between the dose of rhu-TNF and progression-free survival (P = 0.752). In conclusion, our study shows that intra-pleural instillation of rhu-TNF achieves sufficient control of MPE and minimizes invasive intervention.

Diagnostic Accuracy of CT-Guided Transthoracic Needle Biopsy for Solitary Pulmonary Nodules.

To evaluate the diagnostic accuracy of computed tomography (CT)-guided percutaneous lung biopsy for solitary pulmonary nodules. Three hundred and eleven patients (211 males and 100 females), with a mean age of 59.6 years (range, 19-87 years), who were diagnosed with solitary pulmonary nodules and underwent CT-guided percutaneous transthoracic needle biopsy between January 2008 and January 2014 were reviewed. All patients were confirmed by surgery or the clinical course. The overall diagnostic accuracy and incidence of complications were calculated, and the factors influencing these were statistically evaluated and compared. Specimens were successfully obtained from all 311 patients. A total of 217 and 94 cases were found to be malignant and benign lesions, respectively, by biopsy. Two hundred and twenty-five (72.3%) carcinomas, 78 (25.1%) benign lesions, and 8 (2.6%) inconclusive lesions were confirmed by surgery and the clinical course. The diagnostic accuracy, sensitivity, and specificity of CT-guided percutaneous transthoracic needle biopsy were 92.9%, 95.3%, and 95.7%, respectively. The incidences of pneumothorax and self-limiting bleeding were 17.7% and 11.6%, respectively. Taking account of all evidence, CT-guided percutaneous lung biopsy for solitary pulmonary nodules is an efficient, and safe diagnostic method associated with few complications.

An Adenoviral Vector Encoding Full-Length Dectin-1 Promotes Aspergillus-Induced Innate Immune Response in Macrophages.

INTRODUCTION: The incidence of invasive pulmonary aspergillosis (IPA) has increased significantly over the last two decades. Alveolar macrophages (AMs) represent the first line of pulmonary host response to Aspergillus conidia. Recognition of conidia by AMs involves Dectin-1 (CLEC7A), which is a conserved structure to combine ß-glucans. The deficiency of Dectin-1 results in impaired fungal killing and uncontrolled growth of Aspergillus fumigatus. Thus, we hypothesized that high expression of Dectin-1 would enhance the host recognition and fungal killing. METHODS: We set out to develop an adenoviral vector encoding full-length Dectin-1 (Ad-Dectin-1-EGFP) and then transfect it to MH-S cells. Transfect cell model was verified by using real-time RT-PCR, Western blot, flow cytometric, and confocal microscopic assays. And also, the function of Dectin-1 was explored by measuring cytokine release and killing ability during the course of A. fumigatus infection. RESULTS: We constructed a recombinant adenovirus which could upregulate the expression of Dectin-1 and verified that Dectin-1 was expressed on cell membrane. The function of Dectin-1 was also demonstrated by its ability in promoting the production of cytokines and increasing the killing ability during the course of A. fumigatus infection. CONCLUSIONS: An adenoviral vector was successfully applied to the production of a recombinant adenovirus encoding full-length Dectin-1, and also, its function in Aspergillus-induced innate immune response was demonstrated.

A 61-year-old man with cough and white sputum.

A 61-year-old man with cough and white sputum had an abnormal pulmonary mass in the left lower lobe in the computed tomography (CT) imaging. According to the lung cancer multidisciplinary team (MDT) discussion, the patient took the left lower lobe resection and lymphadenectomy and finally diagnosed as left lung adenocarcinoma with TNM stage IIIA (pT3N2M0). After four cycles of postoperative chemotherapy with pemetrexed and nedaplatin and 10-month release, a solitary pulmonary nodule (SPN) appeared in the middle lobe of right lung in CT scanning. The patient took a second operation "the right middle lobe resection" and was diagnosed as left lung adenocarcinoma at TNM stage IV (pT3N2M1a, two lungs) with neither EGFR mutation nor ALK-EML4 fusion gene. After operation, the patient took another four cycles of postoperative chemotherapy with Docetaxel and Nedaplatin. During the follow-up, another PET/CT scanning reported that several enlarged mediastinal lymph nodes, a SPN in left upper lobe and lesion in cerebellum and the brain metastasis was also proved in MRI. The patient was now diagnosed as left lung adenocarcinoma at TNM stage IV (pT3N2M1b, brain). In the third-line therapy, the patient took the stereotactic radiotherapy for metastatic mediastinal lymph nodes and took erlotinib once a day after the radiotherapy. However, the number of small lesions on lungs was increased and the brain metastasis was enlarged. The stereotactic radiotherapy for the single brain metastasis and single agent chemotherapy of abraxane were taken. The whole body examination suggested that there was progression-free after two cycles of chemo. The patient is now took five cycles of single agent chemotherapy of abraxane. The latest whole body examination showed disease was stable with no new lesions and metastasis, performance status (PS) score is 0 and the overall survival (OS) time is 34 months.

Up-regulation of Dectin-1 in airway epithelial cells promotes mice defense against invasive pulmonary aspergillosis.

INTRODUCTION: With the growing number of immunocompromised patients, the incidence of invasive pulmonary aspergillosis increases. Innate immunity plays a significant role in defensing against fungal infection. Airway epithelial cells induce immune responses like the production of cytokine and chemokine via Dectin-1 signaling pathway in response to Aspergillus fumigatus. Thus, we hypothesized that up-regulation of Dectin-1 on airway epithelium cells would promote the defense against A. fumigatus. METHODS: We designed an adenoviral vector encoding full-length Dectin-1, and then transfected it into mice airway epithelial cells via intratracheal injection before the invasion of A. fumigatus. Transfect mice model was verified by using real-time PCR and immunohistochemistry. And also, we studied the effects of up-regulation of Dectin-1 on the production of proinflammatory cytokines, histological changes, fungal burden and survival rate during A. fumigatus infection. RESULTS: The expression level of Dectin-1 in lungs of mice with Dectin-1 recombinant adenoviral vector significantly increased. And also, the mice had higher production of TNF-α, GM-CSF and IL-1ß, lower fungal burden, more recruitment of neutrophils into lungs and higher survival rate in response to A. fumigatus infection. CONCLUSIONS: The administration of Dectin-1 recombinant adenoviral vector through trachea can elevate the expression of Dectin-1 on airway epithelium, and also, its function during the course of A. fumigatus infection was demonstrated.