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Nontuberculous mycobacterial lung disease (NTM-LD) prevalence has been increasing over the recent decades. Numerous host factors are associated with NTM-LD development, including susceptible phenotypes such as ciliary defect and lung structural change, pulmonary clearance defect with poor clearance of secretions, and immune suppression. Specifically, regarding the susceptible host phenotypes without clear pathogenesis, a slender body, pectus excavatum, and postmenopausal female status are common. Also, decreased host immunity to NTM, especially T helper 1 cell responses is frequently observed. Even so, the underlying mechanisms remain unclear and relevant large-scale studies are lacking. Infections due to host genetics associated defects are mostly untreatable but rare in Asia, particularly Taiwan. Nevertheless, some risks for NTM-LD are controllable over disease progression. We suggest that clinicians first manage host factors and deal with the controllable characteristics of NTM-LD, followed by optimizing anti-NTM treatment. Further researches focusing on NTM-LD pathogenesis, especially the host-NTM interaction may advance understanding the nature of the disease and develop efficient therapeutic regimens. [ABSTRACT FROM AUTHOR]

Background Mycobacterium avium complex (MAC)-lung disease (LD) is increasing in patients without human immunodeficiency virus infection. However, data on host vulnerability to MAC-related immune responses, and in particular the interleukin (IL)-23/IL-17 axis, are lacking. Methods We enrolled 50 patients with MAC-LD, 25 age-matched patients with tuberculosis (TB) and 25 controls. We measured levels of plasma cytokines, and studied IL-12/IL-17 responses in macrophage and lymphocyte activation to MAC. Results The plasma level of IL-17 in the MAC group was higher than in the TB and control groups. In in-vitro macrophage stimulation, the expression of IL-23 in macrophages was similar in the patients with MAC-LD and controls, although the expression of IL-12 p40 was lower in the patients with MAC-LD. In assays of lymphocyte activation, IL-17 was induced by MAC-primed macrophages, but its level was lower in the patients with MAC-LD and TB than in the controls. The expression of programmed death (PD)-1 receptor was higher in CD4 + IL17A + lymphocytes in the patients with MAC-LD, and the production of IL-17 was significantly increased by blockade of PD-1 and PD-ligand 1. Conclusions MAC induced a similar expression of IL-23 from macrophages in the patients with MAC-LD compared to the controls, but a lower expression of IL-17 from lymphocytes, which may be through an increased expression of PD-1. The macrophage response of IL-12 p40 was stronger than that of IL-12 p70, and higher in the controls during MAC disease, which may suggest another kind of MAC-related immune evasion. [ABSTRACT FROM AUTHOR]

Docetaxel is widely used in the treatment of non-small cell lung cancer. Fungal immunomodulatory proteins of Flammulina velutipes (FIP- fve ) and Ganoderma tsugae (FIP- gts ) possess immunomodulatory and anti-cancer effects. The abilities of FIP- fve and FIP- gts to protect against docetaxel-induced adverse effects were investigated. FIP- gts , but not FIP- fve , reversed docetaxel-induced decrease in white blood cells (WBCs). On haematoxylin and eosin (H & E), FIP- fve and FIP- gts reduced docetaxel-induced empty vacuoles in bone marrow and damage to small intestinal mucosa. On 3D micro-CT analysis, FIP- fve and FIP- gts significantly reversed docetaxel-induced decreases in percent bone volume (BV/TV), trabecular number (Tb.N) and bone surface density (BS/TV) in mice. Moreover, monocyte chemoattractant protein-1 (MCP-1) production and mRNA expressions induced by docetaxel in A549 cells were diminished by FIP- fve and FIP- gts . Thus, FIP- fve and FIP- gts have the potential to mitigate docetaxel-induced adverse effects in patients undergoing chemotherapy and to serve as novel therapeutic protective agents. [ABSTRACT FROM AUTHOR]

Abstract: Ultrasound sonication with microbubbles (MBs) has the potential to enhance the delivery of nanoparticles into the sonicated tumors. In this study, we investigated the feasibility of focused ultrasound (FUS) sonication with MBs to improve nanodrug delivery and tumor treatment. Tumor-bearing mice were first injected with MBs (SonoVue) intravenously, were then sonicated at the tumors with FUS sonication, and were finally injected with the PEGylated liposomal doxorubicin (DOX). The accumulation of DOX in tumors with time, the tumor growth responses for initial treated tumor size and DOX dosage, and the response for an additional sonication after DOX injection were studied. The results demonstrate that FUS sonication with MBs can significantly enhance DOX accumulation in the sonicated tumor at 24 hours after treatment. A significant hindrance to tumor growth is achieved for a small tumor with a low dose, whereas large tumors require a higher dose. From the Clinical Editor: In this novel research study, focused ultrasound created microbubbles were utilized to enhance the delivery of PEGylated liposomal doxorubicin in a murine tumor model, demonstrating superior drug delivery compared to other methods. Focused ultrasound-based techniques are increasingly studied in cancer research, and this new observation will likely lead to additional investigations of different tumor lines, penetration depths and delivery vehicles. [Copyright &y& Elsevier]

Purpose: Pretreatment with 2- [18F] fluorodeoxyglucose positron emission tomography (18F-FDG-PET) was evaluated as a predictor of local failure-free survival (LFFS), disease-free survival (DFS), and overall survival (OS) in patients with nonkeratinizing nasopharyngeal carcinoma (NPC) treated with intensity-modulated radiation therapy (IMRT) alone or concurrently with chemotherapy (CCRT). Patients and Methods: Seventy-five M0 NPC patients who received FDG-PET before treatment were analyzed. The primary tumor FDG uptake was measured as the maximum standardized uptake value (SUVmax). The LFFS, DFS, and OS were calculated by the Kaplan-Meier method, and the differences were evaluated on log-rank test. The prognostic significance was assessed by univariate and multivariate analyses. Results: Eighteen patients received IMRT alone and 57 received CCRT. The mean SUVmax was significantly higher in 12 patients with locoregional or distant failure than in those without failure (p <0.001). On multivariate analysis, the SUVmax was the only significant variable for 5-year LFFS (p = 0.017) and DFS (p = 0.000) but not for OS (p = 0.065). Conclusion: SUVmax is a potential independent prognostic predictor of clinical outcomes in patients with nasopharyngeal carcinoma treated with IMRT alone or with CCRT. A high 18F-FDG uptake (SUVmax >5) indicates poor outcome in patients with NPC. [ABSTRACT FROM AUTHOR]

Abstract: The correlation between cooking oil fumes, containing relatively higher amounts of heterocyclic amines, and female lung cancer has been revealed. The association of genetic polymorphisms of CYP1A2 and NAT2, two major enzymes responsible for the metabolism of heterocyclic amines, with lung cancer has been investigated with inconclusive results. In this study targeted on never-smoking population with 162 lung cancer patients and 208 non-cancer controls, while the distributions of CYP1A2 phenotypes in lung cancer patients were comparable to that in controls, NAT2 fast acetylators had an OR of 2.44 (95% CI 1.40–4.23, P=0.002) and 2.56 (95% CI 1.37–4.80, P=0.003) for lung cancer in overall and female cases, respectively, but not in males. These results suggested never-smoking females with NAT2 fast acetylator were more prone to lung cancer and reflected the possibility that exposure to heterocyclic amines may contribute to the female lung cancer development in Taiwan. [Copyright &y& Elsevier]

Aryl hydrocarbon receptor (AhR)-regulated cytochrome P4501A1 (CYP1A1) and P4501B1 (CYP1B1) have been shown to metabolically activate some carcinogens. In the present study, we utilized the real-time reverse transcription-polymerase chain reaction (RT-PCR) assay to compare AhR, CYP1A1 and CYP1B1 mRNA levels in peripheral leukocytes from 42 lung cancer patients and 59 non-cancer subjects. We found that CYP1A1 and CYP1B1 levels, but not AhR, were significantly higher in patients than in non-cancer subjects. After stratified by gender, CYP1A1 levels were significantly higher in female patients than in female controls. After controlling for age, smoking status and gender, lung cancer patients were more likely to be CYP1B1 high expressers (P<0.05). Neither AhR nor CYP1A1 levels was associated with lung cancer incidence. Leu–Val polymorphism of CYP1B1 was not associated with lung cancer risk in our study. These data indicated that CYP1B1 mRNA levels were elevated in peripheral leukocytes of lung cancer patients. [Copyright &y& Elsevier]

Background: Chronic obstructive pulmonary disease (COPD) is one of the leading causes of death in the world. Not much is known regarding the influence of non-smoking-related risk factors on COPD in Taiwan. We examined the relationship between exposure to particulate matter <2.5 μm (PM2.5) and COPD among nonsmokers in Taiwan.Methods: This population-based study involved 3941 nonsmoking Taiwanese adults who were recruited in the Taiwan Biobank project between 2008 and 2015. Air pollution data between 2006 and 2011 were obtained from the air quality monitoring database (AQMD). COPD was the outcome of interest and was identified using the National health insurance Research Database (NHIRD). The data were analyzed using multiple logistic regression models.Results: Compared with the lowest quartile (PM2.5 = 29.38), exposure to PM2.5 in the highest quartile (>38.98 μg/m3) was significantly associated with COPD (OR, 1.29; CI 1.01-1.65) after multivariate adjustments. However, exposures to concentrations of 32.07-38.98 μg/m3 (OR, 1.12 CI 0.88-1.44) and 29.38-32.07 μg/m3 (OR, 1.09 CI 0.84-1.41) showed positive but non-significant associations. However, the test for trend was significant (Ptrend = 0.043). The ORs for exposure to sulfur dioxide (SO2), ozone (O3), carbon monoxide (CO) and NOx (nitrogen monoxide (NO were not significant.Conclusions: Based on our data, exposure to PM2.5 at concentrations greater than 38.98 μg/m3 increased susceptibility to COPD among Taiwanese nonsmokers. Combatting COPD would involve integrating tobacco control and pollution management strategies. [ABSTRACT FROM AUTHOR]

Abstract: Ultrasound (US) has recently been used to reduce localized adiposity in humans. The study described here evaluated the combined use of chitosan, which is used to treat hyperlipidemic diseases and fatty liver, and US to control weight and local fat deposition in normal mice over a 5-wk experimental period. Female ICR mice were randomly divided into four groups (n = 5 animals per group): (1) control, (2) US only, (3) chitosan only and (4) chitosan + US. Body weight, epididymal fat pad and intra-abdominal fat thickness (via US imaging) and plasma concentrations of high-density lipoprotein cholesterol, triglycerides and low-density lipoprotein cholesterol were measured in all mice before and after the 5-wk treatment period. After the 5-wk treatment period, weight had decreased significantly in the chitosan + US group (−11.2%) compared with the US only (−5.8%) and chitosan only (−9.3%) groups (p < 0.05). The reduction in epididymal fat pad thickness was significantly more marked in the chitosan + US group (28.2%) than in the other groups (p < 0.05). Furthermore, in the chitosan + US group, plasma levels of triglycerides and low-density lipoprotein cholesterol significantly decreased by 51.5% and 26%, respectively. This is the first report of effective control of weight and local fat by a combination of ultrasound and a putative fat-reducing dietary supplement in mice. The described method significantly decreases local fat pad deposition, weight and plasma lipid levels. [Copyright &y& Elsevier]

Abstract: High telomerase activity (TA) is detected in most cancer cells; and thus, TA inhibition by drug or dietary food components is a new strategy for cancer prevention. In this report, we examined the effects of fourteen natural or synthetic compounds on TA in human lung adenocarcinoma A549 cells. The results demonstrated that some of the tested compounds inhibited TA, being 2′-hydroxy-2,3,4′,6′-tetramethoxychalcone (HTMC) was the most potent among tested. In A549 cells, HTMC also inhibited the cell proliferation, decreased the expression of human telomerase reverse transcriptase (hTERT) and sequentially reduced the hTERT promoter. In soft agar assay HTMC treatment reduced the colony formation of A549 cells. Cellular fractionation and immunofluorescence assay demonstrated that there was no translocation of hTERT from nuclei to cytoplasm. Further studies revealed that the release of Ca2+ was the underlying mechanism of suppressed TA and hTERT transcription in A549 cells exposed to HTMC. These in vitro data support the development of HTMC as a therapeutic agent for cancer complications. [ABSTRACT FROM AUTHOR]

Benzo[a]pyrene (B[a]P) is a potent lung carcinogen derived from tobacco smoking and environmental contamination. This study aimed to investigate the signal transduction pathway responsible for B[a]P-induced non-small cell lung cancer (NSCLC) development. We exposed the human NSCLC cell lines Calu-1, CL3, H1299, CH27, H23, and H1355 to B[a]P and assessed cell cycle progression using flow cytometry. Expression of cell cycle mediators was measured using Western blot analyses and electrophoretic mobility shift assays (EMSAs). B[a]P exposure dramatically induced S-phase accumulation in H1355 cells. Phospho-p53 (Ser15 and Ser20), phospho-ERK, phospho-p38, and Bax were significantly increased in H1355 cells whereas phospho-Rb was decreased in these cells. In addition, B[a]P induced phosphorylation of checkpoint kinase-1 (Chk1) but not Chk2. EMSA experiments revealed a slower migrating band after c-Myc bound the E-box in response to B[a]P treatment, which was abolished upon the addition of the ERK inhibitor PD98059 in H1355 cells. Phospho-ERK inhibition and dominant negative mutant Chk1 expression reversed B[a]P-induced S phase accumulation and downregulated phospho-Chk1 and phospho-ERK expression. Taken together, these results suggest that activation of ERK and its downstream mediator Chk1 may contribute to B[a]P-induced S phase accumulation in H1355 cells. The results could help in the development of lung cancer treatments that target the Chk1 pathway through ERK. [ABSTRACT FROM AUTHOR]

Abstract: Objective: In this study, albumin-shelled, targeted MBs (tMBs) were first demonstrated with the expectation of visualization of biodistribution of albumin-shelled tMBs. The actual biodistribution of albumin-shelled tMBs is of vital importance either for molecular imaging or for drug delivery. Motivation: Recently, albumin microbubbles (MBs) have been studied for drug and gene delivery in vitro and in vivo through cavitation. Targeted lipid-shelled MBs have been applied for ultrasound molecular imaging and conjugated with radiolabeled antibodies for whole-body biodistribution evaluations. The novelty of the work is that, in addition to the lipid tMBs, the albumin tMBs was also applied in biodistribution detection. Methods: Multimodality albumin-shelled, 18F-SFB-labeled VEGFR2 tMBs were synthesized, and their characteristics in mice bearing MDA-MB-231 human breast cancer were investigated with micro-positron-emission tomography (microPET) and high-frequency ultrasound (microUS). Results: Albumin-shelled MBs can be labeled with 18F-SFB directly and conjugated with antibodies for dual molecular imaging. The albumin-shelled tMBs show a lifetime in 30min in the blood pool and a highly specific adherence to tumor vessels in mice bearing human breast cancer. Conclusions: From the evaluations of whole-body biodistribution, the potential of the dual molecular imaging probe for drug or gene delivery in animal experiments with albumin shelled MBs has been investigated. [Copyright &y& Elsevier]

Abstract: The application of drug-loaded microbubbles (MBs) in combination with ultrasound (US), which results in an increase in capillary permeability at the site of US-sonication-induced MB destruction, may be an efficient method of localized drug delivery. This study investigated the mechanism underlying the US-mediated release of luciferin-loaded MBs through the blood vessels to targeted cells using an in vivo bioluminescence imaging (BLI) system. The luciferin-loaded MBs comprised an albumin shell with a diameter of 1234 ± 394 nm (mean ± SD) and contained 2.48 × 109 bubbles/mL; within each MB, the concentration of encapsulated luciferin was 1.48 × 10−10 mg/bubble. The loading efficiency of luciferin in MBs was only about 19.8%, while maintaining both the bioluminescence and acoustic properties. In vitro and in vivo BLI experiments were performed to evaluate the US-mediated release of luciferin-loaded MBs. For in vitro results, the increase in light emission of luciferin-loaded albumin-shelled MBs after destruction via US sonication (6.24 ± 0.72 × 107 photons/s) was significantly higher than that in the luciferin-loaded albumin-shelled MBs (3.11 ± 0.33 × 107 photons/s) (p < 0.05). The efficiency of the US-mediated release of luciferin-loaded MBs in 4T1-luc2 tumor-bearing mice was also estimated. The signal intensity of the tumor with US destruction at 3 W/cm2 for 30 s was significantly higher than without US destruction at 3 (p = 0.025), 5 (p = 0.013), 7 (p = 0.012) and 10 (p = 0.032) min after injecting luciferin-loaded albumin-shelled MBs. The delivery efficiency was, thus, improved with US-mediated release, allowing reduction of the total injection dose of luciferin. [Copyright &y& Elsevier]

Abstract: The p53 tumor suppressor protein is involved in cellular defense against agents that can cause genetic damage. Induction of p53 gene expression at transcriptional and post-transcriptional levels by such agents results in p53-regulated gene activation or suppression. Docetaxel (DOC), a member of the taxanes family that is widely used in cancer chemotherapy, activates p53 at the transcriptional level. We demonstrated that p53 is induced by low dose DOC treatment, resulting in MDR-1 gene suppression in human lung cancer cells. To identify the cis-element of p53 promoter that responds to DOC, p53 promoter region was cloned and promoter activity was analyzed on luciferase gene reporter assay. Promoter region (−78 to +129) contained the highest basal p53 promoter activity and deletion of +86 to +129 severely reduced basal promoter activity. Basal promoter region included the 21-bp element (PE21) that determines UV-inducible expression of p53 and mediates DOC-inducible p53 expression. On site-specific mutagenesis of PE21 (−78 to −58), with mutation of ATTG (−62 to −59) to CGGT, completely diminished the response to DOC. The same mutations also inhibited 5-fluorouracil (5-FU)-inducible p53 expression. Our data revealed that a sequence located at PE21 of p53 core promoter regulates p53 induction by chemotherapeutic agents. [Copyright &y& Elsevier]

Abstract: Recombinant fungal immunomodulatory protein, reFIP-gts, was cloned from Ganoderma tsugae and purified. In our previous study, it was shown that reFIP-gts has anti-telomerase effects in A549 cells. Here, we proved that reFIP-gts entry into the cell and localization in endoplasmic reticulum can result in ER stress, thereby increasing ER stress markers (CHOP/GADD153) and intracellular calcium release in A549 cells. The use of calcium chelator restores reFIP-gts-mediated reduction in telomerase activity. These results strongly suggest that ER stress induces intracellular calcium release and results in inhibition of telomerase activity. Although reFIP-gts decreased hTERT mRNA level in both A549 and H1299 cells, only the telomerase activity in A549 cells was inhibited. Surprisingly, we found that reFIP-gts induces translocation of hTERT from the nucleus into the cytosol in A549 cells but not in H1299 cells. Using leptomycin B, nuclear export inhibitor, we showed that hTERT is not transported. Using MG132, a proteasome inhibitor, reFIP-gts also prevents hTERT translocation from proteasome degradation. Taken together, these results indicate that reFIP-gts inhibits telomerase activity in lung cancer cells through nuclear export mechanisms, which might be mediated by ER stress-induced intracellular calcium level. [Copyright &y& Elsevier]

Context: Undertreatment of cancer pain among outpatient cancer patients needs to be addressed to enhance care and improve patients' quality of life (QoL).Objectives: This prospective, cross-sectional, patient-focused study aimed to explore the prevalence of pain and undertreatment of cancer pain in outpatients in Taiwan.Methods: A total of 2652 non-selected outpatients with cancer and aged 20 years or older from 16 medical centers across Taiwan were included in this survey. All patients completed a questionnaire based on the Brief Pain Inventory. Pain management index (PMI) was used to evaluate the adequacy of pain management. Possible clinical variables of patients with positive PMI were examined by univariate and multivariate logistic regressions.Results: A total of 1659 (62.6%) outpatients had experienced some degree of pain; among these, 32.4% had negative PMI. Patients with a negative PMI score had significantly poor outcomes of QoL and a significantly higher tendency toward dissatisfaction with pain control by the physician and with the prescribed analgesic drugs. Female gender, primary tumor from breast, non-cancer-related cause of pain, and hospital locations from north Taiwan were independent variables that predicated patients with undertreatment of cancer pain. Most importantly, a forward trend of undertreatment of pain among patients who presented with lower prevalent rate of pain was observed.Conclusion: One-third of Taiwanese outpatients experienced pain because of undertreatment. Awareness of the prevalence of undertreatment of cancer pain and identification of the vulnerable subjects may assist in enhancing patient care and improving patient's QoL. [ABSTRACT FROM AUTHOR]