Publications by authors named "Hsin-Yu Fang"

31 Publications

Anti-inflammatory chemoprevention attenuates the phenotype in a mouse model of esophageal adenocarcinoma.

Carcinogenesis 2021 Apr 20. Epub 2021 Apr 20.

Department of Medicine II, Klinikum rechts der Isar, Technical University Munich (TUM), Ismaninger Str, München, Germany.

Barrett´s Esophagus (BE) is the main known precursor condition of Esophageal Adenocarcinoma (EAC). BE is defined by the presence of metaplasia above the normal squamous columnar junction and has mainly been attributed to gastroesophageal reflux disease (GERD) and chronic reflux esophagitis. Thus, the rising incidence of EAC in the Western world is likely mediated by chronic esophageal inflammation, secondary to GERD in combination with environmental risk factors such as a Western diet and obesity. However, (at present) risk prediction tools and endoscopic surveillance have shown limited effectiveness. Chemoprevention as an adjunctive approach remains an attractive option to reduce the incidence of neoplastic disease. Here, we investigate the feasibility of chemopreventive approaches in BE and EAC via inhibition of inflammatory signaling in a transgenic mouse model of BE and EAC (L2-IL1B mice), with accelerated tumor formation on a high fat diet (HFD). L2-IL1B mice were treated with the IL-1 receptor antagonist Anakinra and the nonsteroidal anti-inflammatory drugs (NSAIDs) aspirin or Sulindac. Interleukin-1b antagonism reduced tumor progression in L2-IL1B mice with or without a HFD, while both NSAIDs were effective chemoprevention agents in the accelerated HFD fed L2-IL1B mouse model. Sulindac treatment also resulted in a marked change in the immune profile of L2-IL-1B mice. In summary, anti-inflammatory treatment of HFD-treated L2-IL1B mice acted protectively on disease progression. These results from a mouse model of BE support results from clinical trials that suggest that anti-inflammatory medication may be effective in the chemoprevention of EAC.
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http://dx.doi.org/10.1093/carcin/bgab032DOI Listing
April 2021

Notch signaling drives development of Barrett's metaplasia from Dclk1-positive epithelial tuft cells in the murine gastric mucosa.

Sci Rep 2021 Feb 24;11(1):4509. Epub 2021 Feb 24.

Klinik und Poliklinik für Innere Medizin II, Technical University of Munich, Munich, Germany.

Barrett's esophagus (BE) is a precursor to esophageal adenocarcinoma (EAC), but its cellular origin and mechanism of neoplastic progression remain unresolved. Notch signaling, which plays a key role in regulating intestinal stem cell maintenance, has been implicated in a number of cancers. The kinase Dclk1 labels epithelial post-mitotic tuft cells at the squamo-columnar junction (SCJ), and has also been proposed to contribute to epithelial tumor growth. Here, we find that genetic activation of intracellular Notch signaling in epithelial Dclk1-positive tuft cells resulted in the accelerated development of metaplasia and dysplasia in a mouse model of BE (pL2.Dclk1.N2IC mice). In contrast, genetic ablation of Notch receptor 2 in Dclk1-positive cells delayed BE progression (pL2.Dclk1.N2fl mice), and led to increased secretory cell differentiation. The accelerated BE progression in pL2.Dclk1.N2IC mice correlated with changes to the transcriptomic landscape, most notably for the activation of oncogenic, proliferative pathways in BE tissues, in contrast to upregulated Wnt signalling in pL2.Dclk1.N2fl mice. Collectively, our data show that Notch activation in Dclk1-positive tuft cells in the gastric cardia can contribute to BE development.
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http://dx.doi.org/10.1038/s41598-021-84011-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904766PMC
February 2021

Identification of a PET Radiotracer for Imaging of the Folate Receptor-alpha - A Potential Tool to Select Patients for Targeted Tumor Therapy.

J Nucl Med 2021 Jan 15. Epub 2021 Jan 15.

Paul Scherrer Institute, Switzerland.

The aim of this study was to identify a folate receptor-alpha (FRα)-selective PET agent, potentially suitable for the selection of patients that could profit from FRα-targeted therapies. The 6R- and 6S-isomers of F-aza-5-methyltetrahydrofolate (MTHF) were assessed regarding their binding to the FRα and FRβ, expressed on cancer and inflammatory cells respectively, and compared to F-AzaFol, the folic acid-based analogue. FR selectivity was investigated using FRα-transfected (RT16) and FRβ-transfected (D4) CHO cells. The cell uptake of F-folate tracers was investigated and receptor-binding affinities were determined with the non-radioactive analogues. In vitro autoradiography of the F-folate tracers was performed using RT16 and D4 tissue sections. Biodistribution studies and PET/CT imaging of the radiotracers were performed with mice bearing RT16 and D4 xenografts. The uptake of F-6R-aza-5-MTHF into RT16 cells was high (62 ± 10% of added activity) but much lower when using D4 cells (5 ± 2%). FRα selectivity of F-6R-aza-5-MTHF was further demonstrated by its ~43-fold higher binding affinity to the FRα (IC50 = 1.8 ± 0.1 nM) than to the FRβ (IC50 = 77 ± 27 nM). The uptake of F-6S-aza-5-MTHF and F-AzaFol was equal in both cell lines (52-70%) and similar affinities to the FRα (IC50 = 2.1 ± 0.4 and 0.6 ± 0.3 nM, respectively) and FRβ (0.8 ± 0.2 and 0.3 ± 0.1 nM, respectively) were determined. The autoradiography signal obtained with F-6R-aza-5-MTHF was 11-fold more intense for RT16 than for D4 tissue sections. Biodistribution data showed high uptake of F-6R-aza-5-MTHF in RT16 xenografts (81 ± 20% IA/g, 1 h p.i.), but significantly lower accumulation in D4 xenografts (7.3 ± 2.1% IA/g, 1 h p.i.) which was also visualized using PET. The uptake of F-6S-aza-5-MTHF and F-AzaFol was similar in RT16 (53 ± 10% IA/g and 45 ± 2% IA/g, respectively) and D4 xenografts (77 ± 10% IA/g and 52 ± 7% IA/g, respectively). This study demonstrated FRα selectivity for F-6R-aza-5-MTHF but not for F-6S-aza-5-MTHF and F-AzaFol. This characteristic, together with its favorable tissue distribution, make F-6R-aza-5-MTHF attractive for clinical translation to enable detection of FRα-positive cancer while preventing undesired accumulation in FRβ-expressing inflammatory cells.
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http://dx.doi.org/10.2967/jnumed.120.255760DOI Listing
January 2021

Pilot study to reduce interdialytic weight gain by provision of low-sodium, home-delivered meals in hemodialysis patients.

Hemodial Int 2021 Apr 4;25(2):265-274. Epub 2020 Nov 4.

Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.

Introduction: Patients with kidney failure undergoing maintenance hemodialysis (HD) therapy are routinely counseled to reduce dietary sodium intake to ameliorate sodium retention, volume overload, and hypertension. However, low-sodium diet trials in HD are sparse and indicate that dietary education and behavioral counseling are ineffective in reducing sodium intake. This study aimed to determine whether 4 weeks of low-sodium, home-delivered meals in HD patients reduces interdialytic weight gain (IDWG). Secondary outcomes included changes in dietary sodium intake, thirst, xerostomia, blood pressure, volume overload, and muscle sodium concentration.

Methods: Twenty HD patients (55 ± 12 years, body mass index [BMI] 40.7 ± 16.6 kg/m ) were enrolled in this study. Participants followed a usual (control) diet for the first 4 weeks followed by 4 weeks of three low-sodium, home-delivered meals per day. We measured IDWG, hydration status (bioimpedance), standardized blood pressure (BP), food intake (3-day dietary recall), and muscle sodium (magnetic resonance imaging) at baseline (0 M), after the 4-week period of usual diet (1 M), and after the meal intervention (2 M).

Findings: The low-sodium meal intervention significantly reduced IDWG when compared to the control period (-0.82 ± 0.14 kg; 95% confidence interval, -0.55 to -1.08 kg; P < 0.001). There were also 1 month (1 M) to 2 month (2 M) reductions in dietary sodium intake (-1687 ± 297 mg; P < 0.001); thirst score (-4.4 ± 1.3; P = 0.003), xerostomia score (-6.7 ± 1.9; P = 0.002), SBP (-18.0 ± 3.6 mmHg; P < 0.001), DBP (-5.9 ± 2.0 mmHg; P = 0.008), and plasma phosphorus -1.55 ± 0.21 mg/dL; P = 0.005), as well as a 0 M to 2 M reduction in absolute volume overload (-1.08 ± 0.33 L; P = 0.025). However, there were no significant changes in serum or tissue sodium (all P > 0.05).

Discussion: Low-sodium, home-meal delivery appears to be an effective method for improving volume control and blood pressure in HD patients. Future studies with larger sample sizes are needed to examine the long-term effects of home-delivered meals on these outcomes and to assess cost-effectiveness.
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http://dx.doi.org/10.1111/hdi.12902DOI Listing
April 2021

Promising potential of [Lu]Lu-DOTA-folate to enhance tumor response to immunotherapy-a preclinical study using a syngeneic breast cancer model.

Eur J Nucl Med Mol Imaging 2021 04 19;48(4):984-994. Epub 2020 Oct 19.

Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institute, 5232, Villigen-PSI, Switzerland.

Purpose: It was previously demonstrated that radiation effects can enhance the therapy outcome of immune checkpoint inhibitors. In this study, a syngeneic breast tumor mouse model was used to investigate the effect of [Lu]Lu-DOTA-folate as an immune stimulus to enhance anti-CTLA-4 immunotherapy.

Methods: In vitro and in vivo studies were performed to characterize NF9006 breast tumor cells with regard to folate receptor (FR) expression and the possibility of tumor targeting using [Lu]Lu-DOTA-folate. A preclinical therapy study was performed over 70 days with NF9006 tumor-bearing mice that received vehicle only (group A); [Lu]Lu-DOTA-folate (5 MBq; 3.5 Gy absorbed tumor dose; group B); anti-CTLA-4 antibody (3 × 200 μg; group C), or both agents (group D). The mice were monitored regarding tumor growth over time and signs indicating adverse events of the treatment.

Results: [Lu]Lu-DOTA-folate bound specifically to NF9006 tumor cells and tissue in vitro and accumulated in NF9006 tumors in vivo. The treatment with [Lu]Lu-DOTA-folate or an anti-CTLA-4 antibody had only a minor effect on NF9006 tumor growth and did not substantially increase the median survival time of mice (23 day and 19 days, respectively) as compared with untreated controls (12 days). [Lu]Lu-DOTA-folate sensitized, however, the tumors to anti-CTLA-4 immunotherapy, which became obvious by reduced tumor growth and, hence, a significantly improved median survival time of mice (> 70 days). No obvious signs of adverse effects were observed in treated mice as compared with untreated controls.

Conclusion: Application of [Lu]Lu-DOTA-folate had a positive effect on the therapy outcome of anti-CTLA-4 immunotherapy. The results of this study may open new perspectives for future clinical translation of folate radioconjugates.
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http://dx.doi.org/10.1007/s00259-020-05054-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8041666PMC
April 2021

Elimination of NF-κB signaling in Vimentin+ stromal cells attenuates tumorigenesis in a mouse model of Barrett's Esophagus.

Carcinogenesis 2021 Apr;42(3):405-413

Department of Medicine II, Klinikum rechts der Isar, Technical University Munich (TUM), München, Germany.

Chronic inflammation induces Barrett's Esophagus (BE) which can advance to esophageal adenocarcinoma. Elevated levels of interleukin (IL)-1b, IL-6 and IL-8 together with activated nuclear factor-kappaB (NF-κB), have been identified as important mediators of tumorigenesis. The inflammatory milieu apart from cancer cells and infiltrating immune cells contains myofibroblasts (MFs) that express aSMA and Vimentin. As we observed that increased NF-κB activation and inflammation correlates with increased MF recruitment and an accelerated phenotype we here analyze the role of NF-κB in MF during esophageal carcinogenesis in our L2-IL-1B mouse model. To analyze the effect of NF-κB signaling in MFs, we crossed L2-IL-1B mice to tamoxifen inducible Vim-Cre (Vim-CreTm) mice and floxed RelA (p65fl/fl) mice to specifically eliminate NF-κB signaling in MF (IL-1b.Vim-CreTm.p65fl/fl). The interaction of epithelial cells and stromal cells was further analyzed in mouse BE organoids and patient-derived human organoids. Histological scoring of IL-1b.Vim-CreTm.p65fl/fl mice showed a significantly attenuated phenotype compared with L2-IL-1B mice, with mild inflammation, decreased metaplasia and no dysplasia. This correlated with decreased proliferation and increased differentiation in cardia tissue of IL-1b.Vim-CreTm.p65fl/fl compared with L2-IL-1B mice. Distinct changes of cytokines and chemokines within the local microenvironment in IL-1b.Vim-CreTm.p65fl/fl mice reflected the histopathological abrogated phenotype. Co-cultured NF-κB inhibitor treated MF with mouse BE organoids demonstrated NF-κB-dependent growth and migration. MFs are essential to form an inflammatory and procarcinogenic microenvironment and NF-κB signaling in stromal cells emerges as an important driver of esophageal carcinogenesis. Our data suggest anti-inflammatory approaches as preventive strategies during surveillance of BE patients.
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http://dx.doi.org/10.1093/carcin/bgaa109DOI Listing
April 2021

Adherence to Daily Food Guides Is Associated with Lower Risk of Metabolic Syndrome: The Nutrition and Health Survey in Taiwan.

Nutrients 2020 Sep 27;12(10). Epub 2020 Sep 27.

Department of Public Health, China Medical University College of Public Health, Taichung 406040, Taiwan.

Although nutritional health knowledge serves as the basis for the daily food guides, limited epidemiologic studies were conducted to verify whether adherence to the daily food guides reduced the prevalence of diseases. This study aims to examine whether adherence to the daily food guides relates to the lower risk of having metabolic syndrome, as well as to assess the association between levels of adherence to daily food guides and demographic characteristics. A cross-sectional study was conducted using data from the Nutrition and Health Survey in Taiwan (NAHSIT) 2014-2016. Face-to-face dietary assessments were conducted using a validated food-frequency questionnaire. Six food groups were defined according to the daily food guides in Taiwan. We constructed a daily food guide index to measure the levels of adherence to the daily food guides. Logistic regression was performed to assess the association between the levels of adherence to the daily food guides and the risk of having metabolic syndrome. A total of 2534 participants (51% of females) were included in the final analysis. After adjusting for age, sex, body mass index, education level, marital status, and family income, we found a negative correlation between the levels of adherence to daily food guides and the prevalence of metabolic syndrome. The odds ratios (ORs) for the highest versus lowest quartile of the adherence level was 0.65 (95% confidence interval (CI) = 0.48-0.88). In addition, males, younger age, lower education, divorced, separated, and widowed, and lower family income were associated with lower adherence to daily food guides. In conclusion, participants reporting better adherence to the daily food guides during the past month had a lower risk of having metabolic syndrome.
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http://dx.doi.org/10.3390/nu12102955DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7600265PMC
September 2020

CUL4-DDB1-CRBN E3 Ubiquitin Ligase Regulates Proteostasis of ClC-2 Chloride Channels: Implication for Aldosteronism and Leukodystrophy.

Cells 2020 05 26;9(6). Epub 2020 May 26.

Department of Physiology, College of Medicine, National Taiwan University, Taipei 10051, Taiwan.

Voltage-gated ClC-2 channels are essential for chloride homeostasis. Complete knockout of mouse ClC-2 leads to testicular degeneration and neuronal myelin vacuolation. Gain-of-function and loss-of-function mutations in the ClC-2-encoding human gene are linked to the genetic diseases aldosteronism and leukodystrophy, respectively. The protein homeostasis (proteostasis) mechanism of ClC-2 is currently unclear. Here, we aimed to identify the molecular mechanism of endoplasmic reticulum-associated degradation of ClC-2, and to explore the pathophysiological significance of disease-associated anomalous ClC-2 proteostasis. In both heterologous expression system and native neuronal and testicular cells, ClC-2 is subject to significant regulation by cullin-RING E3 ligase-mediated polyubiquitination and proteasomal degradation. The cullin 4 (CUL4)-damage-specific DNA binding protein 1 (DDB1)-cereblon (CRBN) E3 ubiquitin ligase co-exists in the same complex with and promotes the degradation of ClC-2 channels. The CRBN-targeting immunomodulatory drug lenalidomide and the cullin E3 ligase inhibitor MLN4924 promotes and attenuates, respectively, proteasomal degradation of ClC-2. Analyses of disease-related ClC-2 mutants reveal that aldosteronism and leukodystrophy are associated with opposite alterations in ClC-2 proteostasis. Modifying CUL4 E3 ligase activity with lenalidomide and MLN4924 ameliorates disease-associated ClC-2 proteostasis abnormality. Our results highlight the significant role and therapeutic potential of CUL4 E3 ubiquitin ligase in regulating ClC-2 proteostasis.
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http://dx.doi.org/10.3390/cells9061332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7348978PMC
May 2020

Pilot feasibility study examining the effects of a comprehensive volume reduction protocol on hydration status and blood pressure in hemodialysis patients.

Hemodial Int 2020 07 12;24(3):414-422. Epub 2020 May 12.

Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, Champaign, Illinois, USA.

Introduction: Chronic volume overload is a persistent problem in hemodialysis (HD) patients. The purpose of this study was to investigate the impacts of comprehensive volume reduction protocol on HD patient's hydration status and blood pressure (BP).

Methods: Twenty-three HD patients (age = 55.7 ± 13.3 years) completed a 6-month comprehensive volume control protocol consisting of: reducing postdialysis weight; reducing BP medication prescriptions; and weekly intradialytic counseling to reduce dietary sodium intake and interdialytic weight gain (IDWG). The primary outcome was volume overload (VO) measured by bioelectrical impedance spectroscopy. Secondary outcomes included: IDWG, postdialysis weight, estimated dry weight (EDW), dietary sodium intake, BP and BP medication prescriptions.

Findings: From baseline (0M) to 6 months (6M), significant improvements were noted in: VO (0M 3.9 ± 3.9 L vs. 6M 2.6 ± 3.4 L, P = 0.003), postdialysis weight (0M 89.4 ± 23.1 kg vs. 6M 87.6 ± 22.2 kg; P = 0.012), and EDW (0M 89.0 ± 23.2 vs. 6M 86.7 ± 22.5 kg., P = 0.009). There was also a trend for a reduction in monthly averaged IDWG (P = 0.053), and sodium intake (0M 2.9 ± 1.6 vs. 6M 2.3 ± 1.1 g/d, P = 0.125). Neither systolic BP (0M 162 ± 27 vs. 6M 157 ± 23 mmHg, P = 0.405) nor diastolic BP (0M 82 ± 21 vs. 6M 82 ± 19 mmHg, P = 0.960) changed, though there was a significant reduction in the total number of BP medications prescribed (0M 3.0 ± 1.0 vs. 6M 1.5 ± 1.0 BP meds; P = 0.004).

Discussion: Our volume reduction protocol significantly improved HD patient's hydration status. While BP did not change, the reduction in prescribed BP medication number suggests improved BP control. Despite these overall positive findings, the magnitude of change in most variables was modest. Comprehensive changes in HD clinics may be necessary to realize more clinically significant results.
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http://dx.doi.org/10.1111/hdi.12841DOI Listing
July 2020

Notch Signaling Mediates Differentiation in Barrett's Esophagus and Promotes Progression to Adenocarcinoma.

Gastroenterology 2020 08 20;159(2):575-590. Epub 2020 Apr 20.

Department of Medicine, Columbia University Irving Medical Center, New York, New York; Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York.

Background & Aims: Studies are needed to determine the mechanism by which Barrett's esophagus (BE) progresses to esophageal adenocarcinoma (EAC). Notch signaling maintains stem cells in the gastrointestinal tract and is dysregulated during carcinogenesis. We explored the relationship between Notch signaling and goblet cell maturation, a feature of BE, during EAC pathogenesis.

Methods: We measured goblet cell density and levels of Notch messenger RNAs in BE tissues from 164 patients, with and without dysplasia or EAC, enrolled in a multicenter study. We analyzed the effects of conditional expression of an activated form of NOTCH2 (pL2.Lgr5.N2IC), conditional deletion of NOTCH2 (pL2.Lgr5.N2fl/fl), or loss of nuclear factor κB (NF-κB) (pL2.Lgr5.p65fl/fl), in Lgr5 (progenitor) cells in L2-IL1B mice (which overexpress interleukin 1 beta in esophagus and squamous forestomach and are used as a model of BE). We collected esophageal and stomach tissues and performed histology, immunohistochemistry, flow cytometry, transcriptome, and real-time polymerase chain reaction analyses. Cardia and forestomach tissues from mice were cultured as organoids and incubated with inhibitors of Notch or NF-kB.

Results: Progression of BE to EAC was associated with a significant reduction in goblet cell density comparing nondysplastic regions of tissues from patients; there was an inverse correlation between goblet cell density and levels of NOTCH3 and JAG2 messenger RNA. In mice, expression of the activated intracellular form of NOTCH2 in Lgr5 cells reduced goblet-like cell maturation, increased crypt fission, and accelerated the development of tumors in the squamocolumnar junction. Mice with deletion of NOTCH2 from Lgr5 cells had increased maturation of goblet-like cells, reduced crypt fission, and developed fewer tumors. Esophageal tissues from in pL2.Lgr5.N2IC mice had increased levels of RelA (which encodes the p65 unit of NF-κB) compared to tissues from L2-IL1B mice, and we found evidence of increased NF-κB activity in Lgr5 cells. Esophageal tissues from pL2.Lgr5.p65fl/fl mice had lower inflammation and metaplasia scores than pL2.Lgr5.N2IC mice. In organoids derived from pL2-IL1B mice, the NF-κB inhibitor JSH-23 reduced cell survival and proliferation.

Conclusions: Notch signaling contributes to activation of NF-κB and regulates differentiation of gastric cardia progenitor cells in a mouse model of BE. In human esophageal tissues, progression of BE to EAC was associated with reduced goblet cell density and increased levels of Notch expression. Strategies to block this pathway might be developed to prevent EAC in patients with BE.
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http://dx.doi.org/10.1053/j.gastro.2020.04.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484392PMC
August 2020

The Risk of Depression in Patients with Pemphigus: A Nationwide Cohort Study in Taiwan.

Int J Environ Res Public Health 2020 03 17;17(6). Epub 2020 Mar 17.

Department of Health Services Administration, China Medical University, Taichung 40447, Taiwan.

Pemphigus is a chronic dermatological disorder caused by an autoimmune response and is associated with a high proportion of comorbidities and fatalities. The aim of this study was to investigate the risk of depression in patients with pemphigus. Data were derived from the National Health Insurance Research Database recorded during the period 2000-2010 in Taiwan. Multivariate Cox proportional hazards regression models were used to analyze the data and assess the effects of pemphigus on the risk of depression after adjusting for demographic characteristics and comorbidities. Patients with pemphigus were 1.98 times more likely to suffer from depression than the control group (pemphigus, adjusted HR: 1.99, 95% CI = 1.37-2.86). People aged ≥65 years were 1.69 times more likely to suffer from depression than those aged 20-49 years (≥65 years, adjusted HR: 1.42, 95% CI = 0.92-2.21). Female and male patients with pemphigus were respectively 2.02 and 1.91 times more likely to suffer from depression than the control group (female, adjusted HR: 2.09, 95% CI = 1.24-3.54; male, adjusted HR: 1.87, 95% CI = 0.97-3.60). People with HTN, hyperlipidemia, asthma/COPD, and chronic liver disease were respectively 1.73, 2.3, 2.2, and 1.69 times more likely to suffer from depression than those without these comorbidities (HTN, adjusted HR: 0.75, 95% CI = 0.41-1.42; hyperlipidemia, adjusted HR: 1.48, 95% CI = 0.78-2.82; asthma/COPD, adjusted HR: 1.4, 95% CI = 0.72-2.69; and chronic liver disease, adjusted HR: 1.61, 95% CI = 1.07-2.43). There was a significant association between pemphigus and increased risk of depression. Female patients had a higher incidence of depression.
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http://dx.doi.org/10.3390/ijerph17061983DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7142767PMC
March 2020

A Comparison of Intradialytic versus Out-of-Clinic Exercise Training Programs for Hemodialysis Patients.

Blood Purif 2020 18;49(1-2):151-157. Epub 2019 Dec 18.

Department of Kinesiology and Community Health, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA,

Background: Physical inactivity is prevalent and linked with a variety of unfavorable clinical outcomes in hemodialysis patients. To increase physical activity (PA) and improve quality of life in this population, intradialytic and out-of-clinic exercise interventions have been implemented in many studies. However, there is still a lack of consensus in the literature on which type of exercise intervention is more feasible and effective.

Summary: This review provides a brief overview of intradialytic and out-of-clinic exercise protocols utilized in previous studies. We also examine data related to the feasibility of each approach, and their efficacy for improving cardiovascular health, muscle mass, strength, and physical function. Key Messages: The benefits from most intradialytic and out-of-center exercise training interventions published to date have been modest or inconsistent. Furthermore, neither appears to provide a significant advantage over the other in terms of benefits for cardiovascular health, muscle mass, strength, and physical function. A significant concern is that most intradialytic and out-of-center exercise interventions are mandated exercise prescriptions that include either endurance or resistance training exercises, performed at low-moderate intensities, for a total of 60-135 min of exercise/week. This volume, intensity, and variety of exercise are far less than what is recommended in most PA guidelines. This type of structured activity is also boring for most patients. To enhance the effectiveness of exercise interventions, we suggest using the intradialytic period to provide patients guidance on how they can best incorporate more activity into their lives, based on their individual needs and barriers.
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http://dx.doi.org/10.1159/000503772DOI Listing
December 2020

Resistance Exercise-induced Regulation of Muscle Protein Synthesis to Intraset Rest.

Med Sci Sports Exerc 2020 05;52(5):1022-1030

Army West Point Athletics Association, West Point, NY.

During a traditional set configuration of resistance exercise (TRD), characterized by a continuous completion of repetitions, a decrease in power output tends to occur throughout a set of repetitions. Inclusion of intraset rest, otherwise known as a cluster set configuration (CLU), counteracts this power decline. However, the effect of a CLU configuration on postexercise myofibrillar protein synthesis rates (MPS) and anabolic signaling has not been investigated.

Purpose: We aimed to determine if any mechanistic differences exist between TRD and CLU signaling events associated with muscle anabolism.

Methods: In randomized crossover trials, eight resistance-trained participants (23 ± 1 yr, 81 ± 4.7 kg, body fat: 18% ± 1.9%; 1 repetition maximum [1RM], 150 ± 9.1 kg) performed an acute bout of CLU (4 sets × (2 × 5) repetitions, 30-s intraset rest, 90-s interset rest) and TRD (4 sets × 10 repetitions, 120-s interset rest) barbell back squats at approximately 70% 1RM with total volume load equated during primed continuous L-[ring-C6]phenylalanine infusions. Blood and muscle biopsy samples were collected at rest and after exercise at 0, 2, and 5 h.

Results: There was no difference in postexercise MPS between the CLU and TRD condition (P > 0.05) and no changes in phosphorylation of mTORC1 downstream targets (p70S6K and 4EBP1). Total and phosphorylated yes-associated protein on Ser127 transiently increased (P < 0.01) immediately after exercise (t = 0) in CLU (~2.1-fold) and TRD condition (~2.2-fold).

Conclusions: Our results show that CLU is a viable anabolic option by preserving power output with similar MPS stimulation when compared with the TRD condition in trained young adults.
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http://dx.doi.org/10.1249/MSS.0000000000002213DOI Listing
May 2020

High-Fat Diet Accelerates Carcinogenesis in a Mouse Model of Barrett's Esophagus via Interleukin 8 and Alterations to the Gut Microbiome.

Gastroenterology 2019 08 15;157(2):492-506.e2. Epub 2019 Apr 15.

Irvine Cancer Research Center, Columbia University, New York, New York.

Background & Aims: Barrett's esophagus (BE) is a precursor to esophageal adenocarcinoma (EAC). Progression from BE to cancer is associated with obesity, possibly due to increased abdominal pressure and gastroesophageal reflux disease, although this pathogenic mechanism has not been proven. We investigated whether environmental or dietary factors associated with obesity contribute to the progression of BE to EAC in mice.

Methods: Tg(ED-L2-IL1RN/IL1B)#Tcw mice (a model of BE, called L2-IL1B mice) were fed a chow (control) or high-fat diet (HFD) or were crossbred with mice that express human interleukin (IL) 8 (L2-IL1B/IL8 mice). Esophageal tissues were collected and analyzed for gene expression profiles and by quantitative polymerase chain reaction, immunohistochemistry, and flow cytometry. Organoids were established from BE tissue of mice and cultured with serum from lean or obese individuals or with neutrophils from L2-IL1B mice. Feces from mice were analyzed by 16s ribosomal RNA sequencing and compared to 16s sequencing data from patients with dysplasia or BE. L2-IL1B were mice raised in germ-free conditions.

Results: L2-IL1B mice fed an HFD developed esophageal dysplasia and tumors more rapidly than mice fed the control diet; the speed of tumor development was independent of body weight. The acceleration of dysplasia by the HFD in the L2-IL1B mice was associated with a shift in the gut microbiota and an increased ratio of neutrophils to natural killer cells in esophageal tissues compared with mice fed a control diet. We observed similar differences in the microbiomes from patients with BE that progressed to EAC vs patients with BE that did not develop into cancer. Tissues from dysplasias of L2-IL1B mice fed the HFD contained increased levels of cytokines that are produced in response to CXCL1 (the functional mouse homolog of IL8, also called KC). Serum from obese patients caused organoids from L2-IL1B/IL8 mice to produce IL8. BE tissues from L2-IL1B mice fed the HFD and from L2-IL1B/IL8 mice contained increased numbers of myeloid cells and cells expressing Cxcr2 and Lgr5 messenger RNAs (epithelial progenitors) compared with mice fed control diets. BE tissues from L2-IL1B mice raised in germ-free housing had fewer progenitor cells and developed less dysplasia than in L2-IL1 mice raised under standard conditions; exposure of fecal microbiota from L2-IL1B mice fed the HFD to L2-IL1B mice fed the control diet accelerated tumor development.

Conclusions: In a mouse model of BE, we found that an HFD promoted dysplasia by altering the esophageal microenvironment and gut microbiome, thereby inducing inflammation and stem cell expansion, independent of obesity.
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http://dx.doi.org/10.1053/j.gastro.2019.04.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6662596PMC
August 2019

Vimentin-Induced Cardiac Mesenchymal Stem Cells Proliferate in the Acute Ischemic Myocardium.

Cells Tissues Organs 2018 10;206(1-2):35-45. Epub 2019 Jan 10.

Reference and Translation Center for Cardiac Stem Cell Therapy (RTC), Rostock University Medical Center, Rostock, Germany.

In-depth knowledge of the mechanisms induced by early postischemic cardiac endogenous mesenchymal stem cells (MSCs) in the acutely ischemic heart could advance our understanding of cardiac regeneration. Herein, we aimed to identify, isolate, and initially characterize the origin, kinetics and fate of cardiac MSCs. This was facilitated by in vivo genetic cell fate mapping through green fluorescent protein (GFP) expression under the control of vimentin induction after acute myocardial infarction (MI). Following permanent ligation of the left anterior descending coronary artery in CreER+ mTom/mGFP+ mice, vimentin/GFP+ cells revealed ischemia-responsive activation, survival, and local enrichment inside the peri-infarction border zone. Fluorescence-activated cell sorting (FACS)-isolated vimentin/GFP+ cells could be strongly expanded in vitro with clonogenic precursor formation and revealed MSC-typical cell morphology. Flow-cytometric analyses demonstrated an increase in cardiac vimentin/GFP+ cells in the ischemic heart, from a 0.6% cardiac mononuclear cell (MNC) fraction at 24 h to 1.6% at 72 h following MI. Sca-1+CD45- cells within the vimentin/GFP+ subtype of this MNC fraction increased from 35.2% at 24 h to 74.6% at 72 h after MI. The cardiac postischemic vimentin/GFP+ MNC subtype showed multipotent adipogenic, chondrogenic, and osteogenic differentiation potential, which is distinctive for MSCs. In conclusion, we demonstrated a seemingly proliferative first response of vimentin- induced cardiac endogenous MSCs in the acutely ischemic heart. Genetically, GFP-targeted in vivo cell tracking, isolation, and in vitro expansion of this cardiac MSC subtype could help to clarify their reparative status in inflammation, fibrogenesis, cell turnover, tissue homeostasis, and myocardial regeneration.
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http://dx.doi.org/10.1159/000495527DOI Listing
September 2019

Dysregulated Handling of Dietary Protein and Muscle Protein Synthesis After Mixed-Meal Ingestion in Maintenance Hemodialysis Patients.

Kidney Int Rep 2018 Nov 17;3(6):1403-1415. Epub 2018 Aug 17.

Department of Kinesiology and Community Health, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.

Introduction: Skeletal muscle loss is common in patients with renal failure who receive maintenance hemodialysis (MHD) therapy. Regular ingestion of protein-rich meals are recommended to help offset muscle protein loss in MHD patients, but little is known about the anabolic potential of this strategy.

Methods: Eight MHD patients (age: 56 ± 5 years; body mass index [BMI]: 32 ± 2 kg/m) and 8 nonuremic control subjects (age: 50 ± 2 years: BMI: 31 ± 1 kg/m) received primed continuous L-[-H]phenylalanine and L-[1-C]leucine infusions with blood and muscle biopsy sampling on a nondialysis day. Participants consumed a mixed meal (546 kcal; 20-g protein, 59-g carbohydrates, 26-g fat) with protein provided as L-[5,5,5-H]leucine-labeled eggs.

Results: Circulating dietary amino acid availability was reduced in MHD patients (41 ± 5%) versus control subjects (61 ± 4%;  = 0.03). Basal muscle caspase-3 protein content was elevated ( = 0.03) and large neutral amino acid transporter 1 (LAT1) protein content was reduced ( 0.02) in MHD patients versus control subjects. Basal muscle protein synthesis (MPS) was ∼2-fold higher in MHD patients (0.030 ± 0.005%/h) versus control subjects (0.014 ± 0.003%/h) ( = 0.01). Meal ingestion failed to increase MPS in MHD patients (absolute change from basal: 0.0003 ± 0.007%/h), but stimulated MPS in control subjects (0.009 ± 0.002%/h; 0.004).

Conclusions: MHD patients demonstrated muscle anabolic resistance to meal ingestion. This blunted postprandial MPS response in MHD patients might be related to high basal MPS, which results in a stimulatory and/or reduced plasma dietary amino acid availability after mixed-meal ingestion.
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http://dx.doi.org/10.1016/j.ekir.2018.08.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6224635PMC
November 2018

Is a Potential Target for Diagnostic PET/CT Imaging in Barrett's Dysplasia and Esophageal Adenocarcinoma.

Clin Cancer Res 2018 03 5;24(5):1048-1061. Epub 2017 Dec 5.

II. Medizinische Klinik, Technische Universitat München, Munich, Germany.

Barrett's esophagus represents an early stage in carcinogenesis leading to esophageal adenocarcinoma. Considerable evidence supports a major role for chronic inflammation and diverse chemokine pathways in the development of Barrett's esophagus and esophageal adenocarcinoma. Here we utilized an transgenic mouse model of Barrett's esophagus and esophageal adenocarcinoma and human patient imaging to analyze the importance of CXCR4-expressing cells during esophageal carcinogenesis. IL1β overexpression induces chronic esophageal inflammation and recapitulates the progression to Barrett's esophagus and esophageal adenocarcinoma. CXCR4 expression is increased in both epithelial and immune cells during disease progression in pL2-IL1β mice and also elevated in esophageal adenocarcinoma patient biopsy samples. Specific recruitment of CXCR4-positive (CXCR4) immune cells correlated with dysplasia progression, suggesting that this immune population may be a key contributor to esophageal carcinogenesis. Similarly, with progression to dysplasia, there were increased numbers of CXCR4 columnar epithelial cells at the squamocolumnar junction (SCJ). These findings were supported by stronger CXCR4-related signal intensity in fluorescence imaging and autoradiography with advanced dysplasia. Pilot CXCR4-directed PET/CT imaging studies in patients with esophageal cancer demonstrate the potential utility of CXCR4 imaging for the diagnosis and staging of esophageal cancer. In conclusion, the recruitment of CXCR4 immune cells and expansion of CXCR4 epithelial cells in esophageal dysplasia and cancer highlight the potential of CXCR4 as a biomarker and molecular target for diagnostic imaging of the tumor microenvironment in esophageal adenocarcinoma. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-1756DOI Listing
March 2018

Inhibitory effect of -ferulic acid on proliferation and migration of human lung cancer cells accompanied with increased endogenous reactive oxygen species and β-catenin instability.

Chin Med 2016 1;11:45. Epub 2016 Oct 1.

Department of Biotechnology, Kaohsiung Medical University, Kaohsiung, 807 Taiwan.

Background: -ferulic (FA) acid exhibits antioxidant effects in vitro. However, the underlying mechanism of -FA activity in cellular physiology, especially cancer physiology, remains largely unknown. This study investigated the cellular physiological effects of -FA on the H1299 human lung cancer cell line.

Methods: The 2,2-diphenyl-1-picrylhydrazyl assay was used to determine free radical scavenging capability. Assessment of intracellular reactive oxygen species (ROS) was evaluated using oxidized 2',7'-dichlorofluorescin diacetate and dihydroethidium staining. Trypan blue exclusion, colony formation, and anchorage-independent growth assays were used to determine cellular proliferation. Annexin V staining assay was used to assess cellular apoptosis by flow cytometry. Wound healing and Boyden's well assays were used to detect the migration and invasion of cells. Gelatin zymography was used to detect matrix metalloproteinase (MMP-2 and MMP-9) activity. Western blotting was used to detect expression levels of various signaling pathway proteins.

Results: DPPH assay results indicated that -FA exerted potent antioxidant effects. However, -FA increased intracellular ROS levels, including hydrogen peroxide and superoxide anion, in H1299 cells. -FA treatment inhibited cellular proliferation and induced moderate apoptotic cell death at the highest concentration used (0.6 mM). Furthermore, -FA moderately inhibited the migration of H1299 cells at the concentrations of 0.3 and 0.6 mM and attenuated MMP-2 and MMP-9 activity. -FA caused the phosphorylation of β-catenin, resulting in proteasomal degradation of β-catenin. Conversely, -FA treatment increased the expression of pro-apoptotic factor Bax and decreased the expression of pro-survival factor survivin.

Conclusion: Various concentrations (0.06-0.6 mM) of -FA exert both anti-proliferation and anti-migration effects in the human lung cancer cell line H1299.
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http://dx.doi.org/10.1186/s13020-016-0116-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5045596PMC
October 2016

Adult asthma is associated with an increased risk of herpes zoster: A population-based cohort study.

J Asthma 2017 04 13;54(3):250-257. Epub 2016 Jul 13.

e Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, China Medical University Hospital, China Medical University , Taichung , Taiwan.

Objective: The objective of this study was to determine whether a new diagnosis of asthma is associated with a later diagnosis of herpes zoster (HZ) in a nationwide, retrospective, non-age limited, population-based cohort.

Methods: We used data from the National Health Insurance Research Database in Taiwan. The asthma group consisted of all 40 069 patients in the database with newly diagnosed asthma and using asthma medications from 2000 through 2005. The nonasthma group comprised 40 069 age- and sex-matched patients without any asthma diagnosis. Cox proportional hazards regression analysis was applied to calculate the hazard ratio of HZ in the patients with asthma relative to those without asthma.

Results: During a mean follow-up period of 8.77 years, the risk of HZ was 1.48-fold higher in the asthma group compared with that in the nonasthma group after adjustment for sex, age, comorbidities, inhaled and systemic corticosteroid use, and annual outpatient department visits to dermatologists. Additional stratified analyses revealed that the risk of HZ was significantly higher in patients of both sexes and those aged older than 21 years.

Conclusions: Newly diagnosed adult patients with asthma have a significantly higher risk of developing HZ than do those without asthma.
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http://dx.doi.org/10.1080/02770903.2016.1211142DOI Listing
April 2017

Purpuric Nodules on a Lymphedematous Arm.

Intern Med 2016 15;55(8):1035-6. Epub 2016 Apr 15.

Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, China Medical University Hospital, Taiwan.

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http://dx.doi.org/10.2169/internalmedicine.55.6254DOI Listing
August 2016

Multiple nodules on the bilateral lower extremities.

Eur J Intern Med 2015 Jun 30;26(5):363-4. Epub 2014 Oct 30.

Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, China Medical University Hospital, Taiwan; Graduate Institute of Clinical Medical Science, College of Medicine, China Medical University, Taichung, Taiwan. Electronic address:

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http://dx.doi.org/10.1016/j.ejim.2014.10.015DOI Listing
June 2015

The Eag domain regulates the voltage-dependent inactivation of rat Eag1 K+ channels.

PLoS One 2014 21;9(10):e110423. Epub 2014 Oct 21.

Institute of Anatomy and Cell Biology, School of Medicine, National Yang-Ming University, Taipei, Taiwan; Brain Research Center, National Yang-Ming University, Taipei, Taiwan.

Eag (Kv10) and Erg (Kv11) belong to two distinct subfamilies of the ether-à-go-go K+ channel family (KCNH). While Erg channels are characterized by an inward-rectifying current-voltage relationship that results from a C-type inactivation, mammalian Eag channels display little or no voltage-dependent inactivation. Although the amino (N)-terminal region such as the eag domain is not required for the C-type inactivation of Erg channels, an N-terminal deletion in mouse Eag1 has been shown to produce a voltage-dependent inactivation. To further discern the role of the eag domain in the inactivation of Eag1 channels, we generated N-terminal chimeras between rat Eag (rEag1) and human Erg (hERG1) channels that involved swapping the eag domain alone or the complete cytoplasmic N-terminal region. Functional analyses indicated that introduction of the homologous hERG1 eag domain led to both a fast phase and a slow phase of channel inactivation in the rEag1 chimeras. By contrast, the inactivation features were retained in the reverse hERG1 chimeras. Furthermore, an eag domain-lacking rEag1 deletion mutant also showed the fast phase of inactivation that was notably attenuated upon co-expression with the rEag1 eag domain fragment, but not with the hERG1 eag domain fragment. Additionally, we have identified a point mutation in the S4-S5 linker region of rEag1 that resulted in a similar inactivation phenotype. Biophysical analyses of these mutant constructs suggested that the inactivation gating of rEag1 was distinctly different from that of hERG1. Overall, our findings are consistent with the notion that the eag domain plays a critical role in regulating the inactivation gating of rEag1. We propose that the eag domain may destabilize or mask an inherent voltage-dependent inactivation of rEag1 K+ channels.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0110423PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4204861PMC
June 2015

The subfamily-specific assembly of Eag and Erg K+ channels is determined by both the amino and the carboxyl recognition domains.

J Biol Chem 2014 Aug 9;289(33):22815-22834. Epub 2014 Jul 9.

Institute of Anatomy and Cell Biology, School of Medicine, and National Yang-Ming University, No. 155, Section 2, Li-Non Street, Taipei 12212, Taiwan; Brain Research Center, National Yang-Ming University, No. 155, Section 2, Li-Non Street, Taipei 12212, Taiwan and. Electronic address:

A functional voltage-gated K(+) (Kv) channel comprises four pore-forming α-subunits, and only members of the same Kv channel subfamily may co-assemble to form heterotetramers. The ether-à-go-go family of Kv channels (KCNH) encompasses three distinct subfamilies: Eag (Kv10), Erg (Kv11), and Elk (Kv12). Members of different ether-à-go-go subfamilies, such as Eag and Erg, fail to form heterotetramers. Although a short stretch of amino acid sequences in the distal C-terminal section has been implicated in subfamily-specific subunit assembly, it remains unclear whether this region serves as the sole and/or principal subfamily recognition domain for Eag and Erg. Here we aim to ascertain the structural basis underlying the subfamily specificity of ether-à-go-go channels by generating various chimeric constructs between rat Eag1 and human Erg subunits. Biochemical and electrophysiological characterizations of the subunit interaction properties of a series of different chimeric and truncation constructs over the C terminus suggested that the putative C-terminal recognition domain is dispensable for subfamily-specific assembly. Further chimeric analyses over the N terminus revealed that the N-terminal region may also harbor a subfamily recognition domain. Importantly, exchanging either the N-terminal or the C-terminal domain alone led to a virtual loss of the intersubfamily assembly boundary. By contrast, simultaneously swapping both recognition domains resulted in a reversal of subfamily specificity. Our observations are consistent with the notion that both the N-terminal and the C-terminal recognition domains are required to sustain the subfamily-specific assembly of rat Eag1 and human Erg.
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http://dx.doi.org/10.1074/jbc.M114.574814DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4132786PMC
August 2014

Feruloyl-L-arabinose attenuates migration, invasion and production of reactive oxygen species in H1299 lung cancer cells.

Food Chem Toxicol 2013 Aug 22;58:459-66. Epub 2013 May 22.

Department of Food Nutrition, Chung-Hwa University of Medical Technology, Tainan 701, Taiwan.

Ferulic acid (FA), a phenolic compound, is an abundant dietary antioxidant and exerts the mitogenic effect on cells. Recently, we isolated an active FA derivative, namely feruloyl-L-arabinose (FAA), from coba husk. The aim of this study was to investigate the effects of FAA on the proliferation, migration and invasion of H1299 human lung cancer cells. Our results showed a strong antioxidant potential of FAA. Additionally, FAA inhibited the migration and invasion ability, while causing a significant accumulation of G2/M-population, of H1299 tumor cells in a dose-dependent manner, whereas no significant change on cell proliferation was observed. Results from the wound healing assay revealed that cell migration ability was markedly inhibited by FAA treatments. Similarly, results of gelatin zymography study showed that FAA treatments significantly decreased the activities of matrix metalloproteinase (MMP)-2 and MMP-9, suggesting that FAA-mediated inhibition on migration and invasion of lung cancer cells may be achieved by the down-regulation of the MMPs activities. Taken together, our present work provides a new insight into the novel inhibitory function of FAA on cell migration in H1299 cells, suggesting its promising role in the chemoprevention of lung cancer.
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http://dx.doi.org/10.1016/j.fct.2013.05.019DOI Listing
August 2013

Immunomodulatory effects of feruloylated oligosaccharides from rice bran.

Food Chem 2012 Sep 7;134(2):836-40. Epub 2012 Mar 7.

Department of Food Nutrition, Chung Hwa University of Medical Technology, Tainan 71703, Taiwan.

Feruloylated oligosaccharides (FOs), the ferulic acid ester of oligosaccharides, can be released either by the enzymatic or mild acid hydrolysis of arabinoxylans present in cereal bran, and are usually considered as natural antioxidants. However, no related research is available to explain their immunomodulatory effects. This report elucidated their immunomodulatory effects through the variations of pro-inflammatory mediators in vitro. FOs were obtained from the mild acid hydrolysis of rice bran. We found that FOs (0.1-100 μg/ml) induced tumour necrosis factor alpha (TNF-α), IL-1β, IL-6, nitric oxide (NO) and PGE(2) production in unstimulated macrophages, RAW264.7 cells. Furthermore, pre- and post-treated FOs (0.1-100 μg/ml) dose-dependently suppressed TNF-α, IL-1β, IL-6 and NO production, and induced IL-10 production in lipopolysaccharide (LPS)-stimulated RAW264.7 cells without exerting cytotoxicity. As a result anti-inflammatory and therapeutic activities were revealed. It is noteworthy that prostaglandin E(2) (PGE(2)) production was significantly suppressed at an FO level of 100 μg/ml. The in vitro assessment of inflammatory mediators should be useful in further characterising the effects of FOs on immunomodulation. Moreover, it will create the economical value of rice bran, which has long been considered as conventional agricultural wastes.
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http://dx.doi.org/10.1016/j.foodchem.2012.02.190DOI Listing
September 2012

Khat (Catha edulis) alters the phenotype and anti-microbial activity of peripheral blood mononuclear cells.

J Ethnopharmacol 2011 Dec 28;138(3):780-7. Epub 2011 Oct 28.

Academic Unit of Oral & Maxillofacial Medicine & Surgery, School of Clinical Dentistry, University of Sheffield, Sheffield, UK.

Aims Of Study: The habit of khat chewing has been associated with increased risk of systemic and oral disease. Although research has been conducted on the affects of khat on oral epithelial cells, little is known about its influence on immune cells. This study examined the biological effects of khat on the phenotype and function of peripheral blood mononuclear cells (PBMCs).

Material And Methods: Khat-stimulated PBMCs were examined for signs of cytotoxicity, apoptosis and changes in cell surface receptor and cytokine expression. Khat-induced regulation of transcription factors and stress-related factors were examined, as was PBMC phagocytic activity against oral bacteria.

Results: Khat was cytotoxic to PBMC in a dose- and time-dependent manner and cell death was mediated by apoptosis. Khat-treated PBMC showed increased expression of co-stimulatory molecules (CD80, CD86 and MHC II) and pattern recognition receptors (TLR-2, TLR-4 and TREM-1) but secretion of inflammatory cytokines (TNFα, IL-6, CCL5, CXCL8) was inhibited. In contrast, khat induced an increase in the anti-inflammatory cytokine IL-10 as well as IL-2, IFN-γ, FasL and HSP70. These khat-induced alterations were accompanied by increased expression of transcription factors p38 MAPK and HIF-1α, whilst expression of NFκB p65 was inhibited. Although the ability of PBMC to phagocytose dextran and oral bacteria was inhibited, production of reactive oxygen species was increased.

Conclusion: These data suggest that khat may severely influence the effectiveness of immune surveillance and anti-microbial capacity of PBMCs.
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http://dx.doi.org/10.1016/j.jep.2011.10.030DOI Listing
December 2011

Use of macrophages to target therapeutic adenovirus to human prostate tumors.

Cancer Res 2011 Mar 13;71(5):1805-15. Epub 2011 Jan 13.

Department of Infection & Immunity, University of Sheffield, Sheffield, United Kingdom.

New therapies are required to target hypoxic areas of tumors as these sites are highly resistant to conventional cancer therapies. Monocytes continuously extravasate from the bloodstream into tumors where they differentiate into macrophages and accumulate in hypoxic areas, thereby opening up the possibility of using these cells as vehicles to deliver gene therapy to these otherwise inaccessible sites. We describe a new cell-based method that selectively targets an oncolytic adenovirus to hypoxic areas of prostate tumors. In this approach, macrophages were cotransduced with a hypoxia-regulated E1A/B construct and an E1A-dependent oncolytic adenovirus, whose proliferation is restricted to prostate tumor cells using prostate-specific promoter elements from the TARP, PSA, and PMSA genes. When such cotransduced cells reach an area of extreme hypoxia, the E1A/B proteins are expressed, thereby activating replication of the adenovirus. The virus is subsequently released by the host macrophage and infects neighboring tumor cells. Following systemic injection into mice bearing subcutaneous or orthotopic prostate tumors, cotransduced macrophages migrated into hypoxic tumor areas, upregulated E1A protein, and released multiple copies of adenovirus. The virus then infected neighboring cells but only proliferated and was cytotoxic in prostate tumor cells, resulting in the marked inhibition of tumor growth and reduction of pulmonary metastases. This novel delivery system employs 3 levels of tumor specificity: the natural "homing" of macrophages to hypoxic tumor areas, hypoxia-induced proliferation of the therapeutic adenovirus in host macrophages, and targeted replication of oncolytic virus in prostate tumor cells.
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http://dx.doi.org/10.1158/0008-5472.CAN-10-2349DOI Listing
March 2011

Cell Autonomous and Non-Autonomous Functions of IKKβ and NF-κB during the Pathogenesis of Gastrointestinal Tumors.

Cancers (Basel) 2011 Apr 28;3(2):2214-22. Epub 2011 Apr 28.

Institute of Molecular Immunology, Klinikum rechts der Isar, Technical University Munich, Ismaninger Str. 22, Munich 81675, Germany.

Genetic studies describing a link between cancer and inflammation have increased recently. Activation of the transcription factor nuclear factor-κB (NF-κB) and its effector pathways has been proposed to be the missing link between these two processes. NF-κB is persistently activated in several types of tumors. However, NF-κB has a distinct role in cancer cells and in inflammatory cells. While in tumor cells NF-κB controls cell survival, in inflammatory cells NF-κB activates genes that encode pro-inflammatory cytokines which further act in a paracrine manner within the tumor microenvironment to contribute to tumorigenesis. Inactivation of NF-κB can also reduce chemoresistance and radioresistance of cancer cells. Therefore, specific NF-κB inhibition in combination with cytotoxic drugs and/or irradiation represents a very promising strategy for cancer therapy.
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http://dx.doi.org/10.3390/cancers3022214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3757413PMC
April 2011

Hypoxia-inducible factors 1 and 2 are important transcriptional effectors in primary macrophages experiencing hypoxia.

Blood 2009 Jul 19;114(4):844-59. Epub 2009 May 19.

Academic Unit of Inflammation and Tumour Targeting, Faculty of Medicine, Dentistry and Health,University of Sheffield, Beech Hill Road, Sheffield, United Kingdom.

Ischemia exists in many diseased tissues, including arthritic joints, atherosclerotic plaques, and malignant tumors. Macrophages accumulate in these sites and up-regulate hypoxia-inducible transcription factors (HIFs) 1 and 2 in response to the hypoxia present. Here we show that the gene expression profile in primary human and murine macrophages changes markedly when they are exposed to hypoxia for 18 hours. For example, they were seen to up-regulate the cell surface receptors, CXCR4 and GLUT1, and the potent, tumor-promoting cytokines, vascular endothelial growth factor A, interleukin (IL)-1beta and IL-8, adrenomedullin, CXCR4, and angiopoietin-2. Hypoxia also stimulated their expression and/or phosphorylation of various proteins in the nuclear factor-kappaB (NF-kappaB) signaling pathway. We then used both genetic and pharmacologic methods to manipulate the levels of HIFs-1alpha and 2alpha or NF-kappaB in primary macrophages to elucidate their role in the hypoxic induction of many of these key genes. These studies showed that both HIF-1 and -2, but not NF-kappaB, are important transcriptional effectors regulating the responses of macrophages to such a period of hypoxia. Further studies using experimental mouse models are now warranted to investigate the role of such macrophage responses in the progression of various diseased tissues, such as malignant tumors.
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http://dx.doi.org/10.1182/blood-2008-12-195941DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2882173PMC
July 2009

Evaluation of erythemal UV effective irradiance from UV lamp exposure and the application in shield metal arc welding processing.

Health Phys 2008 Apr;94(4):318-27

Institute of Occupational Safety and Health, Council of Labor Affairs, Executive Yuan, Taipei, Taiwan.

Ultraviolet radiation (UVR) exposure is known to cause potential effects such as erythema in skin. For UV-induced erythema (sunburn), the action spectrum from the Commission Internationale de l'Eclairage, International Commission on Illumination (CIE) was adopted. Erythemal UV effects from UVR lamp exposure were investigated with commercial spectroradiometry devices in this research. Three kinds of portable UV germicidal lamps with broadband UVA (BB UVA, 350-400 nm), broadband UVB (BB UVB, 280-350 nm), and narrowband UVC (NB UVC, 254 nm) wavelengths served as the UVR emission sources. An action spectrum expresses the effectiveness of radiation for assessing the hazard of UVR in the erythemal action spectrum from 250-400 nm. The UV Index (UVI) is an irradiance scale computed by multiplying the CIE erythemal irradiance integral in milliwatts per square meter by 0.04 m mW. A comprehensive approach to detecting erythemal UVR magnitude was developed to monitor the effective exposure from UV lamps. The erythemal UVR measurement was established and the exposure assessment was applied to monitor erythemal UVR magnitude from shield metal arc welding (SMAW) processing. From this study, the erythemal UVR exposures were assessed and evaluated with environmental solar simulation of the UVI exposure.
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http://dx.doi.org/10.1097/01.HP.0000296281.04496.79DOI Listing
April 2008