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At least 37 records · Page 2

Olivine Dissolution in Simulated Lung and Gastric Fluid as an Analog to the Behavior of Lunar Particulate Matter Inside the Human Respiratory and Gastrointestinal Systems

With the Artemis III mission scheduled to land humans on the Moon in 2025, work must be done to understand the hazards lunar dust inhalation would pose to humans. In this study, San Carlos olivine was used as an analog of lunar olivine, a common component of lunar dust. Olivine was dissolved in a flow-through apparatus in both simulated lung fluid and 0.1 M HCl (simulated gastric fluid) over a period of approximately 2 weeks at physiological temperature, 37°C. Effluent samples were collected periodically and analyzed for pH, iron, silicon, and magnesium ion concentrations. The dissolution rate data derived from our measurements allow us to estimate that an inhaled 1.0 μm diameter olivine particle would take approximately 24 years to dissolve in the human lungs and approximately 3 weeks to dissolve in gastric fluid. Results revealed that inhaled olivine particles may generate the toxic chemical, hydroxyl radical, for up to 5–6 days in lung fluid. Olivine dissolved in 0.1 M HCl for 2 weeks transformed to an amorphous silica-rich solid plus the ferric iron oxy-hydroxide ferrihydrite. Olivine dissolved in simulated lung fluid shows no detectable change in composition or crystallinity. Equilibrium thermodynamic models indicate that olivine in the human lungs can precipitate secondary minerals with fibrous crystal structures that have the potential to induce detrimental health effects similar to asbestos exposure. Our work indicates that inhaled lunar dust containing olivine can settle in the human lungs for years and could induce long-term potential health effects like that of silicosis.

63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTAN↗

Effects of periodontitis on postoperative pneumonia in patients with lung and esophageal cancer

Abstract Background Few studies have been conducted on the relationship between chronic periodontitis and postoperative pneumonia (POP) in patients with lung and esophageal cancer. Furthermore, it remains controversial as to whether improving the periodontal condition of patients with lung and esophageal cancer before surgery reduces the incidence of POP. This retrospective study was conducted to assess the effects of periodontal therapy in patients with lung and esophageal cancer to prevent POP. Methods A total of 265 patients with lung or esophageal cancer complicated with chronic periodontitis who underwent open thoracotomy between July 2015 and June 2019 were selected and given the choice of being in the experimental or control group. A total of 141 participants in the experimental group received periodontal therapy, and 124 participants in the control group did not receive periodontal therapy. All clinical data of participants in both groups were retrospectively studied to determine the incidence of POP on the 30th day after discharge from hospital. Results Eight patients in the experimental and six in the control group, respectively, were excluded from the study. It was found that four of the 133 patients suffered from POP in the experimental group (incidence: 3.01%). A total of 18 of 118 patients in the control group had a pulmonary infection (incidence: 15.25%). POP incidence in the experimental group was significantly lower than that in the control group, and in the level analysis of different types of periodontitis, surgical methods, and diseases ( p < 0.05). Conclusions Periodontal treatment is associated with a lower incidence of POP following lung and esophageal cancer surgery. Improving the periodontal condition of patients helps prevent POP. The presence of periodontitis is an important predisposing factor for POP in patients after open thoracotomy. Periodontal examination and therapy are recommended before the surgical treatment of lung or esophageal cancer.

Jia, Chunling↗

Impact of acute temperature and air pollution exposures on adult lung function: A panel study of asthmatics

Background Individuals with respiratory conditions, such as asthma, are particularly susceptible to adverse health effects associated with higher levels of ambient air pollution and temperature. This study evaluates whether hourly levels of fine particulate matter (PM 2.5 ) and dry bulb globe temperature (DBGT) are associated with the lung function of adult participants with asthma. Methods and findings Global positioning system (GPS) location, respiratory function (measured as forced expiratory volume at 1 second (FEV 1 )), and self-reports of asthma medication usage and symptoms were collected as part of the Exposure, Location, and Lung Function (ELF) study. Hourly ambient PM 2.5 and DBGT exposures were estimated by integrating air quality and temperature public records with time-activity patterns using GPS coordinates for each participant (n = 35). The relationships between acute PM 2.5 , DBGT, rescue bronchodilator use, and lung function collected in one week periods and over two seasons (summer/winter) were analyzed by multivariate regression, using different exposure time frames. In separate models, increasing levels in PM 2.5 , but not DBGT, were associated with rescue bronchodilator use. Conversely DBGT, but not PM 2.5 , had a significant association with FEV 1 . When DBGT and PM 2.5 exposures were placed in the same model, the strongest association between cumulative PM 2.5 exposures and the use of rescue bronchodilator was identified at the 0–24 hours (OR = 1.030; 95% CI = 1.012–1.049; p-value = 0.001) and 0–48 hours (OR = 1.030; 95% CI = 1.013–1.057; p-value = 0.001) prior to lung function measure. Conversely, DBGT exposure at 0 hours (β = 3.257; SE = 0.879; p-value>0.001) and 0–6 hours (β = 2.885; SE = 0.903; p-value = 0.001) hours before a reading were associated with FEV 1 . No significant interactions between DBGT and PM 2.5 were observed for rescue bronchodilator use or FEV 1 . Conclusions Short-term increases in PM 2.5 were associated with increased rescue bronchodilator use, while DBGT was associated with higher lung function (i.e. FEV 1 ). Further studies are needed to continue to elucidate the mechanisms of acute exposure to PM 2.5 and DBGT on lung function in asthmatics.

60 APPLIED LIFE SCIENCES↗

Lung Cancer in the Mayak Workers Cohort: Risk Estimation and Uncertainty Analysis

The workers at the Mayak nuclear facility near Ozyorsk, Russia are a primary source of information about exposure to radiation at low-dose rates, since they were subject to protracted exposures to external gamma rays and to internal exposures from plutonium inhalation. Here we re-examine lung cancer mortality rates and assess the effects of external gamma and internal plutonium exposures using recently developed Monte Carlo dosimetry systems. Using individual lagged mean annual lung doses computed from the dose realizations, we fit excess relative risk (ERR) models to the lung cancer mortality data for the Mayak Workers Cohort using risk-modeling software. We then used the corrected information matrix (CIM) approach to widen the confidence intervals of ERR by taking into account the uncertainty in doses represented by multiple realizations from the Monte Carlo dosimetry systems. Findings of this work revealed that there were 930 lung cancer deaths during follow-up. Plutonium lung doses (but not gamma doses) were generally higher in the new dosimetry systems than those used in the previous analysis. This led to a reduction in the risk per unit dose compared to prior estimates. The estimated ERR/Gy for external gamma-ray exposure was 0.19 (95% CI: 0.07 to 0.31) for both sexes combined, while the ERR/Gy for internal exposures based on mean plutonium doses were 3.5 (95% CI: 2.3 to 4.6) and 8.9 (95% CI: 3.4 to 14) for males and females at attained age 60. Accounting for uncertainty in dose had little effect on the confidence intervals for the ERR associated with gamma-ray exposure, but had a marked impact on confidence intervals, particularly the upper bounds, for the effect of plutonium exposure [adjusted 95% CIs: 1.5 to 8.9 for males and 2.7 to 28 for females]. In conclusion, lung cancer rates increased significantly with both external gamma-ray and internal plutonium exposures. Accounting for the effects of dose uncertainty markedly increased the width of the confidence intervals for the plutonium dose response but had little impact on the external gamma dose effect estimate. Adjusting risk estimate confidence intervals using CIM provides a solution to the important problem of dose uncertainty. This work demonstrates, for the first time, that it is possible and practical to use our recently developed CIM method to make such adjustments in a large cohort study.

uncertainty, radiation risk estimation, Mayak Prod↗

A high-performance lung-inspired ceramic 3D-printed heat exchanger for high-temperature energy-efficient systems

The thermal-to-electric conversion efficiency of next-generation supercritical carbon dioxide and concentrated solar power plants is significantly augmented by operating at temperatures exceeding 1000 °C if durable, compact, high-temperature heat exchangers (HXs) are developed. Whereas metal 3D-printed HXs fail to operate under extreme temperature conditions, ceramic 3D-printed HXs are deemed promising candidates for high-temperature, highly oxidizing environments. Ceramic 3D-printed HXs, however, exhibit a high gas permeability issue through hot and cold separating walls due to an excessive non-volatile photopolymer content utilized. Here, in this work, a novel leak-free lung-inspired ceramic 3D-printed HX employing a highly complex heat transfer topology is introduced for high-temperature energy-efficient systems. The high permeability issue of ceramic 3D-printed HXs is fully eliminated through a uniform zinc-based coating. It was determined that the effective thermal conductivity of the sintered ceramic heat exchangers is affected by the coated layer. The high-temperature thermal and hydraulic characteristics of the lung-inspired ceramic 3D-printed HX are comprehensively examined and compared against a millichannel 3D-printed HX module. Experimental results indicated that the lung-inspired 3D-printed ceramic HX significantly outperforms its millichannel counterpart. The lung-inspired HX shows a volume-based power density of 8.2 MW/m3 at a hot-side inlet air temperature of 700°C, a 71 % improvement compared with that of the millichannel HX. More importantly, the higher thermal duty of the lung-inspired 3D-printed HX is realized at a lower normalized pressure drop penalty of 510 Pa/W, 22 % lower than that of the millichannel ceramic HX. This study accelerates the advancement of high-performance ceramic 3D-printed HXs with complex topologies for high-temperature energy-efficient systems and/or corrosive environments.

42 ENGINEERING↗

PCGF3 promotes the proliferation and migration of non-small cell lung cancer cells via the PI3K/AKT signaling pathway

Highlights: • PCGF3 is highly expressed in non-small cell lung cancer (NSCLC) tissues. • PCGF3 overexpression positively correlates with lymph node metastasis and p-TNM staging. • PCGF3 promotes NSCLC cells proliferation by regulating CyclinB1, CyclinD1, and CDK4. • PCGF3 promotes NSCLC cells migration by regulating RhoA, RhoC, and CDC42. • PCGF3 promotes malignant behavior in NSCLC by positively regulating the PI3K/AKT signaling pathway. The Polycomb Group Ring Finger 3 (PCGF3) protein has been reported to be significantly upregulated in pancreatic islet tumors and related to signal transduction; however, its detailed mechanisms and biological roles in other tumors, including non-small cell lung cancer (NSCLC), remain unclear. This study investigated the function of PCGF3 in NSCLC and further elucidated its mechanism of action. The immunohistochemical analysis of 86 selected lung cancer tissues revealed that PCGF3 was highly expressed in NSCLC tissues and positively correlated with lymph node metastasis and p-TNM staging. Additionally, PCGF3 promoted cell proliferation in lung cancer by regulating CyclinB1, CyclinD1, and CDK4 expression, and also promoting their migration by regulating RhoA, RhoC, and CDC42. Furthermore, PCGF3 affected both the proliferation and migration of lung cancer cells by regulating the PI3K/AKT pathway, as verified by inhibiting this pathway using LY294002. The findings of this study suggested that PCGF3 is associated with poor prognosis in patients with NSCLC and could therefore be an important biomarker for treating and preventing NSCLC.

60 APPLIED LIFE SCIENCES↗

Non-small cell lung cancer cell–derived exosomal miR-17-5p promotes osteoclast differentiation by targeting PTEN

Highlights: • exosomes of SPC-A-1BM cell line prompt osteoclastogenesis. • miR-17-5p increased in exosomes of SPC-A-1BM cell line. • miR-17-5p prompt osteoclastogenesis. • miR-17-5p function through PTEN/PI3K/AKT pathway in osteoclastogenesis in NSCLC. Aberrant activity of bone resorbing osteoclasts plays a key role in the development of osteoporosis and cancer bone metastasis. The identification of novel and specific targets will be helpful for the development of new therapeutic strategies for bone metastasis in lung cancer. Herein, we examined microRNAs in tumor cell-derived exosomes to investigate the communication between the bone environment and tumor cells. TCGA database analysis showed that the level of miR-17-5p increased in non-small cell lung cancer tissues compared with non-tumor tissues. To investigate the function of exosomes in inducing osteoclastogenesis, osteoclast precursors were incubated with exosomes isolated from non-small cell lung cancer cell line, as well as receptor activator of NF-KB ligand and M-CSF to induce osteoclastogenesis. We found that exosomal miR-17-5p is upregulated in a non-small cell lung cancer cell line with bone metastasis compared with the original cell line. Overexpression of miR-17-5p enhanced the osteoclastogenesis of RAW264.7 cells. PTEN was identified as a direct target of miR-17-5p and showed negative effects on osteoclastogenesis. Importantly, treatment of LY294002 (an inhibitor of the PI3K/Akt pathway) attenuated miR-17-5p-mediated osteoclastogenesis effects. Taken together, our findings demonstrated that miR-17-5p promotes osteoclastogenesis through the PI3K/Akt pathway via targeting PTEN in lung cancer.

60 APPLIED LIFE SCIENCES↗

Ad-apoptin inhibits glycolysis, migration and invasion in lung cancer cells targeting AMPK/mTOR signaling pathway

Ad-apoptin is a recombinant oncolytic adenovirus constructed by our laboratory that can express apoptin. It can selectively kill tumor cells without damaging normal cells. This study investigated the effects of Ad-apoptin on glycolysis, migration and invasion of non-small cell lung cancer. Cell viability and apoptosis were detected by CCK-8 and flow cytometry, respectively. Glycolysis was investigated by glucose consumption, lactic acid production and glycolytic key enzyme protein levels. Migration and invasion were evaluated via wound healing, transwell assays and epithelial-mesenchymal transition (EMT) protein levels. The interaction between apoptin and AMPK was detected by Co-IP. A nude mice tumor model was established to investigate the anti-cancer role of Ad-apoptin in vivo. The results showed that Ad-apoptin inhibits cell viability and induces apoptosis of A549 and NCI–H23 cells. Ad-apoptin can reduce the glucose uptake and lactic production in lung cancer cells, and reduce the expression of related glycolysis-limiting enzymes. At the same time, Ad-apoptin inhibited the migration and invasion of lung cancer. Immunoprecipitation showed that apoptin and AMPK could interact directly. Moreover, knockdown of AMPK significantly attenuated the inhibitory effect of Ad-apoptin on glycolysis, migration and invasion of A549 and NCI–H23 cells. Ad-apoptin can inhibit the growth of tumors in nude mice. Compared with the control group, Ad-apoptin had a significant inhibitory effect on AMPK knockdown tumors. The immunohistochemical results of tumor tissues were consistent with those in vitro. Collectively, Ad-apoptin targets AMPK and inhibits glycolysis, migration and invasion of lung cancer cells through the AMPK/mTOR signaling pathway. This suggests that Ad-apoptin may have therapeutic potential for lung cancer by targeting AMPK activation.

60 APPLIED LIFE SCIENCES↗

Outgrowth of erlotinib-resistant subpopulations recapitulated in patient-derived lung tumor spheroids and organoids

A model that recapitulates development of acquired therapeutic resistance is needed to improve oncology drug development and patient outcomes. To achieve this end, we established methods for the preparation and growth of spheroids from primary human lung adenocarcinomas, including methods to culture, passage, monitor growth, and evaluate changes in mutational profile over time. Primary lung tumor spheroids were cultured in Matrigel® with varying concentrations of erlotinib, a small molecule kinase inhibitor of epidermal growth factor receptor (EGFR) that is ineffective against KRAS mutant cells. Subtle changes in spheroid size and number were observed within the first two weeks of culture. Spheroids were cultured for up to 24 weeks, during which time interactions between different cell types, movement, and assembly into heterogeneous organoid structures were documented. Allele-specific competitive blocker PCR (ACB-PCR) was used to quantify low frequency BRAF V600E, KRAS G12D, KRAS G12V, and PIK3CA H1047R mutant subpopulations in tumor tissue residue (TR) samples and cultured spheroids. Mutant subpopulations, including multiple mutant subpopulations, were quite prevalent. Twelve examples of mutant enrichment were found in eight of the 14 tumors analyzed, based on the criteria that a statistically-significant increase in mutant fraction was observed relative to both the TR and the no-erlotinib control. Of the mutants quantified in erlotinib-treated cultures, PIK3CA H1047 mutant subpopulations increased most often (5/14 tumors), which is consistent with clinical observations. Thus, this ex vivo lung tumor spheroid model replicates the cellular and mutational tumor heterogeneity of human lung adenocarcinomas and can be used to assess the outgrowth of mutant subpopulations. Spheroid cultures with characterized mutant subpopulations could be used to investigate the efficacy of lung cancer combination therapies.

59 BASIC BIOLOGICAL SCIENCES↗

Guided construction of single cell reference for human and mouse lung

Accurate cell type identification is a key and rate-limiting step in single-cell data analysis. Single-cell references with comprehensive cell types, reproducible and functionally validated cell identities, and common nomenclatures are much needed by the research community for automated cell type annotation, data integration, and data sharing. Here, we develop a computational pipeline utilizing the LungMAP CellCards as a dictionary to consolidate single-cell transcriptomic datasets of 104 human lungs and 17 mouse lung samples to construct LungMAP single-cell reference (CellRef) for both normal human and mouse lungs. CellRefs define 48 human and 40 mouse lung cell types catalogued from diverse anatomic locations and developmental time points. We demonstrate the accuracy and stability of LungMAP CellRefs and their utility for automated cell type annotation of both normal and diseased lungs using multiple independent methods and testing data. We develop user-friendly web interfaces for easy access and maximal utilization of the LungMAP CellRefs.

59 BASIC BIOLOGICAL SCIENCES↗

Phylogenetic and ecological drivers of the avian lung mycobiome and its potentially pathogenic component

Vertebrate lungs contain diverse microbial communities, but little is known about the drivers of community composition or consequences for health. Microbiome assembly by processes such as dispersal, coevolution, and host-switching can be probed with comparative surveys; however, few studies exist for lung microbiomes, particularly for the fungal component, the mycobiome. Distinguishing among fungal taxa that are generalist or specialist symbionts, potential pathogens, or incidentally inhaled spores is urgent because of potential for emerging diseases. Here, we characterize the avian lung mycobiome and test the relative influences of environment, phylogeny, and functional traits. We used metabarcoding and culturing from 195 lung samples representing 32 bird species across 20 families. We identified 526 fungal taxa as estimated by distinct sequence types (zOTUs) including many opportunistic pathogens. These were predominantly from the phylum Ascomycota (79%) followed by Basidiomycota (16%) and Mucoromycota (5%). Yeast and yeast-like taxa (Malassezia, Filobasidium, Saccharomyces, Meyerozyma, and Aureobasidium) and filamentous fungi (Cladosporium, Alternaria, Neurospora, Fusarium, and Aspergillus) were abundant. Lung mycobiomes were strongly shaped by environmental exposure, and further modulated by host identity, traits, and phylogenetic affinities. Our results implicate migratory bird species as potential vectors for long-distance dispersal of opportunistically pathogenic fungi.

59 BASIC BIOLOGICAL SCIENCES↗

Regional differences in tobacco smoking and lung cancer in Portugal in 2018: a population-based analysis using nationwide incidence and mortality data

Objectives: This study aims to estimate the proportion of lung cancer cases and deaths attributable to tobacco smoking in Portugal in 2018, complemented by trends in incidence and mortality, by sex and region. Design: Cancer cases for 1998–2011 and cancer deaths for 1991–2018 were obtained from population-based registries and Statistics Portugal, respectively. We projected cases for 2018 and used reported deaths for the same year to estimate, using Peto’s method, the number and proportion of lung cancer cases and deaths caused by tobacco smoking in 2018. We calculated the age-adjusted incidence and mortality rates in each year of diagnosis and death. We fitted a joinpoint regression to the observed data to estimate the annual percentage change (APC) in the rates. Setting: Portugal. Results: In 2018, an estimated 3859 cases and 3192 deaths from lung cancer were attributable to tobacco smoking in Portugal, with men presenting a population attributable fraction (PAF) of 82.6% (n=3064) for incidence and 84.1% (n=2749) for mortality, while in women those values were 51.0% (n=795) and 42.7% (n=443), respectively. In both sexes and metrics, the Azores were the region with the highest PAF and the Centre with the lowest. During 1998–2011, the APC for incidence ranged from 0.6% to 3.0% in men and 3.6% to 7.9% in women, depending on region, with mortality presenting a similar pattern between sexes. Conclusion: Exposure to tobacco smoking has accounted for most of the lung cancer cases and deaths estimated in Portugal in 2018. Differential patterns of tobacco consumption across the country, varying implementation of primary prevention programmes and differences in personal cancer awareness may have contributed to the disparities observed. Primary prevention of lung cancer remains a public health priority, particularly among women.

60 APPLIED LIFE SCIENCES↗

A computational model tracks whole-lung Mycobacterium tuberculosis infection and predicts factors that inhibit dissemination

Mycobacterium tuberculosis (Mtb), the causative infectious agent of tuberculosis (TB), kills more individuals per year than any other infectious agent. Granulomas, the hallmark of Mtb infection, are complex structures that form in lungs, composed of immune cells surrounding bacteria, infected cells, and a caseous necrotic core. While granulomas serve to physically contain and immunologically restrain bacteria growth, some granulomas are unable to control Mtb growth, leading to bacteria and infected cells leaving the granuloma and disseminating, either resulting in additional granuloma formation (local or non-local) or spread to airways or lymph nodes. Dissemination is associated with development of active TB. It is challenging to experimentally address specific mechanisms driving dissemination from TB lung granulomas. Herein, we develop a novel hybrid multi-scale computational model, MultiGran, that tracks Mtb infection within multiple granulomas in an entire lung. MultiGran follows cells, cytokines, and bacterial populations within each lung granuloma throughout the course of infection and is calibrated to multiple non-human primate (NHP) cellular, granuloma, and whole-lung datasets. We show that MultiGran can recapitulate patterns of in vivo local and non-local dissemination, predict likelihood of dissemination, and predict a crucial role for multifunctional CD8+ T cells and macrophage dynamics for preventing dissemination.

59 BASIC BIOLOGICAL SCIENCES↗

Nanoparticle Mediated Delivery of Therapeutic mRNA for Protection Against Lung Damage

Medical countermeasures (MCMs) based on messenger ribonucleic acid (mRNA) are promising due to their programmability, targeting precision and specificity, predictable physicochemical properties, and amenability to scalable manufacture. However, safe and effective delivery vehicles are needed, especially for targeting the lung. We developed a generalized approach to nanoparticle-mediated mRNA delivery to lung, and used it to evaluate candidate therapies. In initial studies, reporter mRNA was delivered using lipid-coated mesoporous silica nanoparticles (LC-MSNs) and lipid nanoparticles (LNPs), the latter with greater consistency. Then, mRNA encoding known protein therapies were delivered using LNPs. These formulations showed some toxicity in mice with lung damage, but those with IL-1RA, sACE2-Ig, and ANGPT1 mRNA were modestly therapeutic on balance. Our work advances the state of the art for mRNA delivery to lung, and provides a foundation for evaluating and characterizing mRNA-based lung therapies, including three that appear to be exceptionally promising.

59 BASIC BIOLOGICAL SCIENCES↗

An optimized approach and inflation media for obtaining complimentary mass spectrometry-based omics data from human lung tissue

Human disease states are biomolecularly multifaceted and can span across phenotypic states, therefore it is important to understand diseases on all levels, across cell types, and within and across microanatomical tissue compartments. To obtain an accurate and representative view of the molecular landscape within human lungs, this fragile tissue must be inflated and embedded to maintain spatial fidelity of the location of molecules and minimize molecular degradation for molecular imaging experiments. Here, we evaluated agarose inflation and carboxymethyl cellulose embedding media and determined effective tissue preparation protocols for performing bulk and spatial mass spectrometry-based omics measurements. Mass spectrometry imaging methods were optimized to boost the number of annotatable molecules in agarose inflated lung samples. This optimized protocol permitted the observation of unique lipid distributions within several airway regions in the lung tissue block. Laser capture microdissection of these airway regions followed by high-resolution proteomic analysis allowed us to begin linking the lipidome with the proteome in a spatially resolved manner, where we observed proteins with high abundance specifically localized to the airway regions. We also compared our mass spectrometry results to lung tissue samples preserved using two other inflation/embedding media, but we identified several pitfalls with the sample preparation steps using this preservation method. Overall, we demonstrated the versatility of the inflation method, and we can start to reveal how the metabolome, lipidome, and proteome are connected spatially in human lungs and across disease states through a variety of different experiments.

59 BASIC BIOLOGICAL SCIENCES↗

Fractionated Radiation Severely Reduces the Number of CD8+ T Cells and Mature Antigen Presenting Cells Within Lung Tumors

The combination of standard-of-care radiation therapy (RT) with immunotherapy is moving to the mainstream of non-small cell lung cancer treatment. Multiple preclinical studies reported on the CD8{sup +} T cell stimulating properties of RT, resulting in abscopal therapeutic effects. A literature search demonstrates that most preclinical lung cancer studies applied subcutaneous lung tumor models. Hence, in-depth immunologic evaluation of clinically relevant RT in orthotopic lung cancer models is lacking.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

Rictor-targeting exosomal microRNA-16 ameliorates lung fibrosis by inhibiting the mTORC2-SPARC axis

Highlights: • Exosomal miR-16 increases in sera of experimental pulmonary fibrosis model mice. • miR-16 interferes with the mTORC2 component, Rictor. • miR-16 ameliorates pulmonary fibrosis by targeting the mTORC2-SPARC axis. Idiopathic pulmonary fibrosis (IPF), a progressive disorder of unknown etiology, is characterized by pathological lung fibroblast activation and proliferation resulting in abnormal deposition of extracellular matrix proteins within the lung parenchyma. The pathophysiological roles of exosomal microRNAs in pulmonary fibrosis remain unclear; therefore, we aimed to identify and characterize fibrosis-responsive exosomal microRNAs. We used microRNA array analysis and profiled the expression of exosome-derived miRNA in sera of C57BL/6 mice exhibiting bleomycin-induced pulmonary fibrosis. The effect of microRNAs potentially involved in fibrosis was then evaluated in vivo and in vitro. The expression of exosomal microRNA-16 was increased by up to 8.0-fold on day 14 in bleomycin-treated mice, compared to vehicle-treated mice. MicroRNA-16 mimic administration on day 14 after bleomycin challenge ameliorated pulmonary fibrosis and suppressed lung and serum expression of secreted protein acidic and rich in cysteine (SPARC). Pretreatment of human lung fibroblasts with the microRNA-16 mimic decreased the expression of rapamycin-insensitive companion of mTOR (Rictor) and TGF-β1–induced expression of SPARC. This is the first study reporting the anti-fibrotic properties of microRNA-16 and demonstrating that these effects occur via the mTORC2 pathway. These findings support that microRNA-16 may be a promising therapeutic target for IPF.

60 APPLIED LIFE SCIENCES↗

CD47 blockade enhances therapeutic efficacy of cisplatin against lung carcinoma in a murine model

Cisplatin (CDDP) is the first generation of platinum-based drug and is widely used to treat many cancers due to its potency. The present study aims to explore the effects of CDDP on lung carcinoma and its relationship with macrophage phagocytosis. In in vitro study, murine and human lung cancer cell lines were applied and treated with CDDP, CD47 antibody (aCD47), or CDDP plus aCD47. In in vivo study, a tumor xenograft animal model was treated with CDDP, aCD47, or CDDP plus aCD47. Real-time PCR was applied to determine the mRNA expressions. Enzyme-linked immunosorbent assay (ELISA), Western blotting, and Immunofluorescent staining were applied to determine the protein expressions. Flow cytometry was applied to analyze cell apoptosis, phagocytosis, and specific cell populations. CDDP enhanced the expressions of CD47 in lung cancer cells. Interestingly, the blockage of CD47 enhanced the macrophages' phagocytic activity on the CDDP-treated tumor cells. The treatment of CDDP and aCD47 exhibited anti-tumor effects and prolonged the LLC tumor-bearing mice survival time. Mechanistic studies revealed that the treatment of CDDP and aCD47 regulated the phagocytic activity of macrophage, percentage of CD8{sup +} T cells, and cytokines (tumor growth factor (TGF)-β, interleukin (IL)12p70, and interferon (IFN)-γ) in the tumor-bearing model. CD47 blockade enhanced therapeutic efficacy of cisplatin against lung carcinoma in vivo and in vitro.

60 APPLIED LIFE SCIENCES↗