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Asma adalah penyakit pernapasan kronis umum yang mempengaruhi 1–18% populasi di berbagai negara. Telah terjadi peningkatan tajam dalam prevalensi global, morbiditas, mortalitas, dan beban ekonomi yang terkait dengan asma selama 40 tahun terakhir. Saat ini sebagian besar penderita asma merupan asma tidak terkontrol. Pengetahuan mengenai asma sangat penting dalam mencapai kontrol asma. Pasien dan keluarga pasien yang memahami penyakit asma dengan baik secara sadar akan menghindari faktor-faktor pencetus serangan, menggunakan obat secara benar dan berkonsultasi kepada dokter secara tepat. Tujuan kegiatan ini adalah meningkatkan pengetahuan masyarakat mengenai pengertian, gejala, penyebab dan pencetus, pengobatan dan pencegahan asma. Narasumber melakukan presentasi, dilanjutkan dengan diskusi. Peningkatan pengetahuan diukur dengan pre-test dan post-test yang dianalisa dengan menggunakan t-paired test. Kegiatan diikuti oleh 33 peserta dari anggota DWP RSUD Provinsi NTB dan anggota PORPI cabang NTB. Setelah diberikan materi oleh narasumber, terdapat peningkatan pengetahuan yang bermakna pada peserta seminar. Selisih skor peningkatan pengetahuan adalah 14,7532 (p 0.002, 95% IK -23.6579-(-5.8484). Terdapat peningkatan pengetahuan peserta seminar mengenai asma.

COVID-19 disease is a disease that arises due to infection with the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). The purpose of this study was to determine differences in clinical symptoms in elderly and non-elderly patients, as well as patients who had comorbidities and did not have comorbidities. This research is a type of cross-sectional study that was conducted by reviewing the medical records of COVID-19 patients undergoing treatment at Mataram University Hospital in 2021. Data was collected using a consecutive sampling technique. The statistical test used is the Chi-square comparative test. To assess the relationship of age and comorbidities to the severity of symptoms in COVID-19 patients. In this study, 86 subjects were selected based on the inclusion and exclusion criteria applied. The majority of subjects were in the 15-59 year age group, namely 66 (23.3%). With male sex 51 (60.5%) people. The majority of patients with comorbidities experienced severe/critical symptoms 16 (44.4%) and patients without comorbids experienced no symptoms or experienced mild symptoms 35 (35%). The majority of elderly patients experienced severe-critical symptoms 9 (45%) and the majority of non-elderly patients experienced no symptoms or experienced mild symptoms 42 (63.6%). The results of the bivariate analysis test showed a p-value = 0.001 for comorbids with severe symptoms, and a p-value = 0.003 for age with severe symptoms. There is a significant relationship between comorbidities and age on the severity of symptoms in COVID-19 patients.

Latar Belakang: Coronavirus disease 19 (COVID-19) merupakan penyakit infeksi saluran pernapasan akut akibat SARS-CoV-2. Penyakit ini pertama kali ditemukan di kota Wuhan, China pada akhir tahun 2019. Pada beberapa kasus COVID-19 dapat mengancam jiwa akibat fase inflamasi yang tidak terkontrol yang ditandai dengan peningkatan kadar D-dimer dan C-reactive protein (CRP) dalam tubuh. Kondisi ini dapat menyebabkan berbagai komplikasi seperti ARDS, syok, bahkan kematian. Penelitian ini bertujuan untuk mengetahui hubungan kadar D-dimer dan C-reactive proteinterhadap berat gejala pada pasien COVID-19 di Rumah Sakit Universitas Mataram. Metode: Penelitian ini merupakan penelitian analitik komparatif dengan desain cross-sectional. Pengambilan data berlangsung dari bulan Maret – Mei 2022 di Rumah Sakit Universitas Mataram. Subjek dipilih menggunakan metode consecutive sampling melalui data rekam medis. Uji statistik menggunakan uji komparatif Chi-square dan Mann-Whitney. Hasil: Sebanyak 64 subjek terpilih, diantaranya 48 subjek melakukan pemeriksaan D-dimer dan 58 subjek melakukan pemeriksaan CRP. Mayoritas subjek terdapat pada kelompok usia 18-59 tahun (64,1%) dengan jenis kelamin laki-laki (56,3%). Terdapat 10 subjek (20,8%) memiliki kadar D-dimer normal, dan 38 subjek (79,2%) memiliki kadar D-dimer meningkat. Kadar CRP normal terdapat pada 6 subjek (10,3%), dan 52 subjek (89,7%) memiliki kadar CRP meningkat. Hasil analisis uji bivariat menunjukkan nilai p-value = 0,002 untuk kadar D-dimer dengan berat gejala, dan kadar CRP dengan berat gejala menunjukkan p-value = 0,02. Kesimpulan: Terdapat hubungan bermakna secara statistik dan klinis antara kadar D-dimer dan C-reactive proteinterhadap berat gejala pada pasien COVID-19.

Supplementary Figure S5 shows role of MFGE8 in MPM.

Supplementary Figure Legends

Supplementary Table S1 shows the selected genes with statistically significant changes in transcriptome analysis using two different shRNA constructs.

Malignant pleural mesothelioma (MPM) is a highly aggressive tumor that has a low overall survival; however, no significant treatment advances have been made in the past 15 years. Large-scale molecular studies have identified a poor prognostic subset of MPM linked to the epithelial–mesenchymal transition (EMT) that may contribute toward resistance to chemotherapy, suggesting that EMT could be targeted to treat patients with MPM. Previously, we reported that histone modifiers regulating EMT could be therapeutic targets; therefore, in this study, we investigated whether targeting lysine-specific demethylase 1 (LSD1/KDM1), a histone-modifying enzyme responsible for demethylating histone H3 lysine 4 and lysine 9, could represent a novel therapeutic strategy for MPM. We suppressed LSD1 and investigated the EMT phenotype using EMT marker expression and wound-healing assay; and chemosensitivity using apoptosis assay. We found that suppressing LSD1 induces an epithelial phenotype in sarcomatoid MPM cells, while attenuating the mesenchymal phenotype sensitized MPM cells to cisplatin-induced apoptosis. Subsequent genome-wide identification, comprehensive microarray analysis, and Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) to assess genome-wide changes in chromatin accessibility suggested that LSD1 directly regulates milk fat globulin protein E8 (MFGE8), an integrin ligand that is involved in the FAK pathway. Furthermore, we found that LSD1 regulates the mesenchymal phenotype and apoptosis by activating the FAK–AKT–GSK3β pathway via a positive feedback loop involving MFGE8 and Snail expression, thereby leading to cisplatin resistance.Implications:This study suggests that LSD1 regulates the mesenchymal phenotype and apoptosis, and that LSD1 inhibitors could be combined with the cisplatin as a novel therapy for patients with MPM.

Oksigen merupakan substrat penting bagi kehidupan manusia. Pengambilan oksigen dari lingkungan melalui kerja paru memberikan asupan substrat penting untuk proses produksi energi. Pada kondisi gawat napas, pemberian oksigen merupakan hal yang sangat esensial untuk menjaga homeostasis tubuh dan mencegah kerusakan organ lebih lanjut. Sehingga, pengetahuan akan indikasi pemberian oksigen, berapa dosis oksigen yang tepat, bagaimana cara memberikan oksigen yang benar, dan apa yang harus diperhatikan dalam pemberian oksigen sangat perlu dikuasai dengan baik. Pada era pandemi Covid-19 ini, penggunaan terapi oksigen sangat masif, sehingga perlunya dilakukan penyegaran kembali mengenai terapi oksigen terhadap tenaga kesehatan di lingkungan Rumah Sakit Universitas Mataram agar penggunaan oksigen dapat lebih tepat guna, dan optimal. Meningkatkan pengetahuan tenaga kesehatan di Rumah Sakit Universitas Mataram mengenai terapi oksigen. Kegiatan pelatihan ini dilakukan dengan menggunakan metode ceramah interaktif dan dilanjutkan dengan sesi tanya jawab dan diskusi. Pengetahuan peserta dinilai berdasarkan pre-test dan post-test. Kegiatan pelatihan dihadiri oleh 35 orang tenaga kesehatan yang khusus berasal dari instalasi rawat isolasi, instalasi gawat darurat, dan instalasi perawatan kritis (intensive care unit (ICU)) Rumah Sakit Universitas Mataram. Pada pelatihan ini, terdapat peningkatan pengetahuan yang bermakna, dengan selisih skor peningkatan pengetahuan sebesar 10.89 (p=0.0225 (

Infeksi SARS-CoV-2 dapat menyebabkan disregulasi respons imunitas tubuh yang menimbulkan sekresi sitokin proinflamasi yang berlebihan, menyebabkan kondisi yang disebut sebagai badai sitokin. Badai sitokin ini memiliki peran penting dalam progresi penyakit COVID-19 karena dapat menyebabkan disfungsi multi organ, gangguan koagulasi, dan kematian. Sitokin proinflamasi yang paling banyak mengalami peningkatan selama badai sitokin pada pasien COVID-19 adalah IL-6. Dari pengetahuan ini, peneliti mulai mencari tahu kemungkinan digunakannya terapi inhibisi IL-6 sebagai bagian dari tata laksana COVID-19. Tiga macam terapi inhibisi IL-6 yang sedang diteliti adalah inhibitor reseptor IL-6, antagonis IL-6, dan inhibitor JAK. Ketiga agen terapi inhibisi IL-6 ini terbukti dapat memperbaiki klinis dan mengurangi mortalitas pasien COVID-19 dengan gejala berat. Akan tetapi, pemberian terapi inhibisi IL-6 masih belum memberikan hasil yang konsisten pada pasien COVID-19 yang disertai dengan gejala kritis sehingga pemberian pada kelompok ini harus lebih hati-hati. Oleh karena itu, penelitian lebih lanjut mengenai efektivitas dan keamanan terapi ini harus tetap dilakukan.

Background: Coronavirus disease 2019 (COVID-19) is a contagious infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The World Health Organization (WHO) declared this infection a global pandemic in 2020. In addition, various methods have been developed to diagnose COVID-19 rapidly and accurately to reverse transcription-polymerase chain reaction (RT-PCR) as a gold standard method. One of these methods is the detection of volatile organic compounds (VOC) in exhaled breath. Objectives: The aim was to collect and investigate studies on the accuracy of VOC detection as a diagnostic method for COVID-19. Methods: A literature search was performed in five electronic databases, including PubMed, Cochrane Library, ProQuest, EBSCOhost, and Scopus, along with hand searching. The search was conducted in the titles and abstracts of articles using keywords and their equivalent terms, combined with the Boolean operators (OR and AND). The search results were then selected according to the inclusion and exclusion criteria and compatibility with the Population, Intervention, Control, and Outcomes (PICO) framework. Results: Based on the search results, two cross-sectional studies by Wintjens et al. and Ruszkiewicz et al. were selected, which were then critically appraised. Both studies showed good validity. Wintjens et al. reported 86% sensitivity and 54% specificity for their method, with a positive predictive value (PPV) and a negative predictive value (NPV) of 40% and 92%, respectively. Besides, Ruszkiewicz et al., who conducted a study in two different locations, reported 82.4% sensitivity and 75% specificity for their method in Edinburgh (UK), with PPV and NPV of 87.5% and 66.7%, respectively, while they reported 90% sensitivity and 80% specificity in Dortmund (Germany), with PPV and NPV of 45% and 97.8%, respectively. The accuracy of these three methods was 62%, 80%, and 82%, respectively. Conclusions: Detection of VOCs from exhaled breath can be a rapid, cost-effective, and simple method for diagnosing COVID-19. However, the accuracy of this method is still relatively low (62 - 82%) and inconsistent; therefore, it is only recommended for screening.

Indonesia is among the top three countries globally with the highest tuberculosis burden. During the past decades, Indonesian health authorities have struggled to improve tuberculosis care quality in health care facilities by optimizing the regulation and strengthening the private sector contributions. The coronavirus disease 2019 (COVID-19) pandemic has hardly affected the Indonesian health care system, including the National Tuberculosis Control Program. While the end of the COVID-19 pandemic in Indonesia is uncertain, the measure to control tuberculosis must not be weakened. Early identification and measurement of the problem size are essential to decide the most appropriate approach to maintain the sustainability of National Tuberculosis Control Program, particularly in health care facilities during the COVID-19 pandemic. This article points out the possible threats to the sustainability of TB care in Indonesia during the COVID-19 pandemic, including some approaches to overcome those problems.

Background Zinc‐finger E‐box‐binding homeobox 1 (ZEB1) is an important regulator of epithelial‐mesenchymal transition (EMT) and is involved in the maintenance of cancer stem cells (CSCs) via miR‐200c and BMI1 pathway. Recent studies revealed that ZEB1 contributes to the EMT‐mediated acquired resistance to gefitinib in EGFR‐mutant non‐small cell lung cancer (NSCLC). However, the precise role of ZEB1 in the maintenance of lung CSCs that lead to acquired resistance to gefitinib remains unclear. Methods PC9 and HCC827 NSCLC cell lines were treated with high concentrations of gefitinib, and surviving cells were referred to as “gefitinib‐resistant persisters” (GRPs). ZEB1 knockdown or overexpression was performed to determine the biological significance of ZEB1 in the CSC features of GRPs, and animal models were studied for in vivo validation. Expression of ZEB1, BMI1, and ALDH1A1 was analyzed by immunohistochemistry in tumor specimens from NSCLC patients with acquired resistance to gefitinib. Results GRPs had characteristic features of mesenchymal and CSC phenotypes with high expression of ZEB1 and BMI1, and decreased miR‐200c, in vitro and in vivo. ZEB1 silencing attenuated the suppression of miR‐200c, resulting in the reduction in BMI1 and reversed the mesenchymal and CSC features of GRPs. Furthermore, ZEB1 overexpression induced EMT and increased the levels of CD133‐ and BMI1‐positive GRPs in vitro and gefitinib resistance in vivo. Finally, ZEB1, BMI1, and ALDH1A1 were highly expressed in tumor specimens from EGFR‐mutant NSCLC patients with gefitinib resistance. Conclusions ZEB1 plays an important role in gefitinib‐resistant lung CSCs with EMT features via regulation of miR‐200c and BMI1., Gefitinib‐resistant persisters (GRPs) of EGFR‐mutant NSCLC cells have characteristic features of mesenchymal and CSC phenotypes. ZEB1 is highly expressed in GRPs and involved in the maintenance of lung CSCs resistant to gefitinib via miR‐200c‐BMI1 pathway.

Purpose Idiopathic pulmonary fibrosis (IPF) is characterized by the accumulation of extracellular matrix (ECM) protein in the lungs. Transforming growth factor (TGF) β-induced ECM protein synthesis contributes to the development of IPF. Tranilast, an anti-allergy drug, suppresses TGFβ expression and inhibits interstitial renal fibrosis in animal models. However, the beneficial effects of tranilast or its mechanism as a therapy for pulmonary fibrosis have not been clarified. Methods We investigated the in vitro effect of tranilast on ECM production and TGFβ/SMAD2 pathway in TGFβ2-stimulated A549 human alveolar epithelial cells, using quantitative polymerase chain reaction, Western blotting, and immunofluorescence. In vitro observations were validated in the lungs of a murine pulmonary fibrosis model, which we developed by intravenous injection of bleomycin. Results Treatment with tranilast suppressed the expression of ECM proteins, such as fibronectin and type IV collagen, and attenuated SMAD2 phosphorylation in TGFβ2-stimulated A549 cells. In addition, based on a wound healing assay in these cells, tranilast significantly inhibited cell motility, with foci formation that comprised of ECM proteins. Histological analyses revealed that the administration of tranilast significantly attenuated lung fibrosis in mice. Furthermore, tranilast treatment significantly reduced levels of TGFβ, collagen, fibronectin, and phosphorylated SMAD2 in pulmonary fibrotic tissues in mice. Conclusion These findings suggest that tranilast inhibits pulmonary fibrosis by suppressing TGFβ/SMAD2-mediated ECM protein production, presenting tranilast as a promising and novel anti-fibrotic agent for the treatment of IPF.

Indoor air pollution marked with decreased air quality below the set standard. The quality of indoor air is determined by ambient air quality as well as by a harmful substance resulting from the household activity. Indoor air pollution may cause several problems such as sick building syndrome, chronic obstructive pulmonary disease (COPD), asthma, lung cancer, and is responsible for nearly two million death in developing countries. One of the interesting research topics to overcome the indoor air pollution problem is the application of indoor plants. Although there are no established criteria to specify the best indoor plant, several studies have revealed the capability of a particular indoor plant to remove the harmful substances. This paper summarizes important information about indoor air pollution and provides the evidence-based insight of indoor plant usefulness as an alternative way for indoor air remediation.

Background Osimertinib (AZD9291) is a third-generation EGFR-tyrosine kinase inhibitor (TKI) that selectively inhibits the activating EGFR mutation and T790M mutation, and is currently used globally to treat EGFR-mutant non-small cell lung cancer (NSCLC). However, acquired resistance to osimertinib is inevitable. Methods We established osimertinib-resistant cells (PC9/T790M/AZDR and H1975/AZDR) derived from EGFR-mutant NSCLC cells harboring T790M mutation, and investigated the mechanism of acquired resistance to osimertinib by whole-exome sequencing and multiple phospho-receptor tyrosine kinase (RTK) array. A tumor specimen from an EGFR-mutant NSCLC patient with acquired resistance to osimertinib was also subjected to immunohistochemical analysis. Results Whole-exome sequencing analysis demonstrated that genetic alterations, such as acquisition of EGFR C797S, loss of T790M mutation, MET amplification, or mutated KRAS, MEK, BRAF, PIK3CA, were not detected. Analysis of phospho-RTK array revealed that insulin-like growth factor-1 receptor (IGF1R) was activated in PC9/T790M/AZDR and H1975/AZDR cells. Knockdown of IGF1R by siRNA as well as inhibition of IGF1R activation by linstinib (IGF1R inhibitor) significantly restored the sensitivity to osimertinib. Immunohistochemical analysis revealed that the expression level of phosphorylated IGF1R was higher in the tumor specimen from the EGFR-mutant NSCLC patient with acquired resistance to osimertinib than in the specimen collected prior to the treatment. Conclusions IGF1R activation could occur following treatment with osimertinib in EGFR-mutant NSCLC with T790M mutation, and might be one of the mechanisms underlying osimertinib resistance. Combined treatment of osimertinib and IGF1R inhibitor might be effective in overcoming the acquired resistance to osimertinib induced by IGF1R activation. Key points Significant findings of the study: Using osimertinib-resistant cells, we found that IGF1R activation induced by osimertinib treatment in EGFR-mutant NSCLC with T790M mutation is involved in resistance. Increased phosphorylation of IGF1R was observed in the tumor specimen from an EGFR-mutant NSCLC patient with acquired osimertinib resistance. What this study adds IGF1R activation might be one of the mechanisms of osimertinib resistance. A combination therapy with osimertinib and an IGF1R inhibitor might be an optimal approach for overcoming the acquired resistance to osimertinib induced by IGF1R activation.

Background Pirfenidone, an antifibrotic agent used for the treatment of idiopathic pulmonary fibrosis (IPF), functions by inhibiting myofibroblast differentiation, which is involved in transforming growth factor (TGF)-β1-induced IPF pathogenesis. However, unlike normal lung fibroblasts, the relationship between pirfenidone responses of TGF-β1-induced human fibrotic lung fibroblasts and lung fibrosis has not been elucidated. Methods The effects of pirfenidone were evaluated in lung fibroblasts isolated from fibrotic human lung tissues after TGF-β1 exposure. The ability of two new pharmacological targets of pirfenidone, collagen triple helix repeat containing protein 1(CTHRC1) and four-and-a-half LIM domain protein 2 (FHL2), to mediate contraction of collagen gels and migration toward fibronectin were assessed in vitro. Results Compared to control lung fibroblasts, pirfenidone significantly restored TGF-β1-stimulated fibroblast-mediated collagen gel contraction, migration, and CTHRC1 release in lung fibrotic fibroblasts. Furthermore, pirfenidone attenuated TGF-β1- and CTHRC1-induced fibroblast activity, upregulation of bone morphogenic protein-4(BMP-4)/Gremlin1, and downregulation of α-smooth muscle actin, fibronectin, and FHL2, similar to that observed post-CTHRC1 inhibition. In contrast, FHL2 inhibition suppressed migration and fibronectin expression, but did not downregulate CTHRC1. Conclusions Overall, pirfenidone suppressed fibrotic fibroblast-mediated fibrotic processes via inverse regulation of CTHRC1-induced lung fibroblast activity. Thus, CTHRC1 can be used for predicting pirfenidone response and developing new therapeutic targets for lung fibrosis. Electronic supplementary material The online version of this article (10.1186/s12931-019-1093-z) contains supplementary material, which is available to authorized users.

Malignant pleural mesothelioma (MPM) is a highly aggressive tumor that has a low overall survival; however, no significant treatment advances have been made in the past 15 years. Large-scale molecular studies have identified a poor prognostic subset of MPM linked to the epithelial–mesenchymal transition (EMT) that may contribute toward resistance to chemotherapy, suggesting that EMT could be targeted to treat patients with MPM. Previously, we reported that histone modifiers regulating EMT could be therapeutic targets; therefore, in this study, we investigated whether targeting lysine-specific demethylase 1 (LSD1/KDM1), a histone-modifying enzyme responsible for demethylating histone H3 lysine 4 and lysine 9, could represent a novel therapeutic strategy for MPM. We suppressed LSD1 and investigated the EMT phenotype using EMT marker expression and wound-healing assay; and chemosensitivity using apoptosis assay. We found that suppressing LSD1 induces an epithelial phenotype in sarcomatoid MPM cells, while attenuating the mesenchymal phenotype sensitized MPM cells to cisplatin-induced apoptosis. Subsequent genome-wide identification, comprehensive microarray analysis, and Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) to assess genome-wide changes in chromatin accessibility suggested that LSD1 directly regulates milk fat globulin protein E8 (MFGE8), an integrin ligand that is involved in the FAK pathway. Furthermore, we found that LSD1 regulates the mesenchymal phenotype and apoptosis by activating the FAK–AKT–GSK3β pathway via a positive feedback loop involving MFGE8 and Snail expression, thereby leading to cisplatin resistance. Implications: This study suggests that LSD1 regulates the mesenchymal phenotype and apoptosis, and that LSD1 inhibitors could be combined with the cisplatin as a novel therapy for patients with MPM.

The coronavirus disease 2019 (COVID-19) pandemic caused by infection of the SARS-CoV-2 virus has affected millions of people in the world. The pathogenesis and clinical manifestations of COVID-19 disease are tightly influenced by the host immune response to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. In some condition, the immune response might be uncontrolled, giving rise to hyperinflammatory conditions marked by excessive release of proinflammatory cytokines (cytokine storms) in severe COVID-19 patients, which then can cause acute respiratory distress syndrome (ARDS), multiorgan failure, and death. Furthermore, treatment using immunomodulator agents including immunostimulatory and immunosuppressive agents can be an option in achieving successful treatment. In this review, we discuss the pathogenesis of the disease, including host immune responses to SARS-CoV-2 virus infection, and immune mechanisms which contribute to the disease severity and death as well as several potential immunomodulatory agents which can be used in the management of hyperinflammatory syndrome of severe COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel coronavirus that causes coronavirus diseases 2019 (COVID-19). The SARS-CoV-2 is very contagious and nobody is known to be immune to it. The post-infected lung would leave a scar known as fibrosis, a scar tissue. A study from Wuhan, China suggested the development of fibrosis, though it was too early to label these lung changes as irreversible fibrosis in a time range of 3 weeks. The occurrence of fibrosis indicates a chronic infection which greatly contributes to the hallmark symptom of COVID-19 induced ARDS such as shortness of breath and chest pain. However, many of those studies have not yet explained the condition of the patient's lung after total recovery from the COVID-19. This report demonstrates the clinical symptoms, chest CT scan, spirometry, and blood gas analysis of patient after total recovery from the COVID-19 with appearance lung fibrosis.

Purpose Idiopathic pulmonary fibrosis (IPF) is characterized by the accumulation of extracellular matrix (ECM) protein in the lungs. Transforming growth factor (TGF) β-induced ECM protein synthesis contributes to the development of IPF. Tranilast, an anti-allergy drug, suppresses TGFβ expression and inhibits interstitial renal fibrosis in animal models. However, the beneficial effects of tranilast or its mechanism as a therapy for pulmonary fibrosis have not been clarified. Methods We investigated the in vitro effect of tranilast on ECM production and TGFβ/SMAD2 pathway in TGFβ2-stimulated A549 human alveolar epithelial cells, using quantitative polymerase chain reaction, Western blotting, and immunofluorescence. In vitro observations were validated in the lungs of a murine pulmonary fibrosis model, which we developed by intravenous injection of bleomycin. Results Treatment with tranilast suppressed the expression of ECM proteins, such as fibronectin and type IV collagen, and attenuated SMAD2 phosphorylation in TGFβ2-stimulated A549 cells. In addition, based on a wound healing assay in these cells, tranilast significantly inhibited cell motility, with foci formation that comprised of ECM proteins. Histological analyses revealed that the administration of tranilast significantly attenuated lung fibrosis in mice. Furthermore, tranilast treatment significantly reduced levels of TGFβ, collagen, fibronectin, and phosphorylated SMAD2 in pulmonary fibrotic tissues in mice. Conclusion These findings suggest that tranilast inhibits pulmonary fibrosis by suppressing TGFβ/SMAD2-mediated ECM protein production, presenting tranilast as a promising and novel anti-fibrotic agent for the treatment of IPF.

Small cell lung cancer (SCLC) is an aggressive neuroendocrine tumor characterized by rapid progression. The mechanisms that lead to a shift from initial therapeutic sensitivity to ultimate therapeutic resistance are poorly understood. Although the SCLC genomic landscape led to the discovery of promising agents targeting genetic alterations that were already under investigation, results have been disappointing. Achievements in targeted therapeutics have not been observed for over 30 years. Therefore, the underlying disease biology and novel targets urgently require a better understanding. Epigenetic regulation is deeply involved in the cellular plasticity that could shift tumor cells to the malignant phenotype. We have focused on a histone modifier, LSD1, that is overexpressed in SCLC and is a potent therapeutic target. Interestingly, the LSD1 splice variant LSD1+8a, the expression of which has been reported to be restricted to neural tissue, was detected and was involved in the expression of neuroendocrine marker genes in SCLC cell lines. Cells with high expression of LSD1+8a were resistant to CDDP and LSD1 inhibitor. Moreover, suppression of LSD1+8a inhibited cell proliferation, indicating that LSD1+8a could play a critical role in SCLC. These findings suggest that LSD1+8a should be considered a novel therapeutic target in SCLC., Highlights • LSD1+8a, which was reported to be restricted to neural tissue, is expressed in SCLC. • LSD1+8a is involved in the expression of neuroendocrine marker genes. • SCLC cell lines with high expression of LSD1+8a were resistant to chemotherapy.

Background Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disorder. Recent studies have suggested that epithelial-mesenchymal transition (EMT) of alveolar epithelial cells influences development of pulmonary fibrosis, which is mediated by transforming growth factor β (TGF-β). Tumor necrosis factor α (TNF-α), an important proinflammatory cytokine in IPF, has been shown to enhance TGF-β-induced EMT. Nintedanib, a multiple tyrosine kinase inhibitor that is currently used to treat IPF, has been shown to suppress EMT in various cancer cell lines. However, the mechanism of EMT inhibition by nintedanib and its effect on TGF-β and TNF-α signaling pathways in alveolar epithelial cells have not been fully elucidated. Methods A549 alveolar epithelial cells were stimulated with TGF-β2 and TNF-α, and the effects of nintedanib on global gene expression were evaluated using microarray analysis. Furthermore, Smad2/3 phosphorylation was assessed using western blotting. Results We found that in A549 cells, TGF-β2 and TNF-α treatment induces EMT, which was inhibited by nintedanib. Gene ontology analysis showed that nintedanib significantly attenuates the gene expression of EMT-related cellular pathways and the TGF-β signaling pathway, but not in the TNF-α-mediated signaling pathway. Furthermore, hierarchical cluster analysis revealed that EMT-related genes were attenuated in nintedanib-treated cells. Additionally, nintedanib was found to markedly suppress phosphorylation of Smad2/3. Conclusion Nintedanib inhibits EMT by mediating EMT-related gene expression and the TGF-β/Smad pathway in A549 alveolar epithelial cells.

Several recent studies suggest that cancer stem cells (CSCs) are involved in intrinsic resistance to cancer treatment. Maintenance of quiescence is crucial for establishing resistance of CSCs to cancer therapeutics. F-box/WD repeat-containing protein 7 (FBXW7) is a ubiquitin ligase that regulates quiescence by targeting the c-MYC protein for ubiquitination. We previously reported that gefitinib-resistant persisters (GRPs) in EGFR-mutant non-small cell lung cancer (NSCLC) cells highly expressed octamer-binding transcription factor 4 (Oct-4) as well as the lung CSC marker CD133, and they exhibited distinctive features of the CSC phenotype. However, the role of FBXW7 in lung CSCs and their resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors in NSCLC is not fully understood. In this study, we developed GRPs from the two NSCLC cell lines PC9 and HCC827, which express an EGFR exon 19 deletion mutation, by treatment with a high concentration of gefitinib. The GRPs from both PC9 and HCC827 cells expressed high levels of CD133 and FBXW7, but low levels of c-MYC. Cell cycle analysis demonstrated that the majority of GRPs existed in the G0/G1 phase. Knockdown of the FBXW7 gene significantly reduced the cell number of CD133-positive GRPs and reversed the cell population in the G0/G1-phase. We also found that FBXW7 expression in CD133-positive cells was increased and c-MYC expression was decreased in gefitinib-resistant tumors of PC9 cells in mice and in 9 out of 14 tumor specimens from EGFR-mutant NSCLC patients with acquired resistance to gefitinib. These findings suggest that FBXW7 plays a pivotal role in the maintenance of quiescence in gefitinib-resistant lung CSCs in EGFR mutation-positive NSCLC.

Pirfenidone, an antifibrotic agent used for treatment of idiopathic pulmonary fibrosis (IPF), functions by inhibiting myofibroblast differentiation, which is involved in transforming growth factor (TGF)-β1-induced IPF pathogenesis. However, unlike normal lung fibroblasts, the relationship between pirfenidone responses of TGF-β1-induced human fibrotic lung fibroblasts and lung fibrosis is unknown. Here, we investigated the effect of pirfenidone on the functions of two new targets, collagen triple helix repeat containing protein 1 (CTHRC1) and four-and-a-half LIM domain protein 2 (FHL2), which included fibroblast activity, collagen gel contraction, and migration toward fibronectin. Compared to control lung fibroblasts, pirfenidone restored TGF-β1-stimulated fibroblast-mediated collagen gel contraction, migration, and CTHRC1 release in lung fibrotic fibroblasts. Furthermore, pirfenidone attenuated TGF-β1- and CTHRC1-induced fibroblast activity, bone morphogenic protein-4/Gremlin1 upregulation, and α-smooth muscle actin, fibronectin, and FHL2 downregulation, similar to that observed post-CTHRC1 inhibition. In contrast, FHL2 inhibition suppressed migration and fibronectin expression but did not downregulate CTHRC1. Overall, pirfenidone suppressed fibrotic fibroblast-mediated fibrotic processes via inverse regulation of CTHRC1-induced lung fibroblast activity. Thus, CTHRC1 can be used for predicting pirfenidone response and developing new therapeutic target for lung fibrosis.Summary statementPirfenidone suppressed TGF-β1-mediated fibrotic processes in fibrotic lung fibroblasts by attenuating CTHRC1 expression, suggesting that CTHRC1 may be a novel therapeutic target for treating patients with lung fibrosis.

Transforming growth factor β (TGFβ)-mediated epithelial–mesenchymal transition (EMT) of alveolar epithelial cells contributes to pulmonary fibrosis. Dasatinib (DAS), a potent and broad-spectrum tyrosine kinase inhibitor, has been widely studied as an anti-cancer agent. However, the therapeutic application of DAS for pulmonary fibrosis has not been clarified. Our purpose here is to investigate the effect of DAS on TGFβ1-induced EMT in human alveolar and bronchial epithelial cells in vitro and to evaluate the efficacy of DAS on lung fibrosis in vivo. TGFβ1-stimulated human alveolar epithelial (A549) and bronchial epithelial (BEAS-2B) cells were treated with or without DAS in vitro. Murine pulmonary fibrosis model was generated by injection of bleomycin (BLM). A549 and BEAS-2B cells exposed to TGFβ1 underwent EMT, as indicated by downregulation of epithelial protein E-cadherin and induction of the mesenchymal proteins, fibronectin and type I and type IV collagen. These effects were dramatically suppressed by DAS treatment, which also prevented Smad2 and Smad3 phosphorylation. DAS inhibited TGFβ1-induced cell motility and migration. Furthermore, DAS administration significantly attenuated lung fibrosis in mice by histological analysis. Treatment with DAS also significantly reduced the levels of collagen and fibronectin and phosphorylation of Smad2 in the lung tissues of the murine model. These findings suggest that DAS inhibited TGFβ-mediated EMT of alveolar and bronchial epithelial cells and attenuated BLM-induced lung fibrosis in mice by suppressing the TGFβ/Smad pathway. DAS may be a promising and novel anti-fibrotic agent for preventing lung fibrosis.

Insulin-like growth factor 1 receptor (IGF1R) is expressed in many types of solid tumors including non-small cell lung cancer (NSCLC), and enhanced activation of IGF1R is thought to reflect cancer progression. Epithelial-mesenchymal transition (EMT) has been established as one of the mechanisms responsible for cancer progression and metastasis, and microenvironment conditions, such as hypoxia, have been shown to induce EMT. The purposes of this study were to address the role of IGF1R activation in hypoxia-induced EMT in NSCLC and to determine whether inhibition of IGF1R might reverse hypoxia-induced EMT. Human NSCLC cell lines A549 and HCC2935 were exposed to hypoxia to investigate the expression of EMT-related genes and phenotypes. Gene expression analysis was performed by quantitative real-time PCR and cell phenotypes were studied by morphology assessment, scratch wound assay, and immunofluorescence. Hypoxia-exposed cells exhibited a spindle-shaped morphology with increased cell motility reminiscent of EMT, and demonstrated the loss of E-cadherin and increased expression of fibronectin and vimentin. Hypoxia also led to increased expression of IGF1, IGF binding protein-3 (IGFBP3), and IGF1R, but not transforming growth factor β1 (TGFβ1). Inhibition of hypoxia-inducible factor 1α (HIF1α) with YC-1 abrogated activation of IGF1R, and reduced IGF1 and IGFBP3 expression in hypoxic cells. Furthermore, inhibition of IGF1R using AEW541 in hypoxic condition restored E-cadherin expression, and reduced expression of fibronectin and vimentin. Finally, IGF1 stimulation of normoxic cells induced EMT. Our findings indicated that hypoxia induced EMT in NSCLC cells through activation of IGF1R, and that IGF1R inhibition reversed these phenomena. These results suggest a potential role for targeting IGF1R in the prevention of hypoxia-induced cancer progression and metastasis mediated by EMT.

The mechanism underlying increased concentrations of cancer stem cell (CSC)-associated factors in non-small cell lung cancer (NSCLC) cells treated with transforming growth factor β1 (TGFβ1) and tumor necrosis factor α (TNFα), is still not clear. The purpose of this study was to investigate the possible role of CD44 in the regulation of CSC-associated genes, by analyzing the effect of CD44 knockdown on their expression. A549, a NSCLC cell line that expresses CD44 antigen, was treated with TGFβ1 and TNFα. Small-interfering ribonucleic acid (siRNA) that specifically targets the CD44 gene was used to knockdown the expression of CD44 in A549. The gene expressions of CD44, CXCR4, POU5F1 (octamer-binding transcription factor 4 [Oct4]), PROM1, NANOG, c-Myc, KLF4, and SOX2, as well as of CDH1 (E-cadherin), CDH2 (N-cadherin), VIM (vimentin), and FN1 (fibronectin) were analyzed in A549 cells by quantitative reverse transcription polymerase chain reaction (RT-qPCR). Cell morphology was observed using light microscopy. After TGFβ1/TNFα treatment, increased expressions of CXCR4 and POU5F1 were detected. Silencing of CD44 gene expression was confirmed by RT-qPCR. The knockdown of CD44 decreased the CXCR4 and POU5F1 gene expressions in TGFβ1/TNFα-treated A549 cells. However, the silencing of CD44 did not affect the morphology of TGFβ1/TNFα-treated A549 cells nor it reversed epithelial-mesenchymal transition (EMT) gene signature induced by TGFβ1/TNFα in A549 cells. Our preliminary findings suggest that the CD44 gene may have a role in regulating CXCR4 and POU5F1 gene expressions, independently of the EMT signaling pathway.

Several recent studies have suggested that cancer stem cells (CSCs) are involved in resistance to gefitinib in non-small cell lung cancer (NSCLC). Oct4, a member of the POU-domain transcription factor family, has been shown to be involved in CSC properties of various cancers. We previously reported that Oct4 and the putative lung CSC marker CD133 were highly expressed in gefitinib-resistant persisters (GRPs) in NSCLC cells, and GRPs exhibited characteristic features of the CSCs phenotype. The aim of this study was to elucidate the role of Oct4 in the resistance to gefitinib in NSCLC cells with an activating epidermal growth factor receptor (EGFR) mutation. NSCLC cell lines, PC9, which express the EGFR exon 19 deletion mutation, were transplanted into NOG mice, and were treated with gefitinib in vivo. After 14-17 days of gefitinib treatment, the tumors still remained; these tumors were referred to as gefitinib-resistant tumors (GRTs). PC9-GRTs showed higher expression of Oct4 and CD133. To investigate the role of Oct4 in the maintenance of gefitinib-resistant lung CSCs, we introduced the Oct4 gene into PC9 and HCC827 cells carrying an activating EGFR mutation by lentiviral infection. Transfection of Oct4 significantly increased CD133-positive GRPs and the number of sphere formation, reflecting the self-renewal activity, of PC9 and HCC827 cells under the high concentration of gefitinib in vitro. Furthermore, Oct4-overexpressing PC9 cells (PC9-Oct4) significantly formed tumors at 1 × 10 cells/injection in NOG mice as compared to control cells. In addition, PC9-Oct4 tumors were more resistant to gefitinib treatment as compared to control cells in vivo. Finally, immunohistochemical analysis revealed that Oct4 was highly expressed in tumor specimens of EGFR-mutant NSCLC patients with acquired resistance to gefitinib. Collectively, these findings suggest that Oct4 plays a pivotal role in the maintenance of lung CSCs resistant to gefitinib in EGFR mutation-positive NSCLC.

F-box and WD40 repeat domain-containing 7 (FBXW7) adalah protein F-box yang merupakan komponen sistem ubiquitin proteasome yang berhubungan dengan beberapa protein onkogenik penting seperti Notch, c-Myc, cyclin E and c-Jun dalam mengatur proses pertumbuhan dan perkembangan sel, metabolism sel, diferensiasi dan apoptosis. Beberapa studi terkini menunjukkan bahwa FBXW7 berperan dalam perkembangan beberapa stem cell, mencakup proses self-renewal, multipotensi, diferensiasi, dan survival. Cancer stem cell (CSC) diketahui merupakan salah satu penyebab resistensi tumor terhadap berbagai kemoterapi, kekambuhan dan metastasis tumor. FBXW7 berperan terhadap kondisi quiescence pada CSC dengan mengatur substrat downstream c-Myc. Kondisi quiescence pada CSC dapat diinhibisi dengan memblokade peran FBXW7 melalui pathway upstream and downstream FBXW7 sehingga diharapkan dapat mengatasi resistensi dan kekambuhan tumor. Artikel telaah pustaka ini akan memaparkan peran FBXW7 pada stem cell normal dan pada cancer stem cell hubungannya dengan pengembangan terapi.

Tobacco consumption is a major causative agent for various deadly diseases such as coronary artery disease and cancer. It is the largest avoidable health risk in the world, causing more problems than alcohol, drug use, high blood pressure, excess body weight or high cholesterol. As countries like Indonesia prepare to develop national policy guidelines for tobacco harm reduction, the scientific community can help by providing continuous ideas and a forum for sharing and distributing information, drafting guidelines, reviewing best practices, raising funds, and establishing partnerships. We propose several strategies for reducing tobacco consumption, including advertisement interference, cigarette pricing policy, adolescent smoking prevention policy, support for smoking cessation therapy, special informed consent for smokers, smoking prohibition in public spaces, career incentives, economic incentives, and advertisement incentives. We hope that these strategies would assist people to avoid starting smoking or in smoking cessation.