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Background: Viral bronchiolitis presents a heterogeneous spectrum. In this study, we investigated the clinical characteristics and the cytokines/chemokines profiles among respiratory syncytial virus (RSV), rhinovirus (RV), and their dual infection in Taiwanese children with viral bronchiolitis. Method: This study was conducted between October 2014 and June 2017. Viral etiology was identified using a Luminex respiratory virus panel and blood cytokines were evaluated using a MILLIPLEX MAP Human Cytokine/Chemokine Panel. Cytokine/Chemokine expressions were compared by clinical severity, steroid treatment, and viral entities. Results: A total of 184 patients were evaluated; at least one respiratory virus was identified in 163 (88.6%) patients. RSV and RV were the two leading viral etiologies, with 25.5% and 17.3%, respectively. RV bronchiolitis has a comparable severity to RSV but is more common in children of an older age with a history of recurrent wheezing and blood eosinophilia. Decreased tumor necrosis factor-alpha (TNF-α) and interferon gamma (INF-γ) levels were correlated with clinical severity. Patients infected with RV exhibited higher levels of Interleukin (IL)-22, IL-23, IL-25, IL-31, and IL-33 (p

Abstract Background Metastasis is the major cause of morbidity and mortality in cancer that involves in multiple steps including epithelial–mesenchymal transition (EMT) process. Centrosome is an organelle that functions as the major microtubule organizing center (MTOC), and centrosome abnormalities are commonly correlated with tumor aggressiveness. However, the conclusive mechanisms indicating specific centrosomal proteins participated in tumor progression and metastasis remain largely unknown. Methods The expression levels of centriolar/centrosomal genes in various types of cancers were first examined by in silico analysis of the data derived from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and European Bioinformatics Institute (EBI) datasets. The expression of STIL (SCL/TAL1-interrupting locus) protein in clinical specimens was further assessed by Immunohistochemistry (IHC) analysis and the oncogenic roles of STIL in tumorigenesis were analyzed using in vitro and in vivo assays, including cell migration, invasion, xenograft tumor formation, and metastasis assays. The transcriptome differences between low- and high-STIL expression cells were analyzed by RNA-seq to uncover candidate genes involved in oncogenic pathways. The quantitative polymerase chain reaction (qPCR) and reporter assays were performed to confirm the results. The chromatin immunoprecipitation (ChIP)-qPCR assay was applied to demonstrate the binding of transcriptional factors to the promoter. Results The expression of STIL shows the most significant increase in lung and various other types of cancers, and is highly associated with patients’ survival rate. Depletion of STIL inhibits tumor growth and metastasis. Interestingly, excess STIL activates the EMT pathway, and subsequently enhances cancer cell migration and invasion. Importantly, we reveal an unexpected role of STIL in tumor metastasis. A subset of STIL translocate into nucleus and associate with FOXM1 (Forkhead box protein M1) to promote tumor metastasis and stemness via FOXM1-mediated downstream target genes. Furthermore, we demonstrate that hypoxia-inducible factor 1α (HIF1α) directly binds to the STIL promoter and upregulates STIL expression under hypoxic condition. Conclusions Our findings indicate that STIL promotes tumor metastasis through the HIF1α-STIL-FOXM1 axis, and highlight the importance of STIL as a promising therapeutic target for lung cancer treatment.

Abstract Immune checkpoint blockade therapy has revolutionized non-small cell lung cancer treatment. However, not all patients respond to this therapy. Assessing the tumor expression of immune checkpoint molecules, including programmed death-ligand 1 (PD-L1), is the current standard in predicting treatment response. However, the correlation between PD-L1 expression and anti-PD-1/PD-L1 treatment response is not perfect. This is partly caused by tumor heterogeneity and the common practice of assessing PD-L1 expression based on limited biopsy material. To overcome this problem, we developed a novel method that can make formalin-fixed, paraffin-embedded tissue translucent, allowing three-dimensional (3D) imaging. Our protocol can process tissues up to 150 μm in thickness, allowing anti-PD-L1 staining of the entire tissue and producing high resolution 3D images. Compared to a traditional 4 μm section, our 3D image provides 30 times more coverage of the specimen, assessing PD-L1 expression of approximately 10 times more cells. We further developed a computer-assisted PD-L1 quantitation method to analyze these images, and we found marked variation of PD-L1 expression in 3D. In 5 of 33 needle-biopsy-sized specimens (15.2%), the PD-L1 tumor proportion score (TPS) varied by greater than 10% at different depth levels. In 14 cases (42.4%), the TPS at different depth levels fell into different categories (

Introduction: Programmed death-ligand 1 (PD-L1) expression determined by immunohistochemistry is the most widely used biomarker for predicting response to immune checkpoint inhibitors. The characteristics of PD-L1 expression in tumor cells inside lymphovascular spaces are largely unknown. Although PD-L1 expression in circulating tumor cells within vascular spaces had been studied, results were conflicting due to lack of standardized PD-L1 expression assessment. Methods: We investigated PD-L1 expression in lung cancer primary tumor tissue, lymphovascular tumor emboli, and lymph node metastasis using the standard PD-L1 immunohistochemistry 22C3 pharmDx assay. PD-L1 expression was scored in the primary tumor, lymphovascular emboli, and lymph node metastasis by a pathologist using the tumor proportion score (TPS). Results: We collected and analyzed surgical specimens from 36 patients with lung cancer with lymph node metastasis. In the primary tumor, 64% of cases were PD-L1 negative (TPS < 1%), 25% were PD-L1 low (TPS 1%–49%), and 11% were PD-L1 high (TPS ≥ 50%). In contrast, in lymphovascular tumor emboli, 89% of cases were PD-L1 negative, 11% were PD-L1 low, and none were PD-L1 high. In lymph node metastases, 72% of cases were PD-L1 negative, 17% were PD-L1 low, and 11% were PD-L1 high. Conclusions: We observed a significant decrease of PD-L1 expression in lymphovascular tumor emboli compared with that in primary tumors (p = 0.002). Whether such differences are related to intrinsic tumor cell heterogeneity or extrinsic factors such as the microenvironment warrants further investigation.

Primary signet ring cell/histiocytoid carcinoma of the eyelid is a rare ocular malignancy and its diagnosis is often delayed. This neoplasm presents as an insidious, diffusely infiltrative mass in the periocular area that later infiltrates the orbit. An exenteration is usually indicated; however, nearly one-third of patients develop local recurrence or metastasis. Morphologically, it resembles signet ring cell carcinoma of the stomach and breast, raising the possibility of mutations in CDH1, the gene encoding E-cadherin. To determine whether primary signet ring cell/histiocytoid carcinoma harbors the CDH1 mutation or other actionable mutations, we analyzed the tumor tissue via next-generation sequencing. We identified only one case of primary signet ring cell carcinoma of the eyelid with adequate DNA quality for sequencing from the pathological archive during the period 2000 to 2020. A comprehensive evaluation including histopathology, immunohistochemistry, and next-generation sequencing assay was performed on tumor tissue. Immunohistochemically, the tumor exhibited E-cadherin membranous staining with the aberrant cytoplasmic staining of β-catenin. Using next-generation sequencing, we demonstrated the mutation in the CDH1 gene. In addition, other clinically actionable mutations including ERBB2 and PIK3CA were also detected. The alterations in other actionable genes indicate a need for larger studies to evaluate the pathogenesis and potential therapies for primary signet ring cell/histiocytoid carcinoma of the eyelid.

Ya-Lang Huang et al. report a mechanism for TLR3-mediated signaling after immune simulation and influenza virus infection by way of the co-receptor CLEC18A. This study found that a single amino acid change in CLEC18A(S339R) can enhance the production of type I and type III interferons to suppress viral replication, and increase mice survival rate after flu infection infection.

15-40% of non-small cell lung cancer (NSCLC) patients harbor epidermal growth factor receptor (EGFR)-sensitizing mutations. Tyrosine kinase inhibitors (TKIs) provide significant clinical benefit in this population, yet all patients will ultimately progress. Liquid biopsy can reliably identify somatic tumor-associated EGFR mutations in plasma. This study aimed to assess the feasibility and value of the quantitative assessment of EGFR driver mutations in plasma in EGFR-mutated NSCLC patients treated with EGFR-TKIs as a tool to evaluate therapeutic response to TKIs and monitor for disease progression. The study included 136 patients with tissue biopsy-confirmed EGFR-sensitizing, mutation-positive lung adenocarcinoma with plasma collected prior to TKI treatment and at least two post-initiation TKI treatment/follow-up blood samples. Plasma samples were tested with the cobas® EGFR Mutation Test v2 (cobas EGFR Test), and semi-quantitative index (SQI) values for each identified mutation were reported by the assay software. The most common baseline EGFR mutations detected in tissue were L858R (53.7%) and exon 19 deletion (39.7%). Plasma cell-free DNA analysis detected EGFR mutations in 74% of the baseline samples. Objective response rate by RECIST 1.1 was achieved in 72% of patients, while 93% had a molecular response (defined as disappearance of the EGFR mutation from plasma). 83% of patients had molecular progression (MP; 1.5X SQI increase or new T790M mutation), and 82% who had a clinical response had clinical progression. On average, MP occurred 42 days prior to clinical progression. Patients who progressed while on first-line TKI showed MP of the original EGFR-sensitizing mutations prior to the emergence of a T790M mutation, which was detected in 27% of the EGFR plasma-positive patients. Longitudinal monitoring of EGFR mutational load in plasma is feasible and can predict both response and clinical progression in EGFR-mutated NSCLC patients treated with EGFR-TKIs, as well as detect treatment-emergent EGFR mutations.

Abstract Background Adenosquamous carcinoma (ADSC) of the lung, a rare but aggressive subtype of non-small cell lung cancer (NSCLC), is defined as a carcinoma containing components of adenocarcinoma (ADC) and squamous cell carcinoma (SqCC). Mutations of epidermal growth factor receptor (EGFR) are found at a frequency of 15 to 44% in Asian ADSC, and EGFR tyrosine kinase inhibitors (EGFR-TKIs) are a more effective treatment for EGFR-mutated ADSC compared to chemotherapy. However, ADSC in small lung biopsies could be misdiagnosed as SqCC or non-small cell carcinoma (NSCC) favor SqCC due to undersampling, which may result in neglecting of EGFR mutation testing and affecting patients’ clinical management, particularly in Asian patients that relatively have high prevalence of EGFR mutation. Methods A total of 148 small lung biopsy cases with pathological diagnosis of SqCC or NSCC favor SqCC were retrospectively enrolled. The frequency of EGFR mutations and the correlation between patients’ EGFR mutation status and clinicopathological characteristics were evaluated. Results EGFR mutations were found in 8.8% (13 /148) of all cases with 5.2% (7/135) in SqCC and 46.2% (6/13) in NSCC favor SqCC. There were 7 (53.8%) L858R mutation, 4 (30.8%) exon 19 deletions, and 2 (15.4%) cases with coexistent L858R and T790 M mutations. Multivariate analysis showed that EGFR mutations were more prevalent in never-smokers (83.3% versus 16.7%, p = 0.006) and patients diagnosed as NSCC favor SqCC (46.2% versus 5.2%, p = 0.001). Moreover, 75% (3/4) of EGFR mutation-positive cases with subsequent surgical resection or rebiopsy were further diagnosed as ADSC. Conclusions EGFR mutation testing should be performed in Asian patients with SqCC diagnosed from small lung biopsies, especially in never-smokers and patients with diagnosis of NSCC favor SqCC, which have a high probability of being ADSC.

Background: Coronavirus Disease 2019 (COVID-19) has become a worldwide pandemic and affected more than 227 countries or territories, resulting in more than 25 million cases with over 0•85 million deaths, as of September 2, 2020. Taiwan has been successful in countering the COVID-19 outbreak, however, the potential risk for asymptomatic infections and the prevalence rates remain unknown. We aimed to estimate the seroprevalence of COVID-19 in Taiwan via serologically testing hospital patients with neither symptoms indicative of nor positive nucleic acid test for SARS-CoV-2 infection. Methods: Residual specimens from laboratory blood tests for outpatient and emergency department patients visiting a medical centre in Taipei, Taiwan, within one week in May and another in July, 2020, were collected. We used Elecsys Anti-SARS-CoV-2 Assay to screen and further validated cases with high cutoff index by a confirmatory ELISA assay. We also analysed antibody responses against SARS-CoV-2 along disease progression in four nucleic acid test confirmed COVID-19 patients. Findings: Blood samples from a total of 14,765 patients were tested. The unweighted seroprevalence of anti-SARS-CoV-2 antibodies was 0•07% [95% CI, 0•04%-0•13%]; after weighting with the population demographics of Taiwan, the estimated overall seroprevalence was 0•05% [95% CI, 0•02%-0•10%]. Furthermore, based on data of the four COVID-19 cases, the seroconversion dates for IgM were as early as 9 days and that for IgG 11 days after symptoms onset. Interpretation: We screened the anti-SARS-CoV-2 antibodies in a small-scale population-based study and observed an approximately 0•05% seroprevalence of COVID-19, indicating that the current containment protocols emphasising mask wearing, hand washing, social distancing and mandatory quarantine for all incomers are effective in Taiwan. Funding: Taipei Veterans General Hospital, Taipei, Taiwan.

BackgroundThe treatment for stage III non-small cell lung cancer (NSCLC) often involves multi-modality treatment. This retrospective study aimed to evaluate whether multidisciplinary team (MDT) discussion results in better patient survival.Materials and methodsMDT discussion was optional before February 2016 and was actively encouraged by the MDT committee beginning February 2016. We reviewed the medical charts and computer records of patients with stage III NSCLC between January 2013 and December 2018.ResultsA total of 515 patients were included. The median survival of all the patients was 33.9 months (M). The median survival of patients who were treated after MDT discussion was 41.2 M and that of patients treated without MDT discussion was 25.7 M (p = 0.018). The median survival of patients treated before February 2016 was 25.7 M and that of patients treated after February 2016 was 33.9 M (p = 0.003). The median survival of patients with stage IIIA tumors and those with stage IIIB tumors was 39.4 M and 25.7 M, respectively (p = 0.141). Multivariate analysis showed that MDT or not (pConclusionThe results of the study show that MDT discussion results in survival benefit in patients with stage III NSCLC. The MDT discussion, performance status, and if surgery was performed were independent prognostic factors for patients with stage III NSCLC.

Background: Common demographic risk factors are identified in colorectal cancer (CRC) and type 2 diabetes mellitus (DM), nevertheless, the molecular link and mechanism for CRC-DM comorbidity remain elusive. Dysregulated glycogen synthase kinase-3 beta under metabolic imbalance is suggested to accelerate CRC pathogenesis/progression via regulating collpasin response mediator protein-2 (CRMP2). Accordingly, roles of CRMP2 in CRC and CRC-DM patients were investigated for elucidating the molecular convergence of CRC and DM. Methods: CRMP2 profile in tumor tissues from CRC and CRC-DM patients was investigated to explore the link between CRC and DM etiology. Meanwhile, molecular mechanism of glucose to regulate CRMP2 profile and CRC characteristics was examined in vitro and in vivo. Results: CRMP2 was significantly lower in tumor lesions and associated with advanced tumor stage in CRC-DM patients. Physiological hyperglycemia suppressed CRMP2 expression/activity and augmented malignant characteristics of CRC cells. Hyperglycemia promotes actin de-polymerization, cytoskeleton flexibility and cell proliferation/metastasis by downregulating CRMP2 profile and thus contributes to CRC disease progression. Conclusions: This study uncovers molecular evidence to substantiate and elucidate the link between CRC and T2DM, as well as characterizing the roles of CRMP2 in CRC-DM. Accordingly, altered metabolic adaptations are promising targets for anti-diabetic and cancer strategies.

In this study, we investigated the molecular evolution and phylodynamics of respiratory syncytial virus (RSV) over 10 consecutive seasons (2008–2017) and the genetic variability of the RSV genotypes ON1 and BA in central Taiwan. The ectodomain region of the G gene was sequenced for genotyping. The nucleotide and deduced amino acid sequences of the second hypervariable region of the G protein in RSV ON1 and BA were analyzed. A total of 132 RSV-A and 81 RSV-B isolates were obtained. Phylogenetic analysis revealed that the NA1, ON1, and BA9 genotypes were responsible for the RSV epidemics in central Taiwan in the study period. For RSV-A, the NA1 genotype predominated during the 2008–2011 seasons. The ON1 genotype was first detected in 2011 and replaced NA1 after 2012. For RSV-B, the BA9 and BA10 genotypes cocirculated from 2008 to 2010, but the BA9 genotype has predominated since 2012. Amino acid sequence alignments revealed the continuous evolution of the G gene in the ectodomain region. The predicted N-glycosylation sites were relatively conserved in the ON1 (site 237 and 318) and BA9 (site 296 and 310) genotype strains. Our results contribute to the understanding and prediction of the temporal evolution of RSV at the local level.

The lectin receptor CLEC5A is a pattern recognition receptor that has been shown to detect dengue and Japanese encephalitis virus. Here the authors show that CLEC5A is needed for optimal ROS production, NET formation and other immune responses to Listeria monocytogenes in mice.

Hypoxia-induced transcriptional responses mediated by HIF-1a are regulated through the ubiquitin-dependent pathway to control HIF-1a stability. Here the authors show that the deubiquitinase HAUSP modulates the stability of HIF-1a and K63-polyubiquitinated HAUSP serves as an anchor for HIF-1a-induced gene transcription.

A 47-year-old woman presented with spontaneous right side pneumothorax. Image studies showed consolidations and reticular opacities involving the pleural and subpleural regions of bilateral lungs. Wedge biopsy specimens of right upper, middle and lower lobes showed fibrosis of the visceral pleura and subpleural area in all three lobes, more significant in the upper lobe. Elastic Van Gieson stain showed a pattern of alveolar septal elastosis with intra-alveolar fibrosis. The clinical presentation and pathological findings are compatible with pleuroparenchymal fibroelastosis, a rare and distinct type of interstitial lung disease. This entity is different from usual interstitial pneumonia by its relationship to pleura, upper lobe predominance and temporal homogeneity. It is different from non-specific interstitial pneumonia by its pleural involvement and scanty inflammatory cell infiltration. Pleuroparenchymal fibroelastosis is a slowly progressive disease; about half of the patients die in 10 years. No curative treatment is available at present time.

Breast cancer resistance protein [BCRP/ATP-binding cassette subfamily G member 2 (ABCG2)] is a member of the ATP-binding cassette transporter family. The presence of ABCG2 on the plasma membrane in many kinds of human cancer cells contributes to multidrug resistance during chemotherapy, and it has been used as the side population marker for identifying cancer stem cells in lung cancers. We report here that, in addition to the membranous form, ABCG2 proteins are also found inside the nucleus, where they bind to the E-box of CDH1 (E-cadherin) promoter and regulate transcription of this gene. Increased expression of ABCG2 causes an increase of E-cadherin and attenuates cell migration, whereas knockdown of ABCG2 downregulates E-cadherin and enhances cell motility. In mice, xenografted A549 cells that have less ABCG2 are more likely to metastasize from the subcutaneous inoculation site to the internal organs. However, for the cancer cells that have already entered the blood circulation, an increased level of ABCG2, and correspondingly increased E-cadherin, may facilitate circulating cancer cells to colonize at a distant site and form a metastatic tumor. We propose a novel role for nuclear ABCG2 that functions as a transcription regulator and participates in modulation of cancer metastasis.

[This corrects the article DOI: 10.1371/journal.pone.0179527.].

Thymoma has a variable long-term oncological outcome after surgical resection. Survival and tumor recurrence were analyzed to determine the predisposing factors for tumor recurrence.A total of 235 patients who underwent surgery for thymoma or thymic carcinoma from December 1997 to March 2013 were analyzed using Masaoka staging system and World Health Organization (WHO) histological classification. Surgical intervention included extended thymothymectomy via median sternotomy and thymomectomy via thoracotomy/ video-assisted thoracoscopic surgery (VATS).The median duration of follow-up was 105 months (12-198 months). Among these 235 patients, recurrence was observed in 25 patients (10.7%). according to Masaoka stage I, IIA, IIB, III, IVA, IVB, recurrence rates were 1/65(1.5%), 8/106(7.5%), 1/32(3.1%), 6/20(30.0%), 8/10(80.0%), 1/1(100.0%), respectively. Disease or treatment-related mortality was observed in 13 patients. Overall survival rate was 94.4%. After univariate analysis, predisposing factors for tumor recurrence included Masaoka stage, WHO histologic type, tumor size, adjuvant therapy and margin status.Due to the indolent behavior of thymoma, tumor recurrence appears to be a better assessment of oncological outcome rather than survival. Factors associated with tumor recurrence include Masaoka stage, WHO histologic type, tumor size, adjuvant therapy and margin status.