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Pressure–volume–temperature (pvT) diagrams illustrate the behavior of a polymer melt during injection molding and can be used to determine the optimal process parameter settings for producing quality parts. However, the measurements of pvT diagrams are costly and time-consuming and have limitations for process control. This study generated an economic pvT diagram based on sensor data and simulation analysis. To avoid the use of expensive infrared sensors and inaccurate pressure simulations, a pvT curve was constructed by combining the melting temperature, which was simulated using computer-aided engineering, and the actual cavity pressure. The specific volume of the polymer melt was then calculated using a modified Tait model. The pvT diagram could be used to investigate the changes in specific volume at various injection stages, which could be applied to quality prediction. In this study, a flat plate with uneven thickness was used as the research vehicle. The specific volume of each sensor position of the plastic component cooled to room temperature was calculated. Thereafter, a correlation analysis between the changes in specific volume and the shrinkage ratio of the plastic part was conducted. The experiment indicated that both variables were highly correlated. Therefore, monitoring changes in specific volume could predict part size. Additionally, the proposed measurements of the pvT diagram could be used to compute the cooling time, which greatly affects the quality and production efficiency of injection-molded parts. A 25-s cooling time setting demonstrated a stable molding quality compared with the traditional heat transfer formula (16 s) and the commercial simulation (17 s).

Background: Methods synthesizing multiple data sources without prospective datasets have been proposed for absolute risk model development. This study proposed methods for adapting risk models for another population without prospective cohorts, which would help alleviate the health disparities caused by advances in absolute risk models. To exemplify, we adapted the lung cancer risk model PLCOM2012, well studied in the west, for Taiwan. Methods: Using Taiwanese multiple data sources, we formed an age-matched case–control study of ever-smokers (AMCCSE), estimated the number of ever-smoking lung cancer patients in 2011–2016 (NESLP2011), and synthesized a dataset resembling the population of cancer-free ever-smokers in 2010 regarding the PLCOM2012 risk factors (SPES2010). The AMCCSE was used to estimate the overall calibration slope, and the requirement that NESLP2011 equals the estimated total risk of individuals in SPES2010 was used to handle the calibration-in-the-large problem. Results: The adapted model PLCOT-1 (PLCOT-2) had an AUC of 0.78 (0.75). They had high performance in calibration and clinical usefulness on subgroups of SPES2010 defined by age and smoking experience. Selecting the same number of individuals for low-dose computed tomography screening using PLCOT-1 (PLCOT-2) would have identified approximately 6% (8%) more lung cancers than the US Preventive Services Task Forces 2021 criteria. Smokers having 40+ pack-years had an average PLCOT-1 (PLCOT-2) risk of 3.8% (2.6%). Conclusions: The adapted PLCOT models had high predictive performance. Impact: The PLCOT models could be used to design lung cancer screening programs in Taiwan. The methods could be applicable to other cancer models.

Background:Methods synthesizing multiple data sources without prospective datasets have been proposed for absolute risk model development. This study proposed methods for adapting risk models for another population without prospective cohorts, which would help alleviate the health disparities caused by advances in absolute risk models. To exemplify, we adapted the lung cancer risk model PLCOM2012, well studied in the west, for Taiwan.Methods:Using Taiwanese multiple data sources, we formed an age-matched case–control study of ever-smokers (AMCCSE), estimated the number of ever-smoking lung cancer patients in 2011–2016 (NESLP2011), and synthesized a dataset resembling the population of cancer-free ever-smokers in 2010 regarding the PLCOM2012 risk factors (SPES2010). The AMCCSE was used to estimate the overall calibration slope, and the requirement that NESLP2011 equals the estimated total risk of individuals in SPES2010 was used to handle the calibration-in-the-large problem.Results:The adapted model PLCOT-1 (PLCOT-2) had an AUC of 0.78 (0.75). They had high performance in calibration and clinical usefulness on subgroups of SPES2010 defined by age and smoking experience. Selecting the same number of individuals for low-dose computed tomography screening using PLCOT-1 (PLCOT-2) would have identified approximately 6% (8%) more lung cancers than the US Preventive Services Task Forces 2021 criteria. Smokers having 40+ pack-years had an average PLCOT-1 (PLCOT-2) risk of 3.8% (2.6%).Conclusions:The adapted PLCOT models had high predictive performance.Impact:The PLCOT models could be used to design lung cancer screening programs in Taiwan. The methods could be applicable to other cancer models.

Supplementary Data from Recalibrating Risk Prediction Models by Synthesizing Data Sources: Adapting the Lung Cancer PLCO Model for Taiwan

Supplementary Figure from Recalibrating Risk Prediction Models by Synthesizing Data Sources: Adapting the Lung Cancer PLCO Model for Taiwan

With the advantages of high efficiency and low manufacturing cost, injection molding is a primary method of polymer processing. However, comprehensive inspection of part quality is limited due to high costs of time, labor, and equipment, often hindering quality control. There is an urgent need to develop a rapid and low-cost inspection method that can perform various quality inspections on injection-molded parts. Accordingly, this study proposes a virtual measurement technique based on a multi-quality prediction neural network that combines with an autoencoder network (AE) and a multilayer perceptron network (MLP). The research focused primarily on extracting and reducing the dimension of captured data using machine perception, quality index, and automatic feature extraction technologies to aid the rapid training of a hybrid AE/MLP model. Experimental case studies demonstrated that the method instantly predicted the residual stress distribution, weight, and geometric dimensions of plastic parts, and the model prediction error (root mean squared error) was less than 5% of the total tolerance. In particular, the predicted residual stress distribution was highly similar to the actual image, providing a substitute for the actual measurement of the residual stress within the molded part.

BackgroundAdult asthma is phenotypically heterogeneous with unclear aetiology. We aimed to evaluate the potential contribution of environmental exposure and its ensuing response to asthma and its heterogeneity.MethodsEnvironmental risk was evaluated by assessing the records of National Health Insurance Research Database (NHIRD) and residence-based air pollution (particulate matter with diameter less than 2.5 micrometers (PM2.5) and PM2.5-bound polycyclic aromatic hydrocarbons (PAHs)), integrating biomonitoring analysis of environmental pollutants, inflammatory markers and sphingolipid metabolites in case–control populations with mass spectrometry and ELISA. Phenotypic clustering was evaluated by t-distributed stochastic neighbor embedding (t-SNE) integrating 18 clinical and demographic variables.FindingsIn the NHIRD dataset, modest increase in the relative risk with time-lag effect for emergency (N=209 837) and outpatient visits (N=638 538) was observed with increasing levels of PM2.5and PAHs. Biomonitoring analysis revealed a panel of metals and organic pollutants, particularly metal Ni and PAH, posing a significant risk for current asthma (ORs=1.28–3.48) and its severity, correlating with the level of oxidative stress markers, notably Nε-(hexanoyl)-lysine (r=0.108–0.311, p2.5exposure. Further, levels of circulating sphingosine-1-phosphate and ceramide-1-phosphate were found to discriminate asthma (pInterpretationThese results suggest the potential contribution of environmental factors from multiple sources, their ensuing oxidative stress and sphingolipid remodeling to adult asthma and its phenotypic heterogeneity.

Additional background information of CL1-0 and CL1-5 cells

Follistatin-like protein 1 (FSTL1) plays a critical role in lung organogenesis, but is downregulated during lung cancer development and progression. The prognostic significance and functional consequences of FSTL1 downregulation in lung cancer are unclear. Here, reduced levels of FSTL1 were detected in various tumors compared with normal tissues and were associated with poor clinical outcome in patients with non–small cell lung cancer, particularly those with lung adenocarcinoma. FSTL1 expression negatively correlated with the metastatic potential of lung cancer cells. Antibody-based neutralization of extracellular FSTL1 increased cellular migration/invasion while addition of recombinant FSTL1 protein diminished the metastatic capacity of lung cancer cells in vitro and in vivo. Notably, treatment with FSTL1 effectively prevented the metastatic progression of lung cancer cells in an orthotopic animal model. Mechanistically, FSTL1 directly bound to the proform of secreted phosphoprotein 1 (SPP1)/osteopontin, restraining proteolytic activation of SPP1, which led to inactivation of integrin/CD44-associated signaling and rearrangement of the actin cytoskeleton. Combined low expression of FSTL1 and high expression of SPP1 predicted a poorer prognosis for patients with lung cancer. This study highlights the novel interaction between FSTL1 and SPP1 and new opportunities to effectively target SPP1-driven metastatic cancers characterized by FSTL1 downregulation.Significance:These findings describe the novel interaction between FSTL1 and SPP1 and its role in the metastatic progression of lung adenocarcinoma.

Purpose: To assess whether polymorphisms of genes related to estrogen biosynthesis and metabolism are associated with EGFR mutations.Experimental Design: We studied 617 patients with lung adenocarcinoma, including 302 never-smoking women. On the basis of multiple candidate genes approach, the effects of polymorphisms of CYP17, CYP19A1, ERα, and COMT in association with the occurrence of EGFR mutations were evaluated using logistic regression analysis.Results: In female never-smokers, significant associations with EGFR L858R mutation were found for the tetranucleotide (TTTA)n repeats in CYP19A1 (odds ratio, 2.6; 95%CI, 1.2–5.7 for 1 or 2 alleles with (TTTA)n repeats >7 compared with both alleles with (TTTA)n repeats ≤7), and the rs2234693 in ERα (OR, 2.1; 95% CI, 1.1–4.0 for C/T and C/C genotypes compared with T/T genotype). The C/C genotype (vs. T/T genotype) of ERα was significantly associated with EGFR L858R mutation (OR, 3.0; 95% CI, 1.1–8.1), in-frame deletion (OR, 2.9; 95% CI, 1.1–7.6) and other mutations (OR, 4.3; 95% CI, 1.3–14.0). The genotype of COMT rs4680 was significantly associated with EGFR L858R mutation in female and male never-smokers showing OR's (95% CI) of 1.8 (1.0–3.2) and 3.6 (1.1–11.3), respectively, for genotypes G/A and G/G compared with genotype A/A. The number of risk alleles of CYP17, CYP19A1, ERα, and COMT was associated with an increasing OR of EGFR L858R mutation in female never-smokers (P = 0.0002 for trend).Conclusions: The L858R mutation of EGFR is associated with polymorphisms of genes related to estrogen biosynthesis and metabolism in never-smoking female lung adenocarcinoma patients. Clin Cancer Res; 17(8); 2149–58. ©2011 AACR.

Supplementary Methods; Supplementary Table S1.

Supplementary material and methods; Supplementary Table 1. Additional background information of CL1-0 and CL1-5 cells; Supplementary Table 2. Mass spectrometric analysis of FSTL1-interacting protein in CL1-5/FSTL1 conditioned medium; Supplementary Table 3. Association between FSTL1 expression and clinical pathological characteristics in patients. Supplementary Figure 1. The RNA expression level of FST family members in lung cancer clinical cohort; Supplementary Figure 2. The protein expression level of FSTL1 protein family in LUAD cell lines; Supplementary Figure 3. Confirmation and functional assays of the knockdown of FSTL1 in CL1-0 and PC14 cells; Supplementary Figure 4. Confirmation and functional assays of the overexpression of FSTL1 in CL1-5 and A549 cells; Supplementary Figure 5. FSTL1 did not alter cell proliferation rates in LUAD cells; Supplementary Figure 6. rhFSTL1 inhibited metastasis of lung cancer in orthotopic model; Supplementary Figure 7. FSTL1 administration effectively inhibits metastatic progression of malignant LUAD cells; Supplementary Figure 8. Migration assay of FSTL1 antibody treated CL1-0 cells with different signaling inhibitors; Supplementary Figure 9. Reduced mRNA expression of FSTL1 correlated with a poor prognosis in patients with breast cancer.

PDF file - 287K, Cisplatin-induced enrichment of CD133+ cells

PDF file - 289K, Carboplatin induced DNA damage and CD133+ cell enrichment

PDF file - 342K, Inhibition of cisplatin-induced enrichment of CD133+ cells by Notch1 knockdown

Supplementary Methods, Figure Legends 1-12, Tables 1-5 from H3K9 Histone Methyltransferase G9a Promotes Lung Cancer Invasion and Metastasis by Silencing the Cell Adhesion Molecule Ep-CAM

PDF file - 587K, Manhattan Plot.

Supplementary Figures 1-12 from H3K9 Histone Methyltransferase G9a Promotes Lung Cancer Invasion and Metastasis by Silencing the Cell Adhesion Molecule Ep-CAM

PDF file - 255K, The role of ABC transporters in cisplatin-induced multi-drug resistance to paclitaxol in H460 and H661 cell lines

PDF file - 57K, Q-Q plot.

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PDF file - 2.1MB, Cell differentiation and migration of GFP+ cells isolated from H460 cell line

PDF file - 138K, The role of Notch signaling in enrichment of CD133+ cells and multi-drug resistance of H661 cells

IntroductionAnaplastic lymphoma kinase (ALK) fusion mutation is more common in younger and never-smoking lung cancer patients. The association of smoking and ALK-tyrosine kinase inhibitors (TKIs) on overall survival (OS) of treatment-naïve ALK-positive advanced lung adenocarcinoma remains unclear in real-world.MethodsThis retrospective study evaluated all 33170 lung adenocarcinoma patients registered in the National Taiwan Cancer Registry from 2017 to 2019, of whom 9575 advanced stage patients had ALK mutation data.ResultsAmong the 9575 patients, 650 (6.8%) patients had ALK mutation with the median follow-up survival time 30.97 months (median age, 62 years; 125 [19.2%] were aged ≥75 years; 357 (54.9%) females; 179 (27.5) smokers, 461 (70.9%) never-smokers, 10 (1.5%) with unknown smoking status; and 544 (83.7%) with first-line ALK-TKI treatment). Overall, of 535 patients with known smoking status who received first-line ALK-TKI treatment, never-smokers and smokers had a median OS of 40.7 months (95% confidence interval (CI), 33.1-47.2 months) and 23.5 months (95% CI, 11.5-35.5 months) (P=0.015), respectively. Among never-smokers, those who received first-line ALK-TKI treatment had a median OS of 40.7 months (95% CI, 22.7-57.8 months), while those ALK-TKI not as first-line treatment had a median OS of 31.7 months (95% CI, 15.2-42.8 months) (P=0.23). In smokers, the median OS for these patients was 23.5 months (95% CI, 11.5-35.5 months) and 15.6 months (95% CI, 10.2-21.1 months) (P=0.026), respectively.Conclusions and relevanceFor patients with treatment-naïve advanced lung adenocarcinoma, the ALK test should be performed irrespective of smoking status and age. Smokers had shorter median OS than never-smokers among treatment-naïve-ALK-positive patients with first-line ALK-TKI treatment. Furthermore, smokers not receiving first-line ALK-TKI treatment had inferior OS. Further investigations for the first-line treatment of ALK-positive smoking advanced lung adenocarcinoma patients are needed.

Background: The imbalance of gut microbiota, dysbiosis, is associated with various malignant diseases. This study aimed to identify the characteristics of gut microbiota in age-matched treatment-naïve non-small-cell lung cancer (NSCLC) patients and healthy individuals to investigate possible gut-microbe-related pathways involved in the development of NSCLC. Methods: We enrolled 34 age-matched NSCLC patients and 268 healthy individuals. Hypervariable V3–V4 amplicons of 16S rRNA in freshly collected fecal samples were sequenced. Diversity, microbial composition, functional pathways, smoking history, and gut-microbe-related comorbidities were analyzed to assess the factors associated with the risk of NSCLC. Results: Microbial alpha diversity was decreased in the patients with NSCLC, and beta diversity was significantly different between the patients and controls (p < 0.001). After adjustments for sex, smoking history, hypertension, diabetes mellitus, chronic obstructive pulmonary disease, and 11 abundant microbes with significant differences between the patients and controls, the enrichment of Anaerotruncus spp. and Bacteroides caccae was associated with an increased risk of NSCLC (p = 0.003 and 0.007, respectively). The areas under receiver operating characteristic curves were 71.4% and 66.9% for Anaerotruncus spp. and Bacteroides caccae, respectively (both p < 0.001). Furthermore, the abundance of Bacteroides caccae was positively correlated with steroid hormone biosynthesis (p < 0.001), N-glycan biosynthesis (p = 0.023), glycosaminoglycan degradation (p < 0.001), lipoic acid metabolism (p = 0.039), peroxisome (p < 0.001), and apoptosis (p < 0.001), but inversely related to glycerolipid metabolism (p < 0.001). Anaerotruncus spp. was positively associated with decreased biosynthesis of ansamycin only (p = 0.001). No overlapping signaling pathways were modulated by Bacteroides caccae or Anaerotruncus spp. Conclusions: Our results revealed that fecal Anaerotruncus spp. and Bacteroides caccae were abundant and may be associated with the risk of NSCLC regardless of sex, smoking history, and gut-microbe-related comorbidities. Further investigations on the mechanism underlying the potential association between gut dysbiosis and the development of NSCLC are warranted.

Aberrant metabolism has been proposed as one of the emerging hallmarks of cancer. However, the interplay between metabolic disorders and cancer metastasis remains to be defined. To explore the sophisticated metabolic processes during metastatic progression, we analyzed differentially expressed metabolic genes during the epithelial-mesenchymal transition (EMT) of lung cancer cells and defined the EMT-associated metabolic gene signature in lung adenocarcinoma patients. We found that the glycosaminoglycan (GAG)-chondroitin sulfate (CS) biosynthesis pathway was upregulated in the mesenchymal state of lung cancer and associated with poor prognosis. Notably, carbohydrate sulfotransferase 11 (CHST11), a crucial CS biosynthetic enzyme, was confirmed as a poor prognosis marker in non-small cell lung cancer (NSCLC) by immunohistochemical analysis. Moreover, forced CHST11 expression promoted invasion and metastasis, which was abolished by depleting the final product of CS biosynthesis by chondroitinase ABC treatment or active-domain negative CHST11. In vivo metastasis mouse models showed that CHST11 increased lung colonies number and sulfated mucosubstance expression. Furthermore, microarray analysis revealed ceruloplasmin (CP), which facilitated iron metabolism, was the downstream effector of CHST11. CP was upregulated by CHST11 through interferon-γ signaling pathway stimulation and related to unfavorable prognosis. Both forced CP expression and long-term iron treatment increased invasion and lung colony formation. Furthermore, we found 3-AP, an iron chelator, hampered the CHST11-induced metastasis. Our findings implicate that the novel CHST11-CP-iron axis enhances EMT and may serve as a new therapeutic target to treat NSCLC patients.

Quality consistency is essential in maximizing the productivity rate of the injection molding process and minimizing the production cost. The quality consistency problem is particularly acute in the case of injection molding processes performed using regrind resin, for which the rheological properties are less uniform and more unpredictable than those of virgin material. Accordingly, the present study proposes a two-stage approach for optimizing the injection molding process parameters in such a way as to achieve a consistent molding quality over repeated injection molding cycles. In the first stage, the values of the injection speed/pressure, velocity-to-pressure (V/P) switchover point, and packing pressure are individually determined based on an inspection of the cavity pressure profile and machine parameters provided by the injection molding machine controller. In the second stage, a robust parametric search method based on a first-order regression model is employed to determine the optimal combination of the process parameter settings. Using an Integrated Circuit (IC) tray fabricated from regrind resin for illustration purposes, the results confirm that the proposed method overcomes the problem of small variations in the melt quality and therefore provides an effective technique for improving the yield rate and quality of the continuous mass production.

We investigated whether genetic susceptibility to tuberculosis (TB) influences lung adenocarcinoma development among never-smokers using TB genome-wide association study (GWAS) results within the Female Lung Cancer Consortium in Asia. Pathway analysis with the adaptive rank truncated product method was used to assess the association between a TB-related gene-set and lung adenocarcinoma using GWAS data from 5512 lung adenocarcinoma cases and 6277 controls. The gene-set consisted of 31 genes containing known/suggestive associations with genetic variants from previous TB-GWAS. Subsequently, we followed-up with Mendelian Randomization to evaluate the association between TB and lung adenocarcinoma using three genome-wide significant variants from previous TB-GWAS in East Asians. The TB-related gene-set was associated with lung adenocarcinoma (p = 0.016). Additionally, the Mendelian Randomization showed an association between TB and lung adenocarcinoma (OR = 1.31, 95% CI: 1.03, 1.66, p = 0.027). Our findings support TB as a causal risk factor for lung cancer development among never-smoking Asian women.

Background: High disease burden suggests the desirability to identify high-risk Asian never-smoking females (NSF) who may benefit from low-dose CT (LDCT) screening. In North America, one is eligible for LDCT screening if one satisfies the U.S. Preventive Services Task Force (USPSTF) criteria or has model-estimated 6-year risk greater than 0.0151. According to two U.S. reports, only 36.6% female patients with lung cancer met the USPSTF criteria, while 38% of the ever-smokers ages 55 to 74 years met the USPSTF criteria. Methods: Using data on NSFs in the Taiwan Genetic Epidemiology Study of Lung Adenocarcinoma and the Taiwan Biobank before August 2016, we formed an age-matched case–control study consisting of 1,748 patients with lung cancer and 6,535 controls. Using these and an estimated age-specific lung cancer 6-year incidence rate among Taiwanese NSFs, we developed the Taiwanese NSF Lung Cancer Risk Models using genetic information and simplified questionnaire (TNSF-SQ). Performance evaluation was based on the newer independent datasets: Taiwan Lung Cancer Pharmacogenomics Study (LCPG) and Taiwan Biobank data after August 2016 (TWB2). Results: The AUC based on the NSFs ages 55 to 70 years in LCPG and TWB2 was 0.714 [95% confidence intervals (CI), 0.660–0.768]. For women in TWB2 ages 55 to 70 years, 3.94% (95% CI, 2.95–5.13) had risk higher than 0.0151. For women in LCPG ages 55 to 74 years, 27.03% (95% CI, 19.04–36.28) had risk higher than 0.0151. Conclusions: TNSF-SQ demonstrated good discriminative power. The ability to identify 27.03% of high-risk Asian NSFs ages 55 to 74 years deserves attention. Impact: TNSF-SQ seems potentially useful in selecting Asian NSFs for LDCT screening.

An increasing number of enzymes involved in serine biosynthesis have been identified and correlated with malignant evolution in various types of cancer. Here we showed that the overexpression of phosphoserine aminotransferase 1 (PSAT1) is widely found in lung cancer tissues compared with nontumor tissues and predicts a poorer prognosis in patients with lung adenocarcinoma. PSAT1 expression was examined in a tissue microarray by immunohistochemistry. The data show that the knockdown of PSAT1 dramatically inhibits the in vitro and in vivo metastatic potential of highly metastatic lung cancer cells; conversely, the enforced expression of exogenous PSAT1 predominantly enhances the metastatic potential of lung cancer cells. Importantly, manipulating PSAT1 expression regulates the in vivo tumor metastatic abilities in lung cancer cells. Adjusting the glucose and glutamine concentrations did not alter the PSAT1-driven cell invasion properties, indicating that this process might not rely on the activation of its enzymatic function. RNA microarray analysis of transcriptional profiling from PSAT1 alternation in CL1-5 and CL1-0 cells demonstrated that interferon regulatory factor 1 (IRF1) acts as a crucial regulator of PSAT1-induced gene expression upon metastatic progression. Decreasing the IRF1-IFIH1 axis compromised the PSAT1-prompted transcriptional reprogramming in cancer cells. Our results identify PSAT1 as a key regulator by a novel PSAT1/IRF1 axis in lung cancer progression, which may serve as a potential biomarker and therapeutic target for the treatment of lung cancer patients.

Histone deacetylase 6 (HDAC6) controls many cellular processes via its catalyzing deacetylation of downstream substrates or interacting with its partner proteins. Dysregulation of HDAC6 signaling links to many diseases. Our previous study has been reported peptidyl-prolyl cis/trans isomerase, and NIMA-interacting 1 (Pin1) involving in HDAC6-mediated cell motility. To gain insight into precisely coordination of HDAC6 and Pin1 in cell migration, shRNA-mediated gene silencing and ectopic expression were applied to manipulate protein expression level to evaluate relationship between HDAC6 and Pin1 expression. Quantitative RT-PCR and the cycloheximide (CHX) chase assay resulted in HDAC6 expression is correlated with Pin1 level in H1299 cells. It hints that the Pin1 increases HDAC6 expression through increased transcripts and posttranslational stabilization. Furthermore, wound healing assay and transwell invasion assay evidenced the contribution of Pin1 on cell motility in H1299 cells. Our data suggest that Pin1 acts as an important regulator to manage HDAC6 expression for cell motility in lung cancer cells.

Background Epidemiologic evidence suggests that exposure to particulate matter of 2.5 μm or less in diameter (PM2.5) aggravates asthma. Objective We sought to investigate the underlying mechanisms between PM2.5 exposure and asthma severity. Methods The relationship between PM2.5 exposure and asthma severity was investigated in an asthma model with CD4+ T cell–specific aryl hydrocarbon receptor (AhR)–null mice. Effects of PM2.5 and polycyclic aromatic hydrocarbons (PAHs) on differentiation of TH17/regulatory T (Treg) cells were investigated by using flow cytometry and quantitative RT-PCR. Mechanisms were investigated by using mRNA sequencing, chromatin immunoprecipitation, bisulfite sequencing, and glycolysis rates. Results PM2.5 impaired differentiation of Treg cells, promoted differentiation of TH17 cells, and aggravated asthma in an AhR-dependent manner. PM2.5 and one of its prominent PAHs, indeno[1,2,3-cd]pyrene (IP), promoted differentiation of TH17 cells by upregulating hypoxia-inducible factor 1α expression and enhancing glycolysis through AhRs. Exposure to PM2.5 and IP enhanced glutamate oxaloacetate transaminase 1 (Got1) expression through AhRs and accumulation of 2-hydroxyglutarate, which inhibited ten-eleven translocation methylcytosine dioxygenase 2 activity, resulting in hypermethylation in the forkhead box P3 locus and impaired differentiation of Treg cells. A GOT1 inhibitor, (aminooxy)acetic acid, ameliorated asthma by shifting differentiation of TH17 cells to Treg cells. Similar regulatory effects of exposure to PM2.5 or IP on TH17/Treg cell imbalance were noted in human T cells, and in a case-control design PAH exposure appeared to be a potential risk factor for asthma. Conclusions The AhR–hypoxia-inducible factor 1α and AhR-GOT1 molecular pathways mediate pulmonary responses on exposure to PM2.5 through their ability to disturb the balance of TH17/Treg cells.

Backgrounds: Immune checkpoint inhibitors (ICIs) alone or in combination with chemotherapy (CT) are the standard of care for first-line therapy in metastatic non-small cell lung cancer (NSCLC) patients without actionable mutations. The safety ranking of different ICI and CT combination regimens has not been investigated. This study was aimed to provide a toxicity profile and safety ranking of different ICI and CT combination regimens.Methods: We performed comprehensive searches of phase 2 and 3 randomized clinical trials (RCTs) comparing different ICI regimens (alone or combination) or CT for the first-line treatment of advanced NSCLC. Outcomes of interest were the cumulative incidence of any treatment-related adverse events (TRAEs), grade 3-5 TRAEs (grade 3-5), any immune-related adverse events (irAEs), and grade 3-5 irAEs (grade 3-5). Odds ratios and 95% credible intervals were calculated as summary statistics to quantify the effect of different ICI combination regimens. Results: We included 23 RCTs from 2016 to 2021 with a total of 14,378 patients. The incidence of any TRAEs and grade 3-5 TRAEs ranked from high to low were ICI-CT (probability: 74.88%), ICI-ICI-CT (50.60%), CT alone (74.79%), ICI-ICI (98.37%), and ICI monotherapy (99.37%). Adding CT to ICI regimens resulted in a higher incidence of any grade or grade 3-5 TRAEs compared to ICI-ICI combinations or ICI monotherapy. However, ICI-ICI-CT combinations did not result in a higher incidence of TRAEs than ICI-CT combinations. For any irAEs and grade 3-5 irAEs, the ranking was ICI-ICI (probability: 97.38), ICI monotherapy (96.98%), ICI-CT (99.44%), and CT alone (99.98%). Notably, the incidence of any grade and grade 3-5 irAEs was lower when adding CT to ICI monotherapy. Conclusion: Lack of head-to-head comparisons, these findings provide evidence for clinical decision-making when considering different ICI combination regimens for advanced NSCLC patients.

Injection molding has been broadly used in the mass production of plastic parts and must meet the requirements of efficiency and quality consistency. Machine learning can effectively predict the quality of injection molded part. However, the performance of machine learning models largely depends on the accuracy of the training. Hyperparameters such as activation functions, momentum, and learning rate are crucial to the accuracy and efficiency of model training. This research further analyzed the influence of hyperparameters on testing accuracy, explored the corresponding optimal learning rate, and provided the optimal training model for predicting the quality of injection molded parts. In this study, stochastic gradient descent (SGD) and stochastic gradient descent with momentum were used to optimize the artificial neural network model. Through optimization of these training model hyperparameters, the width testing accuracy of the injection product improved. The experimental results indicated that in the absence of momentum effects, all five activation functions can achieve more than 90% of the training accuracy with a learning rate of 0.1. Moreover, when optimized with the SGD, the learning rate of the Sigmoid activation function was 0.1, and the testing accuracy reached 95.8%. Although momentum had the least influence on accuracy, it affected the convergence speed of the Sigmoid function, which reduced the number of required learning iterations (82.4% reduction rate). Optimizing hyperparameter settings can improve the accuracy of model testing and markedly reduce training time.

Follistatin-like protein 1 (FSTL1) plays a critical role in lung organogenesis, but is downregulated during lung cancer development and progression. The prognostic significance and functional consequences of FSTL1 downregulation in lung cancer are unclear. Here, reduced levels of FSTL1 were detected in various tumors compared with normal tissues and were associated with poor clinical outcome in patients with non–small cell lung cancer, particularly those with lung adenocarcinoma. FSTL1 expression negatively correlated with the metastatic potential of lung cancer cells. Antibody-based neutralization of extracellular FSTL1 increased cellular migration/invasion while addition of recombinant FSTL1 protein diminished the metastatic capacity of lung cancer cells in vitro and in vivo. Notably, treatment with FSTL1 effectively prevented the metastatic progression of lung cancer cells in an orthotopic animal model. Mechanistically, FSTL1 directly bound to the proform of secreted phosphoprotein 1 (SPP1)/osteopontin, restraining proteolytic activation of SPP1, which led to inactivation of integrin/CD44-associated signaling and rearrangement of the actin cytoskeleton. Combined low expression of FSTL1 and high expression of SPP1 predicted a poorer prognosis for patients with lung cancer. This study highlights the novel interaction between FSTL1 and SPP1 and new opportunities to effectively target SPP1-driven metastatic cancers characterized by FSTL1 downregulation. Significance: These findings describe the novel interaction between FSTL1 and SPP1 and its role in the metastatic progression of lung adenocarcinoma.

Quality consistency is essential in the injection molding process for maximizing the yield rate and minimizing the production cost, and this issue is more concerned proceeding with recycled material. Effective methods are therefore required for performing the real-time monitoring and control of the injection molded part quality and tuning the injection molding process parameters. Accordingly, the present study proposes a real-time quality monitoring and control system based on the clamping force increment characteristic, as determined by the measured tie-bar elongation. Notably, the proposed method is applicable to both virgin raw materials and recycled plastic materials. The effectiveness of the proposed approach is evaluated for three different processing parameters, namely the barrel temperature, the back pressure and the V/P switchover point. It is shown that the three processing parameters all have a significant effect on the molded part weight and thickness. Moreover, for each parameter, the part weight and thickness are strongly correlated. The clamping force increment is also highly correlated with the molded part weight. It is hence inferred that the clamping force increment provides an appropriate quality index for monitoring the injection molding quality. Furthermore, through the integration with a V/P switchover point calibration model, the clamping force increment index can be used to control the molded part weight to within a small tolerance on a shot-by-shot basis. When performing the injection molding process with virgin raw material, the tensile strength of the molded part increases with an increasing barrel temperature due to an increasing part weight if the proposed quality monitoring and control system is not applied. However, when the proposed system is employed, the tensile strength reduces slightly at a higher barrel temperature. When using recycled material in the injection molding process, the tensile strength remains approximately constant as the barrel temperature increases, irrespective of whether or not the proposed quality control system is applied. The difference in tendencies of the two materials can be attributed to a difference in their viscosities (i.e., molecular weights).

Metastatic tumors have been shown to establish a supportive pre-metastatic niche (PMN) in distant organs, which in turn determines disseminated tumor cells’ targeting of such organs. PMN is formed through the recruitment of bone-marrow-derived cells (BMDCs); however, the role of BMDCs in PMN formation is not fully understood. On the basis of RNA-seq data and bioinformatic analysis, secretion of extracellular vesicle (EV) miR-92a by BMDCs of lung cancer-bearing mice contributes to the establishment of liver PMN. Both BMDC-derived EVs and miR-92a mimics potentiate the activation of hepatic stellate cells (HSCs), subsequently increasing extracellular matrix (ECM) deposition in mice. Consequently, remodeling of the liver microenvironment enhanced immunosuppressive cell accumulation and cancer cell attachment. EVs miR-92a directly suppressed its target SMAD7, leading to the enhancement of transforming growth factor-β signaling in HSC. Elevated levels of circulating miR-92a are found in the sera of lung cancer patients, and EVs isolated from these patients have a similar ability to increase HSCs activation and ECM protein expression. Our study reveals the sequential steps of liver PMN formation in lung cancer, providing critical mediators that prepare PMN in the liver, and identifies new targets that offer valuable options for diagnosis and therapeutic intervention.

Traditional injection molding machines use resistance heating (RH) bands to heat the barrel. However, RH has a low energy rate; thus, the time required to reach the target temperature is rather long. Consequently, the use of inductive techniques, with a faster heating rate and improved energy rate, has attracted growing interest in recent years. However, an inappropriate design of the inductive coils and plasticization barrel may result in a strong repulsive magnetic field between neighboring coils and a corresponding reduction in the heating performance. Thus, developing an appropriate inductive heating design is essential in improving the barrel heating performance. The present study therefore performed a simulation and experimental investigation into the magnetic field and temperature distribution for different barrel geometries and coil current designs. The simulation results showed that the application of spiral grooves to the barrel improved both the heating rate and the temperature uniformity (TU) and effectively solved the proximity effect. The results indicated that the application of induction heating together with a novel grooved barrel design yields an effective improvement in both the thermal efficiency and the TU compared to that achieved using the traditional RH method with a single- or double-section barrel.

Cancer metabolic reprogramming promotes tumorigenesis and metastasis; however, the underlying molecular mechanisms are still being uncovered. In this study, we show that the glycolytic enzyme aldolase A (ALDOA) is a key enzyme involved in lung cancer metabolic reprogramming and metastasis. Overexpression of ALDOA increased migration and invasion of lung cancer cell lines in vitro and formation of metastatic lung cancer foci in vivo. ALDOA promoted metastasis independent of its enzymatic activity. Immunoprecipitation and proteomic analyses revealed γ-actin binds to ALDOA; blocking this interaction using specific peptides decreased metastasis both in vitro and in vivo. Screening of clinically available drugs based on the crystal structure of ALDOA identified raltegravir, an antiretroviral agent that targets HIV integrase, as a pharmacologic inhibitor of ALDOA-γ-actin binding that produced antimetastatic and survival benefits in a xenograft model with no significant toxicity. In summary, ALDOA promotes lung cancer metastasis by interacting with γ-actin. Targeting this interaction provides a new therapeutic strategy to treat lung cancer metastasis. Significance: This study demonstrates the role of aldolase A and its interaction with γ-actin in the metastasis of non–small lung cancer and that blocking this interaction could be an effective cancer treatment.

Quality control is a crucial issue in the injection molding process with target of obtaining a high yield rate and reducing production cost. Consequently, effective methods for monitoring the injection conditions (e.g., pressure, velocity, and temperature) in real-time and adjusting these conditions adaptively as required to ensure a consistent part quality are essential. This study proposes a quality index based on the clamping force increment during the injection cycle, as determined by four strain gauges attached to the tie bars of the injection molding machine. Also, various quality indexes for online quality monitoring and prediction purposes based on the pressure, viscosity, and energy features extracted from the pressure profiles obtained at the load cell, nozzle, and molding cavity, respectively, are compared. The feasibility of the proposed quality indexes is investigated experimentally for various settings of the barrel temperature, back pressure, and rotational speed of the plasticizing screw. It is shown that all of the quality indexes are correlated with the injection-molded quality and hence provide a feasible basis for the realization of an on-line quality monitoring and control system. Particularly, the tie-bar elongation quality index requires no modification or invasion of the injection molding system or cavity and hence provides a particularly attractive solution for monitoring and controlling the part quality.

Background: Adult asthma is phenotypically heterogeneous with unclear etiology. We aimed to evaluate the potential contribution of environmental exposure and its ensuing response to asthma and its heterogeneity. Methods: Environmental risk was evaluated by assessing the records of National Health Insurance Research database (NHIRD) and residence-based air pollution [PM2.5 and PM2.5-bound polycyclic aromatic hydrocarbons (PAHs)], integrating biomonitoring analysis of environmental pollutants, inflammatory markers and sphingolipid metabolites in case-control populations with mass spectrometry and ELISA. Phenotypic clustering was evaluated by t-SNE integrating 18 clinical and demographic variables. Findings: In the NHIRD dataset, a modest increase in the relative risk with time-lag effect for emergency (N=209,837) and outpatient visits (N=638,538) was observed with increasing levels of PM2.5 and PAHs. Biomonitoring analysis revealed a panel of metals and organic pollutants, particularly metal Ni and PAH originated from multiple sources, posing a significant risk for current asthma and its severity, correlating with the level of oxidative stress markers, notably Ne-(hexanoyl)-lysine (HEL) as a marker of response in both cases and controls. Further, levels of circulating sphingosine-1-phosphate (S1P) and ceramide-1-phosphate (C1P) were found to discriminate asthma, correlating with the levels of exposure to PAH and metals, respectively, and both correlating with a panel of circulating inflammatory markers. Stratification of the combined datasets by 6 phenotypic clusters among 1,163 asthmatic subjects and those with comorbid T2DM revealed cluster-selective environmental risks and biosignatures. Interpretation: These results suggest the potential contribution of environmental factors, their ensuing oxidative stress and sphingolipid remodeling to adult asthma and its phenotypic heterogeneity. Funding Information: This work was supported, in part, by grants from National Health Research Institutes, Taiwan (EOPP10-014, EOSP07-014 and NHRI-102A1-PDCO-03010201) and Ministry of Health, Taiwan (EODOH01), National Science Council (NSC 102-2314-B-037-052), Ministry of Health (EODOH01), Ministry of Science and Technology (MOST 103-2320-B-110-001), and Academic Sinica (BM-102021170), Taiwan. Declaration of Interests: We declare no competing interests. Ethics Approval Statement: All eligible subjects were enrolled in the study after signing the informed consent approved by the respective recruitment hospitals.

Background: The number of people aged greater than 65 years is growing in many countries. Taiwan will be a superaged society in 2026, and health care utilization will increase considerably. Our study aimed to evaluate the efficacy of the geriatric integrated outpatient clinic model for reducing health care utilization by older people.Methods: This was a retrospective case-control study. Patients aged greater than 65 years seen at the geriatric outpatient clinic (Geri-OPD) and non-geriatric outpatient clinic (non-Geri-OPD) at a single medical centre were age and sex matched. Data on the number of outpatient clinic visits, emergency department visits, hospitalizations and medical expenditures were collected during the first and second years. A subgroup analysis by Charlson comorbidity index (CCI) and older age (age≧80 years) was performed, and the results were compared between the Geri-OPD and non-Geri-OPD groups.Results: A total of 6723 patients were included (3796 women and 2927 men). The mean age was 80.42 ± 6.39 years. There were 1291 (19.2%) patients in the Geri-OPD group and 5432 (80.8%) patients in the non-Geri-OPD group. After one year of regular follow-up, the Geri-OPD patients showed a significant reduction in the types of drugs included in each prescription (5.62±10.85) and the number of clinic visits per year (18.18 ± 48.85) (PConclusion: The Geri-OPD reduced medical costs, the number of drugs prescribed, and the frequency of outpatient clinic visits, emergency department visits and hospitalizations in older patients with complicated conditions. The effect was even better in the second year.

Background The number of people aged greater than 65 years is growing in many countries. Taiwan will be a superaged society in 2026, and health care utilization will increase considerably. Our study aimed to evaluate the efficacy of the geriatric integrated outpatient clinic model for reducing health care utilization by older people. Methods This was a retrospective case-control study. Patients aged greater than 65 years seen at the geriatric outpatient clinic (Geri-OPD) and non-geriatric outpatient clinic (non-Geri-OPD) at a single medical centre were age and sex matched. Data on the number of outpatient clinic visits, emergency department visits, hospitalizations and medical expenditures were collected during the first and second years. A subgroup analysis by Charlson comorbidity index (CCI) and older age (age≧80 years) was performed, and the results were compared between the Geri-OPD and non-Geri-OPD groups. Results A total of 6723 patients were included (3796 women and 2927 men). The mean age was 80.42 ± 6.39 years. There were 1291 (19.2%) patients in the Geri-OPD group and 5432 (80.8%) patients in the non-Geri-OPD group. After one year of regular follow-up, the Geri-OPD patients showed a significant reduction in the types of drugs included in each prescription (5.62 ± 10.85) and the number of clinic visits per year (18.18 ± 48.85) (P Conclusion The Geri-OPD reduced medical costs, the number of drugs prescribed, and the frequency of outpatient clinic visits, emergency department visits and hospitalizations in older patients with complicated conditions. The effect was even better in the second year.