Browsing by Author "Huang, Yuh-Chin T"

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    Afatinib induces apoptosis in NSCLC without EGFR mutation through Elk-1-mediated suppression of CIP2A.
    (Oncotarget, 2015-02) Chao, Ting-Ting; Wang, Cheng-Yi; Chen, Yen-Lin; Lai, Chih-Cheng; Chang, Fang-Yu; Tsai, Yi-Ting; Chao, Chung-Hao H; Shiau, Chung-Wai; Huang, Yuh-Chin T; Yu, Chong-Jen; Chen, Kuen-Feng
    Afatinib has anti-tumor effect in non-small cell lung carcinoma (NSCLC) with epidermal growth factor receptor (EGFR) mutation. We found afatinib can also induce apoptosis in NSCLC cells without EGFR mutation through CIP2A pathway. Four NSCLC cell lines (H358 H441 H460 and A549) were treated with afatinib to determine their sensitivity to afatinib-induced cell death and apoptosis. The effects of CIP2A on afatinib-induced apoptosis were confirmed by overexpression and knockdown of CIP2A expression in the sensitive and resistant cells, respectively. Reduction of Elk-1 binding to the CIP2A promoter and suppression of CIP2A transcription were analyzed. In vivo efficacy of afatinib against H358 and H460 xenografts tumors were also determined in nude mice. Afatinib induced significant cell death and apoptosis in H358 and H441 cells, but not in H460 or A549 cells. The apoptotic effect of afatinib in sensitive cells was associated with downregulation of CIP2A, promotion of PP2A activity and decrease in AKT phosphorylation. Afatinib suppressed CIP2A at the gene transcription level by reducing the promoter binding activity of Elk-1. Clinical samples showed that higher CIP2A expression predicted a poor prognosis and Elk-1 and CIP2A expressions were highly correlated. In conclusion, afatinib induces apoptosis in NSCLC without EGFR mutations through Elk-1/CIP2A/PP2A/AKT pathway.
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    Application of Machine Learning in Pulmonary Function Assessment Where Are We Now and Where Are We Going?
    (Frontiers in physiology, 2021-01) Giri, Paresh C; Chowdhury, Anand M; Bedoya, Armando; Chen, Hengji; Lee, Hyun Suk; Lee, Patty; Henriquez, Craig; MacIntyre, Neil R; Huang, Yuh-Chin T
    Analysis of pulmonary function tests (PFTs) is an area where machine learning (ML) may benefit clinicians, researchers, and the patients. PFT measures spirometry, lung volumes, and carbon monoxide diffusion capacity of the lung (DLCO). The results are usually interpreted by the clinicians using discrete numeric data according to published guidelines. PFT interpretations by clinicians, however, are known to have inter-rater variability and the inaccuracy can impact patient care. This variability may be caused by unfamiliarity of the guidelines, lack of training, inadequate understanding of lung physiology, or simply mental lapses. A rules-based automated interpretation system can recapitulate expert's pattern recognition capability and decrease errors. ML can also be used to analyze continuous data or the graphics, including the flow-volume loop, the DLCO and the nitrogen washout curves. These analyses can discover novel physiological biomarkers. In the era of wearables and telehealth, particularly with the COVID-19 pandemic restricting PFTs to be done in the clinical laboratories, ML can also be used to combine mobile spirometry results with an individual's clinical profile to deliver precision medicine. There are, however, hurdles in the development and commercialization of the ML-assisted PFT interpretation programs, including the need for high quality representative data, the existence of different formats for data acquisition and sharing in PFT software by different vendors, and the need for collaboration amongst clinicians, biomedical engineers, and information technologists. Hurdles notwithstanding, the new developments would represent significant advances that could be the future of PFT, the oldest test still in use in clinical medicine.
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    Chronic hypersensitivity pneumonitis in the southeastern United States: an assessment of how clinicians reached the diagnosis.
    (BMC pulmonary medicine, 2020-02-05) Gu, Jessie P; Tsai, Chen-Liang; Wysham, Nicholas G; Huang, Yuh-Chin T
    BACKGROUND:Chronic hypersensitivity pneumonitis (cHP) is a disease caused by exposure to inhaled environmental antigens. Diagnosis of cHP is influenced by the awareness of the disease prevalence, which varies significantly in different regions, and how clinicians utilize relevant clinical information. We conducted a retrospective study to evaluate how clinicians in the Southeast United States, where the climate is humid favoring mold growth, diagnosed cHP using items identified in the international modified Delphi survey of experts, i.e., environmental exposure, CT imaging and lung pathology, METHODS: We searched Duke University Medical Center database for patients over the age of 18 with a diagnosis of cHP (ICD-9 code: 495) between Jan. 1, 2008 to Dec. 31, 2013 using a query tool, Duke Enterprise Data Unified Content Explorer (DEDUCE). RESULTS:Five hundred patients were identified and 261 patients had cHP confirmed in clinic notes by a pulmonologist or an allergist. About half of the patients lived in the Research Triangle area where our medical center is located, giving an estimated prevalence rate of 6.5 per 100,000 persons. An exposure source was mentioned in 69.3% of the patient. The most common exposure sources were environmental molds (43.1%) and birds (26.0%). We used Venn diagram to evaluate how the patients met the three most common cHP diagnostic criteria: evidence of environmental exposures (history or precipitin) (E), chest CT imaging (C) and pathology from lung biopsies (P). Eighteen patients (6.9%) met none of three criteria. Of the remaining 243 patients, 135 patients (55.6%) had one (E 35.0%, C 3.3%, P 17.3%), 81 patients (33.3%) had two (E + C 12.3%, E + P 17.3%, C + P 4.9%), and 27 patients (11.1%) had all three criteria (E + C + P). Overall, 49.4% of patients had pathology from lung biopsy compared to 31.6% with CT scan. CONCLUSIONS:Environmental mold was the most common exposure for cHP in the Southeast United States. Lung pathology was available in more than half of cHP cases in our tertiary care center, perhaps reflecting the complexity of referrals. Differences in exposure sources and referral patterns should be considered in devising future diagnostic pathways or guidelines for cHP.
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    Controlled human exposures to ambient pollutant particles in susceptible populations.
    (Environmental health : a global access science source, 2009-01) Huang, Yuh-Chin T; Ghio, Andrew J
    Epidemiologic studies have established an association between exposures to air pollution particles and human mortality and morbidity at concentrations of particles currently found in major metropolitan areas. The adverse effects of pollution particles are most prominent in susceptible subjects, including the elderly and patients with cardiopulmonary diseases. Controlled human exposure studies have been used to confirm the causal relationship between pollution particle exposure and adverse health effects. Earlier studies enrolled mostly young healthy subjects and have largely confirmed the capability of particles to cause adverse health effects shown in epidemiological studies. In the last few years, more studies involving susceptible populations have been published. These recent studies in susceptible populations, however, have shown that the adverse responses to particles appear diminished in these susceptible subjects compared to those in healthy subjects. The present paper reviewed and compared control human exposure studies to particles and sought to explain the "unexpected" response to particle exposure in these susceptible populations and make recommendations for future studies. We found that the causes for the discrepant results are likely multifactorial. Factors such as medications, the disease itself, genetic susceptibility, subject selection bias that is intrinsic to many controlled exposure studies and nonspecificity of study endpoints may explain part of the results. Future controlled exposure studies should select endpoints that are more closely related to the pathogenesis of the disease and reflect the severity of particle-induced health effects in the specific populations under investigation. Future studies should also attempt to control for medications and genetic susceptibility. Using a different study design, such as exposing subjects to filtered air and ambient levels of particles, and assessing the improvement in biological endpoints during filtered air exposure, may allow the inclusion of higher risk patients who are likely the main contributors to the increased particle-induced health effects in epidemiological studies.
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    Development and Evaluation of a Small Airway Disease Index Derived From Modeling the Late-Expiratory Flattening of the Flow-Volume Loop.
    (Frontiers in physiology, 2022-01) Chen, Hengji; Joshi, Sangeeta; Oberle, Amber J; Wong, An-Kwok; Shaz, David; Thapamagar, Suman; Tan, Laren; Anholm, James D; Giri, Paresh C; Henriquez, Craig; Huang, Yuh-Chin T
    Excessive decrease in the flow of the late expiratory portion of a flow volume loop (FVL) or "flattening", reflects small airway dysfunction. The assessment of the flattening is currently determined by visual inspection by the pulmonary function test (PFT) interpreters and is highly variable. In this study, we developed an objective measure to quantify the flattening. We downloaded 172 PFT reports in PDF format from the electronic medical records and digitized and extracted the expiratory portion of the FVL. We located point A (the point of the peak expiratory flow), point B (the point corresponding to 75% of the expiratory vital capacity), and point C (the end of the expiratory portion of the FVL intersecting with the x-axis). We did a linear fitting to the A-B segment and the B-C segment. We calculated: 1) the AB-BC angle (∠ABC), 2) BC-x-axis angle (∠BCX), and 3) the log ratio of the BC slope over the vertical distance between point A and x-axis [log (BC/A-x)]. We asked an expert pulmonologist to assess the FVLs and separated the 172 PFTs into the flattening and the non-flattening groups. We defined the cutoff value as the mean minus one standard deviation using data from the non-flattening group. ∠ABC had the best concordance rate of 80.2% with a cutoff value of 149.7°. We then asked eight pulmonologists to evaluate the flattening with and without ∠ABC in another 168 PFTs. The Fleiss' kappa was 0.320 (lower and upper confidence intervals [CIs]: 0.293 and 0.348 respectively) without ∠ABC and increased to 0.522 (lower and upper CIs: 0.494 and 0.550) with ∠ABC. There were 147 CT scans performed within 6 months of the 172 PFTs. Twenty-six of 55 PFTs (47.3%) with ∠ABC <149.7° had CT scans showing small airway disease patterns while 44 of 92 PFTs (47.8%) with ∠ABC ≥149.7° had no CT evidence of small airway disease. We concluded that ∠ABC improved the inter-rater agreement on the presence of the late expiratory flattening in FVL. It could be a useful addition to the assessment of small airway disease in the PFT interpretation algorithm and reporting.
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    Discrimination of vanadium from zinc using gene profiling in human bronchial epithelial cells.
    (Environmental health perspectives, 2005-12) Li, Zhuowei; Stonehuerner, Jackie; Devlin, Robert B; Huang, Yuh-Chin T
    We hypothesized that gene expression profiling may discriminate vanadium from zinc in human bronchial epithelial cells (HBECs). RNA from HBECs exposed to vehicle, V (50 microM), or Zn (50 microM) for 4 hr (n = 4 paired experiments) was hybridized to Affymetrix Hu133A chips. Using one-class t-test with p < 0.01, we identified 140 and 76 genes with treatment:control ratios > or = 2.0 or < or = 0.5 for V and Zn, respectively. We then categorized these genes into functional pathways and compared the number of genes in each pathway between V and Zn using Fisher's exact test. Three pathways regulating gene transcription, inflammatory response, and cell proliferation distinguished V from Zn. When genes in these three pathways were matched with the 163 genes flagged by the same statistical filtration for V:Zn ratios, 12 genes were identified. The hierarchical clustering analysis showed that these 12 genes discriminated V from Zn and consisted of two clusters. Cluster 1 genes (ZBTB1, PML, ZNF44, SIX1, BCL6, ZNF450) were down-regulated by V and involved in gene transcription, whereas cluster 2 genes (IL8, IL1A, PTGS2, DTR, TNFAIP3, CXCL3) were up-regulated and linked to inflammatory response and cell proliferation. Also, metallothionein 1 genes (MT1F, MT1G, MT1K) were up-regulated by Zn only. Thus, using microarray analysis, we identified a small set of genes that may be used as biomarkers for discriminating V from Zn. The novel genes and pathways identified by the microarray may help us understand the pathogenesis of health effects caused by environmental V and Zn exposure.
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    Exposure to concentrated coarse air pollution particles causes mild cardiopulmonary effects in healthy young adults.
    (Environmental health perspectives, 2009-07) Graff, Donald W; Cascio, Wayne E; Rappold, Ana; Zhou, Haibo; Huang, Yuh-Chin T; Devlin, Robert B
    BACKGROUND: There is ample epidemiologic and toxicologic evidence that exposure to fine particulate matter (PM) air pollution [aerodynamic diameter < or = 2.5 microm (PM(2.5))], which derives primarily from combustion processes, can result in increased mortality and morbidity. There is less certainty as to the contribution of coarse PM (PM(2.5-10)), which derives from crustal materials and from mechanical processes, to mortality and morbidity. OBJECTIVE: To determine whether coarse PM causes cardiopulmonary effects, we exposed 14 healthy young volunteers to coarse concentrated ambient particles (CAPs) and filtered air. Coarse PM concentration averaged 89.0 microg/m(3) (range, 23.7-159.6 microg/m(3)). Volunteers were exposed to coarse CAPs and filtered air for 2 hr while they underwent intermittent exercise in a single-blind, crossover study. We measured pulmonary, cardiac, and hematologic end points before exposure, immediately after exposure, and again 20 hr after exposure. RESULTS: Compared with filtered air exposure, coarse CAP exposure produced a small increase in polymorphonuclear neutrophils in the bronchoalveolar lavage fluid 20 hr postexposure, indicating mild pulmonary inflammation. We observed no changes in pulmonary function. Blood tissue plasminogen activator, which is involved in fibrinolysis, was decreased 20 hr after exposure. The standard deviation of normal-to-normal intervals (SDNN), a measure of overall heart rate variability, also decreased 20 hr after exposure to CAPs. CONCLUSIONS: Coarse CAP exposure produces a mild physiologic response in healthy young volunteers approximately 20 hr postexposure. These changes are similar in scope and magnitude to changes we and others have previously reported for volunteers exposed to fine CAPs, suggesting that both size fractions are comparable at inducing cardiopulmonary changes in acute exposure settings.
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    Letters of Correspondence: Telehealth, Post-Acute Sequelae of COVID-19, Lung Cancer Screening Rates.
    (North Carolina medical journal, 2022-03) Fagan, Blake; Baratta, John M; King, Louise; Joshi, Sangeeta; Huang, Yuh-Chin T
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    Pollutant particles produce vasoconstriction and enhance MAPK signaling via angiotensin type I receptor.
    (Environmental health perspectives, 2005-08) Li, Zhuowei; Carter, Jacqueline D; Dailey, Lisa A; Huang, Yuh-Chin T
    Exposure to particulate matter (PM) is associated with acute cardiovascular mortality and morbidity, but the mechanisms are not entirely clear. In this study, we hypothesized that PM may activate the angiotensin type 1 receptor (AT1R), a G protein-coupled receptor that regulates inflammation and vascular function. We investigated the acute effects of St. Louis, Missouri, urban particles (UPs; Standard Reference Material 1648) on the constriction of isolated rat pulmonary artery rings and the activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and p38 mitogen-activated protein kinases (MAPKs) in human pulmonary artery endothelial cells with or without losartan, an antagonist of AT1R. UPs at 1-100 microg/mL induced acute vasoconstriction in pulmonary artery. UPs also produced a time- and dose-dependent increase in phosphorylation of ERK1/2 and p38 MAPK. Losartan pretreatment inhibited both the vasoconstriction and the activation of ERK1/2 and p38. The water-soluble fraction of UPs was sufficient for inducing ERK1/2 and p38 phosphorylation, which was also losartan inhibitable. Copper and vanadium, two soluble transition metals contained in UPs, induced pulmonary vasoconstriction and phosphorylation of ERK1/2 and p38, but only the phosphorylation of p38 was inhibited by losartan. The UP-induced activation of ERK1/2 and p38 was attenuated by captopril, an angiotensin-converting enzyme inhibitor. These results indicate that activation of the local renin-angiotensin system may play an important role in cardiovascular effects induced by PM.
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    Seasonal variations in air pollution particle-induced inflammatory mediator release and oxidative stress.
    (Environmental health perspectives, 2005-08) Becker, Susanne; Dailey, Lisa A; Soukup, Joleen M; Grambow, Steven C; Devlin, Robert B; Huang, Yuh-Chin T
    Health effects associated with particulate matter (PM) show seasonal variations. We hypothesized that these heterogeneous effects may be attributed partly to the differences in the elemental composition of PM. Normal human bronchial epithelial (NHBE) cells and alveolar macrophages (AMs) were exposed to equal mass of coarse [PM with aerodynamic diameter of 2.5-10 microm (PM(2.5-10)], fine (PM(2.5)), and ultrafine (PM(<0.1)) ambient PM from Chapel Hill, North Carolina, during October 2001 (fall) and January (winter), April (spring), and July (summer) 2002. Production of interleukin (IL)-8, IL-6, and reactive oxygen species (ROS) was measured. Coarse PM was more potent in inducing cytokines, but not ROSs, than was fine or ultrafine PM. In AMs, the October coarse PM was the most potent stimulator for IL-6 release, whereas the July PM consistently stimulated the highest ROS production measured by dichlorofluorescein acetate and dihydrorhodamine 123 (DHR). In NHBE cells, the January and the October PM were consistently the strongest stimulators for IL-8 and ROS, respectively. The July PM increased only ROS measured by DHR. PM had minimal effects on chemiluminescence. Principal-component analysis on elemental constituents of PM of all size fractions identified two factors, Cr/Al/Si/Ti/Fe/Cu and Zn/As/V/Ni/Pb/Se, with only the first factor correlating with IL-6/IL-8 release. Among the elements in the first factor, Fe and Si correlated with IL-6 release, whereas Cr correlated with IL-8 release. These positive correlations were confirmed in additional experiments with PM from all 12 months. These results indicate that elemental constituents of PM may in part account for the seasonal variations in PM-induced adverse health effects related to lung inflammation.
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    Vanadyl sulfate inhibits NO production via threonine phosphorylation of eNOS.
    (Environmental health perspectives, 2004-02) Li, Zhuowei; Carter, Jacqueline D; Dailey, Lisa A; Huang, Yuh-Chin T
    Exposure to excessive vanadium occurs in some occupations and with consumption of some dietary regimens for weight reduction and body building. Because vanadium is vasoactive, individuals exposed to excessive vanadium may develop adverse vascular effects. We have previously shown that vanadyl sulfate causes acute pulmonary vasoconstriction, which could be attributed in part to inhibition of nitric oxide production. In the present study we investigated whether NO inhibition was related to phosphorylation of endothelial nitric oxide synthase (eNOS). VOSO4 produced dose-dependent constriction of pulmonary arteries in isolated perfused lungs and pulmonary arterial rings and a right shift of the acetylcholine-dependent vasorelaxation curve. VOSO4 inhibited constitutive as well as A23187-stimulated NO production. Constitutive NO inhibition was accompanied by increased Thr495 (threonine at codon 495) phosphorylation of eNOS, which would inhibit eNOS activity. Thr495 phosphorylation of eNOS and inhibition of NO were partially reversed by pretreatment with calphostin C, a protein kinase C (PKC) inhibitor. There were no changes in Ser1177 (serine at codon 1177) or tyrosine phosphorylation of eNOS. These results indicate that VOSO4 induced acute pulmonary vasoconstriction that was mediated in part by the inhibition of endothelial NO production via PKC-dependent phosphorylation of Thr495 of eNOS. Exposure to excessive vanadium may contribute to pulmonary vascular diseases.