Inhalation toxicity of polyhexamethylene guanidine-phosphate in rats: A 4-week inhalation exposure and 24-week recovery period study.

Humidifier disinfectant (HD) is a causative agent of atypical lung injury reported in 2011 in South Korea, and various diseases caused by HD after exposure cessation have been reported to date. However, there is limited research on most of the reported diseases in terms of their association with HD exposure, and information on the progression of diseases caused by HD exposure is also limited. Therefore, we investigated the effects of HD inhalation on the body in rats. Rats were exposed to 0.15, 0.50, and 1.60 mg/m3 polyhexamethylene guanidine-phosphate (PHMG-p), which is the major component of HDs and most closely related to HD-associated lung injury. We conducted necropsy four times during the recovery period (0, 4, 12, and 24 weeks) and evaluated general systemic toxicities. There were significant changes in the mortality rate, body weight, and food consumption in the PHMG-p-exposed groups. Hematology revealed changes in hemoglobin level, hematocrit, red blood cell, reticulocyte, and white blood cell counts until 12 weeks of the recovery period. PHMG-p induced a delay in prothrombin time until 12 weeks of the recovery period. The aspartate aminotransferase, alanine aminotransferase, total bilirubin, and triglyceride levels were higher in the PHMG-p-exposed groups than in the control group at week 4 of the recovery period, and these parameters normalized after 12 weeks of the recovery period. Histopathological examination in PHMG-p exposed groups revealed several changes in the lungs, including the presence of alveolar macrophages, chronic inflammation, squamous metaplasia, alveolar emphysema, and pulmonary fibrosis. The severity of these symptoms was maintained or exacerbated till 24 weeks. Overall, PHMG-p inhalation can induce irreversible histological changes in the lungs and cause various types of damage throughout the body, even after exposure ends.

Wavelet subband-specific learning for low-dose computed tomography denoising.

Deep neural networks have shown great improvements in low-dose computed tomography (CT) denoising. Early algorithms were primarily optimized to obtain an accurate image with low distortion between the denoised image and reference full-dose image at the cost of yielding an overly smoothed unrealistic CT image. Recent research has sought to preserve the fine details of denoised images with high perceptual quality, which has been accompanied by a decrease in objective quality due to a trade-off between perceptual quality and distortion. We pursue a network that can generate accurate and realistic CT images with high objective and perceptual quality within one network, achieving a better perception-distortion trade-off. To achieve this goal, we propose a stationary wavelet transform-assisted network employing the characteristics of high- and low-frequency domains of the wavelet transform and frequency subband-specific losses defined in the wavelet domain. We first introduce a stationary wavelet transform for the network training procedure. Then, we train the network using objective loss functions defined for high- and low-frequency domains to enhance the objective quality of the denoised CT image. With this network design, we train the network again after replacing the objective loss functions with perceptual loss functions in high- and low-frequency domains. As a result, we acquired denoised CT images with high perceptual quality using this strategy while minimizing the objective quality loss. We evaluated our algorithms on the phantom and clinical images, and the quantitative and qualitative results indicate that ours outperform the existing state-of-the-art algorithms in terms of objective and perceptual quality.

The influence of socialization agents on consumer responses to over-the-counter medicine advertising.

BACKGROUND: Despite the prevalence of over-the-counter medicine advertising (OTCA) in electronic and print media, scholarly focus has tended to concentrate on direct-to-consumer prescription medicine advertising (DTCA). OBJECTIVES: The purpose of this study is to examine the mechanisms through which attitudes toward OTCA in general and OTCA prompted behaviors are formed based on a consumer socialization framework. METHODS: An online survey was conducted as part of a larger medicine and pharmaceutical advertising project using the Qualtrics online panel. A total of 819 individuals who had taken a prescription medicine in the last six months participated in the survey and yielded 539 completed questionnaires (Completion rate: 65.8%). Of those, 304 responses from U.S. adults who had taken an OTC medicine and had seen an advertisement for OTC medicines in the past six months were analyzed to test the proposed model. A series of structural equation modeling analyses of the survey data was performed. RESULTS: The study results showed that consumers' use of mass media and professional interpersonal channels directly influenced attitudes toward OTCA and OTCA prompted behaviors. On the other hand, consumers' use of non-professional interpersonal channels indirectly influenced OTCA outcomes through their use of mass media and professional interpersonal channels. Younger respondents were more likely to obtain OTC medicine information from non-professional interpersonal and mass media sources whereas older respondents were more likely to obtain OTC medicine information from physicians and pharmacists. CONCLUSIONS: Application of the consumer socialization framework in the context of OTCA provides expanded understanding of the mechanisms through which responses to OTCA are formed. The findings of this study provide implications for pharmaceutical marketers, health professionals, and consumers of OTC medicines.

Genomic Alterations in Biliary Tract Cancer Using Targeted Sequencing.

BACKGROUND: Biliary tract cancers (BTCs) are rare and heterogeneous group of tumors classified anatomically into intrahepatic and extrahepatic bile ducts and gallbladder adenocarcinomas. Patient-derived tumor cell (PDC) models with genome analysis can be a valuable platform to develop a method to overcome the clinical barrier on BTCs. MATERIAL AND METHODS: Between January 2012 and June 2015, 40 BTC patients' samples were collected. PDCs were isolated and cultured from surgical specimens, biopsy tissues, or malignant effusions including ascites and pleural fluid. Genome analysis using targeted panel sequencing as well as digital multiplexed gene analysis was applied to PDCs as well as primary tumors. RESULTS: Extrahepatic cholangiocarcinoma (N=15, 37.5%), intrahepatic cholangiocarcinoma (N=10, 25.0%), gallbladder cancer (N=14, 35.0%), and ampulla of Vater cancer (N=1, 2.5%) were included. We identified 15 mutations with diverse genetic alterations in 19 cases of BTC from primary tumor specimens. The most common molecular alterations were in TP53 (8/19, 42.1%), including missense mutations such as C242Y, E285K, G112S, P19T, R148T, R248Q, and R273L. We also detected two NRAS mutations (G12C and Q61L), two KRAS mutations (G12A and G12S), two ERBB2 mutations (V777L and pM774delinsMA) and amplification, and three PIK3CA mutations (N345K, E545K, and E521K). PDC models were successfully established in 27 of 40 samples (67.5%), including 22/24 from body fluids (91.7%) and 5/16 from tissue specimens (31.3%). CONCLUSIONS: PDC models are promising tools for uncovering driver mutations and identifying rational therapeutic strategies in BTC. Application of this model is expected to inform clinical trials of drugs for molecular-based targeted therapy.

Molecular characterization of colorectal cancer patients and concomitant patient-derived tumor cell establishment.

BACKGROUND: We aimed to establish a prospectively enrolled colorectal cancer (CRC) cohort for targeted sequencing of primary tumors from CRC patients. In parallel, we established collateral PDC models from the matched primary tumor tissues, which may be later used as preclinical models for genome-directed targeted therapy experiments. RESULTS: In all, we identified 27 SNVs in the 6 genes such as PIK3CA (N = 16), BRAF (N = 6), NRAS (N = 2), and CTNNB1 (N = 1), PTEN (N = 1), and ERBB2 (N = 1). RET-NCOA4 translocation was observed in one out of 105 patients (0.9%). PDC models were successfully established from 62 (55.4%) of the 112 samples. To confirm the genomic features of various tumor cells, we compared variant allele frequency results of the primary tumor and progeny PDCs. The Pearson correlation coefficient between the variants from primary tumor cells and PDCs was 0.881. METHODS: Between April 2014 and June 2015, 112 patients with CRC who underwent resection of the primary tumor were enrolled in the SMC Oncology Biomarker study. The PDC culture protocol was performed for all eligible patients. All of the primary tumors from the 112 patients who provided written informed consent were genomically sequenced with targeted sequencing. In parallel, PDC establishment was attempted for all sequenced tumors. CONCLUSIONS: We have prospectively sequenced a CRC cohort of 105 patients and successfully established 62 PDC in parallel. Each genomically characterized PDCs can be used as a preclinical model especially in rare genomic alteration event.

P21 and CD166 as predictive markers of poor response and outcome after fluorouracil-based chemoradiotherapy for the patients with rectal cancer.

BACKGROUND: Pre-operative chemoradiotherapy (CRT) is the standard treatment in clinical stage T3/4 or node positive rectal cancer. However, there are no established biomarkers that can predict the pathological response and clinical outcome to CRT. METHODS: Immunohistochemical staining was performed in tissue arrays constructed from core tissue specimens taken before treatment and from operative specimens from 112 patients who received 5-FU based pre-operative CRT and surgery. Expression of Ki67, TS, BAX, EpCAM, p53, p21, EGFR, CD44, CD133, CD166, HIF1α and ALDH1 were assessed and correlated with tumor regression grades and disease free survival. RESULTS: Of the 112 patients (M/F 74/38, median age: 62), 20 (17.9%) patients achieved pathologic complete remission (pCR). In analyzing the associations between marker expressions and tumor regression grades, high p21 expression at the pretreatment biopsy was significantly associated with non-pCR (p = 0.022) and poor disease free survival (median DFS - low vs high p21: 75.8 vs 58.1 months, p = 0.002). In the multivariate analysis, high p21 expression level at the pre-treatment biopsy was significantly associated with poor DFS (p = 0.001, HR 6.14; 95% CI 2.03, 18.55). High CD166 expression level at the pretreatment biopsy was also associated with poor DFS (p = 0.003; HR 5.61; 95% CI 1.81, 17.35). CONCLUSION: These show high p21 and CD166 expression at the pretreatment biopsy were associated with tumor regression and poor prognosis in patients treated with 5-FU based CRT. Larger, prospective and functional studies are warranted to determine the role of p21 and CD166 as predictive biomarker of response to CRT.

Innovation characteristics and intention to adopt sustainable facilities management practices.

Sustainable facilities management (SFM) is important because typical buildings consume more resources and energy than necessary, negatively impact the environment and generate lots of waste (US Department of Energy, 2003, Green Buildings). This study examined innovation characteristics that relate to facility managers' intention to adopt SFM practices. Based on the diffusion of innovations theory (Rogers 1962, 1995, Diffusion of Innovations. 4th ed. New York: The Free Press), an SFM innovation and adoption model was proposed. A survey was conducted with a convenience sample of 240 public facilities managers in 25 facilities management divisions in Seoul, Korea, and its metropolitan areas. Structural equation modelling was employed to analyse the data. The results showed that economic advantage and human comfort aspects are predictors for the intention of SFM adoption. Observability is positively relevant to the intention of SFM adoption. Complexity, however, is not a significant predictor for the intention of SFM adoption. Practical implications for sustainable products and systems and the built environment are suggested. PRACTITIONER SUMMARY: To incorporate an innovation like sustainable practices, it is required to meet the needs of potential adopters. Innovation characteristics that influence facility managers' intention to adopt sustainable facilities management were examined. A survey was conducted. Economic advantage, human comfort and observability are predictors for the intention of adoption of sustainable practice.

Substance P stimulates the recovery of bone marrow after the irradiation.

The therapeutic use of ionizing radiation (e.g., X-rays and γ-rays) needs to inflict minimal damage on non-target tissue. Recent studies have shown that substance P (SP) mediates multiple activities in various cell types, including cell proliferation, anti-apoptotic responses, and inflammatory processes. The present study investigated the effects of SP on γ-irradiated bone marrow stem cells (BMSCs). In mouse bone marrow extracts, SP prolonged activation of Erk1/2 and enhanced Bcl-2 expression, but attenuated the activation of apoptotic molecules (e.g., p38 and cleaved caspase-3) and down-regulated Bax. We also observed that SP-decreased apoptotic cell death and stimulated cell proliferation in γ-irradiated mouse bone marrow tissues through TUNEL assay and PCNA analysis. To determine how SP affects bone marrow stem cell populations, mouse bone marrow cells were isolated and colony-forming unit (CFU) of mesenchymal stem cells (MSCs) and hematopoietic stem cells (HSCs) was estimated. SP-pretreated ones showed higher CFUs of MSC and HSC than untreated ones. Furthermore, when SP was pretreated in cultured human MSC, it significantly decreased apoptotic cells at 48 and 72 h after γ-irradiation. Compared with untreated cells, SP-treated human MSCs showed reduced cleavage of apoptotic molecules such as caspase-8, -9, -3, and poly ADP-ribose polymerase (PARP). Thus, our results suggest that SP alleviates γ-radiation-induced damage to mouse BMSCs and human MSCs via regulation of the apoptotic pathway.

Substance P accelerates intestinal tissue regeneration after gamma-irradiation-induced damage.

Radiation therapy causes varying degrees of damage to biological systems. Many groups are investigating the mechanism underlying radiation-induced cellular damage but there are limited therapeutic solutions for affected patients. Recent studies show that substance P (SP) participates in cell proliferation. In the present study, we characterized the mechanism underlying SP-induced cellular signaling in radiation-induced damage of the intestine. Exposure of Caco-2 cells to SP increases cell proliferation and Erk phosphorylation in a time- and dose-dependent manner. The proliferation of cells exposed to gamma-irradiation is also stimulated by exposure to SP, a phenomenon that may result from inhibition of apoptosis because SP activates Akt and inhibits the cleavage of caspase-3. The effect of SP on cell proliferation and protection was confirmed by investigations in mice. Proliferating cell nuclear antigen staining shows that cell proliferation in radiation-damaged mouse intestine increases significantly upon exposure to SP. Furthermore, terminal deoxynucleotidyl transferase-mediated dUTP-fluorescein nick end labeling assay reveals fewer cells stained in SP-treated mice compared with untreated controls. These findings show the potential for SP-induced acceleration of intestinal wound healing and reveal that the mechanism underlying this process involves activation of Erk and Akt and inhibition of caspase-3 cleavage.