Longitudinal long term follow up investigation on the carcinogenic impact of polyhexamethylene guanidine phosphate in rat models.

Polyhexamethylene guanidine phosphate (PHMG-p) is a major component in humidifier disinfectants, which cause life-threatening lung injuries. However, to our knowledge, no published studies have investigated associations between PHMG-p dose and lung damage severity with long-term follow-up. Therefore, we evaluated longitudinal dose-dependent changes in lung injuries using repeated chest computed tomography (CT). Rats were exposed to low (0.2 mg/kg, n = 10), intermediate (1.0 mg/kg, n = 10), and high (5.0 mg/kg, n = 10) doses of PHMG-p. All rats underwent repeated CT scans after 10 and 40 weeks following the first exposure. All CT images were quantitatively analyzed using commercial software. Inflammation/fibrosis and tumor counts underwent histopathological evaluation. In both radiological and histopathologic results, the lung damage severity increased as the PHMG-p dose increased. Moreover, the number, size, and malignancy of the lung tumors increased as the dose increased. Bronchiolar-alveolar hyperplasia developed in all groups. During follow-up, there was intergroup variation in bronchiolar-alveolar hyperplasia progression, although bronchiolar-alveolar adenomas or carcinomas usually increase in size over time. Thirty-three carcinomas were detected in the high-dose group in two rats. Overall, lung damage from PHMG-p and the number and malignancy of lung tumors were shown to be dose-dependent in a rat model using repeated chest CT scans during a long-term follow-up.

Comprehensive feasibility evaluation of small-diameter 3D templated vascular graft via physical characterizations andin-vivoexperiments.

3D printing (3DP) technology for tissue engineering applications has been extensively studied for materials and processes. However, clinical application to the vascular system was limited owing to mechanical inconsistency and toxicity. Here, we characterized 3D templated artificial vascular grafts (3D grafts), which were fabricated by an integrative method involving 3DP, dip coating, and salt leaching method. The as-fabricated grafts were featured with micrometer-scale porosity enabling tissue-mimetic mechanical softness comparable with native blood vessels. In terms of mechanical properties and water permeability, the fabricated 3D grafts exhibited comparable or superior performances compared to the commercialized grafts. Furthermore, thein-vivostability of the 3D graft was validated through a toxicity test, and the small-diameter 3D graft was transplanted into a rat to confirm the implant's performance. Overall, the experimental results demonstrated the clinical feasibility of the 3D graft with retaining the mechanical biocompatibility and also revealed the possibility of patient-specific customization.

Particulate matter induces arrhythmia-like cardiotoxicity in zebrafish embryos by altering the expression levels of cardiac development- and ion channel-related genes.

Air pollution is a risk factor that increases cardiovascular morbidity and mortality. In this study, we investigated the cardiotoxicity of particulate matter (PM) exposure using a zebrafish embryo model. We found that PM exposure induced cardiotoxicity, such as arrhythmia, during cardiac development. PM exposure caused cardiotoxicity by altering the expression levels of cardiac development (T-box transcription factor 20, natriuretic peptide A, and GATA-binding protein 4)- and ion-channel (scn5lab, kcnq1, kcnh2a/b, and kcnh6a/b)-related genes. In conclusion, this study showed that PM induces the aberrant expression of cardiac development- and ion channel-related genes, leading to arrhythmia-like cardiotoxicity in zebrafish embryos. Our study provides a foundation for further research on the molecular and genetic mechanisms of cardiotoxicity induced by PM exposure.

Hematotoxic Effect of Respiratory Exposure to PHMG-p and Its Integrated Genetic Analysis.

Polyhexamethylene guanidine phosphate (PHMG-p), the main ingredient of humidifier disinfectants, circulates systemically through the lungs; however, its toxicological assessment has been primarily limited to pulmonary disease. Herein, we investigated the possible abnormalities in hematopoietic function 20 weeks after intratracheal instillation of PHMG-p in a rat model. Notable abnormalities were found out in the peripheral blood cell count and bone marrow (BM) biopsy, while RNA sequencing of BM tissue revealed markedly altered gene expression. Furthermore, signaling involved in hematopoietic dysfunction was predicted by analyzing candidate genes through Ingenuity Pathway Analysis (IPA) program. Respiratory PHMG-p exposure significantly decreased monocyte and platelet (PLT) counts and total protein, while significantly increasing hemoglobin and hematocrit levels in peripheral blood. Histopathological analysis of the BM revealed a reduced number of megakaryocytes, with no significant differences in spleen and liver weight to body weight. Moreover, PHMG-p exposure significantly activated estrogen receptor signaling and RHOA signaling, and inhibited RHOGDI signaling. In IPA analysis, candidate genes were found to be strongly related to 'hematological system development and function' and 'hematological disease.' Accordingly, our results suggest that PHMG-p could affect hematopoiesis, which participates in monocyte differentiation and PLT production, and may induce hematologic diseases via the respiratory tract.

Exposure to airborne particulate matter induces renal tubular cell injury in vitro: the role of vitamin D signaling and renin-angiotensin system.

Background: Exposure to air pollution can interfere with the vitamin D endocrine system. This study investigated the effects of airborne particulate matter (PM) on renal tubular cell injury in vitro and explored the underlying mechanisms. Methods: HK-2 human renal proximal tubule cells were treated with PM with or without 1,25(OH)2D3 analog, 19-Nor-1,25(OH)2D2 (paricalcitol, 10 nM) for 48 h. The dose- and time-dependent cytotoxicity of PM with or without paricalcitol was determined via cell counting kit-8 assay. Cellular oxidative stress was assessed using commercially available enzyme-linked immunosorbent assay kits. The protein expression of vitamin D receptor (VDR), cytochrome P450(CYP)27B1, CYP24A1, renin, angiotensin converting enzyme (ACE), angiotensin II type 1 receptor (AT1), nuclear factor erythroid 2-related factor 2 (Nrf2), nuclear factor-kB (NF-kB), tumor necrosis factor (TNF)-α, and interleukin (IL)-6 was determined. Results: PM exposure decreased HK-2 cell viability in a dose- and time-dependent manner. The activities of superoxide dismutase and malondialdehyde in HK-2 cells increased significantly in the group exposed to PM. PM exposure decreased VDR and Nrf2, while increasing CYP27B1, renin, ACE, AT1, NF-kB, TNF-α, and IL-6. The expression of VDR, CYP27B1, renin, ACE, AT1, and TNF-α was reversed by paricalcitol treatment. Paricalcitol also restored the cell viability of PM-exposed HK-2 cells. Conclusion: Our findings indicate that exposure to PM induces renal proximal tubular cell injury, concomitant with alteration of vitamin D endocrine system and renin angiotensin system. Vitamin D could attenuate renal tubular cell damage following PM exposure by suppressing the renin-angiotensin system and by partially inhibiting the inflammatory response.

Pulmonary fibrosis model using micro-CT analyzable human PSC-derived alveolar organoids containing alveolar macrophage-like cells.

Human lung organoids (hLOs) are useful for disease modelling and drug screening. However, a lack of immune cells in hLOs limits the recapitulation of in vivo cellular physiology. Here, we generated hLOs containing alveolar macrophage (AMφ)-like cells derived from pluripotent stem cells (PSC). To bridge hLOs with advanced human lung high-resolution X-ray computed tomography (CT), we acquired quantitative micro-CT images. Three hLO types were observed during differentiation. Among them, alveolar hLOs highly expressed not only lung epithelial cell markers but also AMφ-specific markers. Furthermore, CD68+ AMφ-like cells were spatially organized on the luminal epithelial surface of alveolar hLOs. Bleomycin-treated alveolar hLOs showed upregulated expression of fibrosis-related markers and extracellular matrix deposits in the alveolar sacs. Alveolar hLOs also showed structural alterations such as excessive tissue fraction under bleomycin treatment. Therefore, we suggest that micro-CT analyzable PSC-derived alveolar hLOs are a promising in vitro model to predict lung toxicity manifestations, including fibrosis.

Analysis of lung cancer-related genetic changes in long-term and low-dose polyhexamethylene guanidine phosphate (PHMG-p) treated human pulmonary alveolar epithelial cells.

BACKGROUND: Lung injury elicited by respiratory exposure to humidifier disinfectants (HDs) is known as HD-associated lung injury (HDLI). Current elucidation of the molecular mechanisms related to HDLI is mostly restricted to fibrotic and inflammatory lung diseases. In our previous report, we found that lung tumors were caused by intratracheal instillation of polyhexamethylene guanidine phosphate (PHMG-p) in a rat model. However, the lung cancer-related genetic changes concomitant with the development of these lung tumors have not yet been fully defined. We aimed to discover the effect of long-term exposure of PHMG-p on normal human lung alveolar cells. METHODS: We investigated whether PHMG-p could increase distorted homeostasis of oncogenes and tumor-suppressor genes, with long-term and low-dose treatment, in human pulmonary alveolar epithelial cells (HPAEpiCs). Total RNA sequencing was performed with cells continuously treated with PHMG-p and harvested after 35 days. RESULTS: After PHMG-p treatment, genes with transcriptional expression changes of more than 2.0-fold or less than 0.5-fold were identified. Within 10 days of exposure, 2 protein-coding and 5 non-coding genes were selected, whereas in the group treated for 27-35 days, 24 protein-coding and 5 non-coding genes were identified. Furthermore, in the long-term treatment group, 11 of the 15 upregulated genes and 9 of the 14 downregulated genes were reported as oncogenes and tumor suppressor genes in lung cancer, respectively. We also found that 10 genes of the selected 24 protein-coding genes were clinically significant in lung adenocarcinoma patients. CONCLUSIONS: Our findings demonstrate that long-term exposure of human pulmonary normal alveolar cells to low-dose PHMG-p caused genetic changes, mainly in lung cancer-associated genes, in a time-dependent manner.

Significance of Altered Fatty Acid Transporter Expressions in Uterine Cervical Cancer and Its Precursor Lesions.

BACKGROUND: High-risk human papilloma virus (HR HPV) infection is a major factor leading to the development of uterine cervical cancer. Data suggest that alterations in lipid metabolism are related to the pathogenesis of cervical cancer. Specifically, the uptake of exogenous fatty acids and their intracellular storage in lipid droplets enables cancer cells to survive and adapt to the changing tumor environment. MATERIALS AND METHODS: We compared the immunohistochemical expression of fatty acid transport protein 4 (FATP4), and cluster of differentiation 36/fatty acid translocase (CD36/FAT) in normal cervical epithelium, low-grade squamous intraepithelial lesion (LSIL), high-grade squamous intraepithelial lesion (HSIL), and squamous cell carcinoma (SCC) tissues of the uterine cervix. We also investigated the clinicopathological implications of these fatty acid transporters in SCC. RESULTS: Compared with that in normal cervical tissues, the expression of FATP4 was lower in LSIL (p=0.002), HSIL (p=0.006), and SCC (p=0.001). In contrast, CD36 expression was higher in SCC tissues than in normal cervical tissues (p<0.001). In normal cervical tissues, HR HPV-infected lesions exhibited a decrease in FATP4 (p<0.001) and an increase of CD36 (p=0.134), compared to those that were not infected with HR HPV. High CD36 expression was associated with a shorter recurrence-free survival (p<0.001). However, high FATP4 levels showed no significant correlation with the clinicopathological parameters of SCC. CONCLUSION: Altered expression levels of FATP4 and CD36 are unique features that might be related to HR HPV infection and promote tumorigenesis and progression of cervical cancer.

Cavity-dumped mode-locked Alexandrite laser oscillator with 100 mJ pulses stabilized by using a double trigger system.

We report a mode-locked Alexandrite single pulse laser with cavity dumping. Mode locking was achieved by using an AOM and an EOM was used for Q-switching and cavity dumping. The instability of the single pulse laser energy output was reduced down to a tenth of that of the conventional single trigger system by introducing a novel double trigger system. The single pulse laser energy and pulse width were 100 mJ and 475 ps in multiple mode and 12.5 mJ and 275 ps in single mode, obtained without a laser amplifier.

Establishment and characterization of two human cutaneous angiosarcoma cell lines, KU-CAS3 and KU-CAS5.

BACKGROUND: Cutaneous angiosarcoma (CAS) is a rare but fatal cancer. Established CAS cell lines are necessary for the investigation of their properties and treatment options. METHODS: Two cell lines, KU-CAS3 and KU-CAS5, were established from human angiosarcoma specimens obtained from the scalp. Flow cytometric assay, tube formation assay, low-density lipoprotein (LDL) uptake assay, immunofluorescence analysis, real-time PCR, tumorigenesis assay, and STR analysis were conducted. RESULTS: The cells showed endothelial cell properties, based on the cobblestone appearance upon reaching confluence, CD31 positivity, tube-formation activity, active uptake of acetylated LDL, and vWF expression. The two cell lines expressed relatively high levels of adrenergic ß2 receptor, and the VEGF1 and VEGF2 receptors. In the in vivo study, the growing neoplasms, confirmed as CAS, were identified as subcutaneous dark papules. KU-CAS cell lines were considered authentic based on STR profiling. CONCLUSIONS: KU-CAS3 and KU-CAS5 are the first human CAS cell lines having tumorigenic potential in vivo.

Evaluation of the effect of filtered ultrafine particulate matter on bleomycin-induced lung fibrosis in a rat model using computed tomography, histopathologic analysis, and RNA sequencing.

We aimed to investigate the effect of chronic particulate matter (PM) exposure on bleomycin-induced lung fibrosis in a rat model using chest CT, histopathologic evaluation, and RNA-sequencing. A bleomycin solution was intratracheally administrated to 20 male rats. For chronic PM exposure, after four weeks of bleomycin treatment to induce lung fibrosis, PM suspension (experimental group) or normal saline (control group) was intratracheally administrated for 10 weeks. Chest CT was carried out in all rats, and then both lungs were extracted for histopathologic evaluation. One lobe from three rats in each group underwent RNA sequencing, and one lobe from five rats in each group was evaluated by western blotting. Inflammation and fibrosis scores in both chest CT and pathologic analysis were significantly more aggravated in rats with chronic PM exposure than in the control group. Several genes associated with inflammation and immunity were also upregulated with chronic PM exposure. Our study revealed that chronic PM exposure in a bleomycin-induced lung fibrosis rat model aggravated pulmonary fibrosis and inflammation, proven by chest CT, pathologic analysis, and RNA sequencing.

Evaluation of the long-term effect of polyhexamethylene guanidine phosphate in a rat lung model using conventional chest computed tomography with histopathologic analysis.

There have been no studies on the effects of polyhexamethylene guanidine phosphate (PHMG) after a long period of exposure in the rodent model. We aimed to evaluate long-term lung damage after PHMG exposure using conventional chest computed tomography (CT) and histopathologic analysis in a rat model. A PHMG solution was intratracheally administrated to 24 male rats. At 8, 26, and 52 weeks after PHMG instillation, conventional chest CT was performed in all rats and both lungs were extracted for histopathologic evaluation. At 52 weeks after PHMG instillation, four carcinomas had developed in three of the eight rats (37.5%). Bronchiolo-alveolar hyperplasia and adenoma were found in rats at 8, 26, and 52 weeks post-instillation. The number of bronchiolo-alveolar hyperplasia significantly increased over time (P-value for trend< 0.001). The severity of lung fibrosis and fibrosis scores significantly increased over time (P-values for trend = 0.002 and 0.023, respectively). Conventional chest CT analysis showed that bronchiectasis and linear density scores suggestive of fibrosis significantly increased over time (P-value for trend < 0.001). Our study revealed that one instillation of PHMG in a rat model resulted in lung carcinomas and progressive and irreversible fibrosis one year later based on conventional chest CT and histopathologic analysis. PHMG may be a lung carcinogen in the rat model.

MTF1 Is Essential for the Expression of MT1B, MT1F, MT1G, and MT1H Induced by PHMG, but Not CMIT, in the Human Pulmonary Alveolar Epithelial Cells.

The inhalation of humidifier disinfectants (HDs) is linked to HD-associated lung injury (HDLI). Polyhexamethylene guanidine (PHMG) is significantly involved in HDLI, but the correlation between chloromethylisothiazolinone (CMIT) and HDLI remains ambiguous. Additionally, the differences in the molecular responses to PHMG and CMIT are poorly understood. In this study, RNA sequencing (RNA-seq) data showed that the expression levels of metallothionein-1 (MT1) isoforms, including MT1B, MT1E, MT1F, MT1G, MT1H, MT1M, and MT1X, were increased in human pulmonary alveolar epithelial cells (HPAEpiCs) that were treated with PHMG but not in those treated with CMIT. Moreover, upregulation of MT1B, MT1F, MT1G, and MT1H was observed only in PHMG-treated HPAEpiCs. The protein expression level of metal regulatory transcription factor 1 (MTF1), which binds to the promoters of MT1 isoforms, was increased in PHMG-treated HPAEpiCs but not in CMIT-treated HPAEpiCs. However, the expression of early growth response 1 (EGR1) and nuclear receptor superfamily 3, group C, member 1 (NR3C1), other transcriptional regulators involved in MT1 isomers, were increased regardless of treatment with PHMG or CMIT. These results suggest that MTF1 is an essential transcription factor for the induction of MT1B, MT1F, MT1G, and MT1H by PHMG but not by CMIT.

Upregulation of Fatty Acid Transporters is Associated With Tumor Progression in Non-Muscle-Invasive Bladder Cancer.

As patients with non-muscle-invasive bladder cancer (NMIBC) show a high degree of heterogeneity in tumor recurrence or progression, many clinicians demand a detailed risk stratification. Although modified fatty acid metabolism in cancer cells is reported to reflect malignant phenotypes such as metastasis, the impact of fatty acid transporters on NMIBC has never been investigated. This study examined the clinicopathologic implications of fatty acid transporters such as fatty acid transport protein 4 (FATP4), cluster of differentiation 36/fatty acid translocase (CD36/FAT), and long chain acyl CoA synthetase 1 (ACSL1) in 286 NMIBC cases. This study revealed that FATP4, CD36, and ACSL1 were overexpressed in 123 (43.0%), 43 (15.0%), and 35 (12.2%) NMIBC cases, respectively. High FATP4 in tumor cells was associated with high grade (p = 0.004) and high stage (p = 0.039). High CD36 was related to high grade (p < 0.001), high stage (p = 0.002), and non-papillary growth type (p = 0.004). High ACSL1 showed an association with high grade (p < 0.001), high stage (p = 0.01), non-papillary growth type (p = 0.002), and metastasis (p = 0.033). High FATP4 was an independent factor predicting short overall survival (OS) (hazard ratio = 3.32; 95% confidence interval, 1.07-10.31; p = 0.038). In conclusion, upregulation of FATP4, CD36, and ACSL1 might promote the NMIBC progression and could be exploited in clinical risk stratification and targeted therapy.

Investigation into the impact of the recovery time of a saturable absorber for stable dissipative soliton generation in Yb-doped fiber lasers.

In this study, we conduct a numerical evaluation of the impact of the recovery time of a saturable absorber (SA) on the output performance of an Yb-doped fiber laser operating in the dissipative soliton regime. Particularly, we evaluate the output pulse characteristics, such as the pulse width, spectral bandwidth, pulse peak power, and pulse energy depending on the change in recovery time. Applying a too-slow SA recovery time above a certain critical value is shown to make the output pulse unstable and broken. Furthermore, we demonstrate that there is an optimum recovery time range for stable dissipative soliton pulse generation, depending on the cavity dispersion and modulation depth of the SA. Further, we perform an additional numerical simulation of the pulse compression to demonstrate the relationship between the output dechirped pulse width and SA recovery time. The optimum approach for the generation of the shortest dechirped pulses in the dissipative soliton regime will be to construct a fiber laser cavity with a small normal cavity group velocity dispersion and use an SA with an appropriate recovery time.

Increased expression levels of AURKA and KIFC1 are promising predictors of progression and poor survival associated with gastric cancer.

Increased cell proliferation is a critical hallmark of cancer development and progression. The proliferation of tumor cells depends on mitotic deregulation. Here, we identified the differentially expressed genes (DEGs) in gastric cancer (GC) through RNA sequencing data and bioinformatics analysis. Subsequent functional and pathway enrichment analyses showed that the screened DEGs were enriched in the mitosis-associated pathway. Based on the analysis results, we selected two signatures (aurora kinase A [AURKA] and kinesin family member C1 [KIFC1]) to determine their clinicopathological significance. The results showed a significant positive correlation between AURKA and KIFC1 expression both at the mRNA and protein levels. AURKA expression was positively correlated with distant metastases (p = 0.032) and tumor-node-metastasis (TNM) stage (p = 0.001). Elevated KIFC1 expression was significantly associated with tumor size (p = 0.029), depth of invasion (p < 0.001), lymph node metastasis (p < 0.001), distant metastasis (p = 0.023), and TNM stage (p < 0.001). Higher AURKA (hazard ratio [HR] = 1.3, p < 0.001) and KIFC1 (HR = 1.41, p < 0.001) mRNA levels were also significantly correlated with poor overall survival. Thus, AURKA and KIFC1 could serve as potential prognostic markers and therapeutic targets for GC.

Nonlinear optical property measurements of rhenium diselenide used for ultrafast fiber laser mode-locking at 1.9 µm.

An experimental investigation into the nonlinear optical properties of rhenium diselenide (ReSe2) was conducted at a wavelength of 1.9 µm using the open-aperture and closed-aperture Z-scan techniques for the nonlinear optical coefficient (ß) and nonlinear refractive index (n2) of ReSe2, respectively. ß and n2 measured at 1.9 µm were ~ - 11.3 × 103 cm/GW and ~ - 6.2 × 10-2 cm2/GW, respectively, which to the best of our knowledge, are the first reported measurements for ReSe2 in the 1.9-µm spectral region. The electronic band structures of both ReSe2 and its defective structures were also calculated via the Perdew-Becke-Erzenhof functional to better understand their absorption properties. A saturable absorber (SA) was subsequently fabricated to demonstrate the usefulness of ReSe2 for implementing a practical nonlinear optical device at 1.9 µm. The 1.9-µm SA exhibited a modulation depth of ~ 8% and saturation intensity of ~ 11.4 MW/cm2. The successful use of the ReSe2-based SA for mode-locking of a thulium-holmium (Tm-Ho) co-doped fiber ring cavity was achieved with output pulses of ~ 840 fs at 1927 nm. We believe that the mode-locking was achieved through a hybrid mechanism of saturable absorption and nonlinear polarization rotation.

Evaluation of 3D Templated Synthetic Vascular Graft Compared with Standard Graft in a Rat Model: Potential Use as an Artificial Vascular Graft in Cardiovascular Disease.

Although the number of vascular surgeries using vascular grafts is increasing, they are limited by vascular graft-related complications and size discrepancy. Current efforts to develop the ideal synthetic vascular graft for clinical application using tissue engineering or 3D printing are far from satisfactory. Therefore, we aimed to re-design the vascular graft with modified materials and 3D printing techniques and also demonstrated the improved applications of our new vascular graft clinically. We designed the 3D printed polyvinyl alcohol (PVA) templates according to the vessel size and shape, and these were dip-coated with salt-suspended thermoplastic polyurethane (TPU). Next, the core template was removed to obtain a customized porous TPU graft. The mechanical testing and cytotoxicity studies of the new synthetic 3D templated vascular grafts (3DT) were more appropriate compared with commercially available polytetrafluoroethylene (PTFE) grafts (ePTFE; standard graft, SG) for clinical use. Finally, we performed implantation of the 3DTs and SGs into the rat abdominal aorta as a patch technique. Four groups of the animal model (SG_7 days, SG_30 days, 3DT_7 days, and 3DT_30 days) were enrolled in this study. The abdominal aorta was surgically opened and sutured with SG or 3DT with 8/0 Prolene. The degree of endothelial cell activation, neovascularization, thrombus formation, calcification, inflammatory infiltrates, and fibrosis were analyzed histopathologically. There was significantly decreased thrombogenesis in the group treated with the 3DT for 30 days compared with the group treated with the SG for 7 and 30 days, and the 3DT for 7 days. In addition, the group treated with the 3DT for 30 days may also have shown increased postoperative endothelialization in the early stages. In conclusion, this study suggests the possibility of using the 3DT as an SG substitute in vascular surgery.

Evaluation of polyhexamethylene guanidine-induced lung injuries by chest CT, pathologic examination, and RNA sequencing in a rat model.

Our aim was to correlate chest CT and pathologic findings of polyhexamethylene guanidine phosphate (PHMG)-induced lung injuries in a rat model, to determine whether PHMG exposure causes lung tumors, and to explore genetic alterations according to PHMG exposure under the guidance of CT. A PHMG solution was intratracheally administrated to 40 male rats. Chest CT was carried out in all rats and both lungs were collected for histopathologic evaluation. At 4- and 8-weeks post-instillation, one lobe of the right lung from 3 rats was subjected to RNA sequencing. At least one abnormal CT finding was found in all rats at all weeks. The major CT findings were inflammation, fibrosis, and tumors in the pathologic analysis, where significant changes were observed over time. The lung lesions remained persistent after 8 weeks of PHMG exposure. In the pathologic analysis, the extent/severity of inflammation did not show statistically significant changes over time, whereas the extent/severity of fibrosis increased continuously up to 6 weeks after PHMG exposure and then decreased significantly at 8 weeks. Bronchiolar-alveolar adenomas which have malignant potential were found in 50% of rats at 6 and 8 weeks after PHMG exposure. Also, several genes associated with lung cancer, acute lung injury, and pulmonary fibrosis were detected. Our study revealed that PHMG-induced lung injury and its changes according to the number of weeks after exposure were demonstrated using chest CT and pathologic evaluation. In addition, we showed that PHMG exposure caused lung tumors and genetic alterations according to PHMG exposure under the guidance of CT.

Presence of a survival benefit of HLA-incompatible living donor kidney transplantation compared to waiting or HLA-compatible deceased donor kidney transplantation with a long waiting time.

HLA-incompatible living donor kidney transplantation (LDKT) is one of efforts to increase kidney transplantation opportunity for sensitized patients with kidney failure. However, there are conflicting reports for outcomes of HLA-incompatible kidney transplantation compared to patients who wait for HLA-compatible deceased donor kidney transplantation (DDKT) in the United States and United Kingdom. Waiting for an HLA-compatible DDKT is relatively disadvantageous in Korea, because the average waiting time is more than five years. To study this further, we compared outcomes of HLA-incompatible LDKT with those who wait for HLA-compatible DDKT in Korea. One hundred eighty nine patients underwent HLA-incompatible LDKT after desensitization between 2006 and 2018 in two Korean hospitals (42 with a positive complement-dependent cytotoxicity cross-match, 89 with a positive flow cytometric cross-match, and 58 with a positive donor-specific antibody with negative cross-match). The distribution of matched variables was comparable between the HLA-incompatible LDKT group and the matched control groups (waiting-list-only group; and the waiting-list-or-HLA-compatible-DDKT groups; 930 patients each). The HLA-incompatible LDKT group showed a significantly better patient survival rate compared to the waiting-list-only group and the waiting-list-or-HLA-compatible-DDKT groups. Furthermore, the HLA-incompatible LDKT group showed a significant survival benefit as compared with the matched groups at all strength of donor-specific antibodies. Thus, HLA-incompatible LDKT could have a survival benefit as compared with patients who were waitlisted for HLA-compatible DDKT or received HLA-compatible DDKT in Korea. This suggests that HLA-incompatible LDKT as a good option for sensitized patients with kidney failure in countries with prolonged waiting times for DDKT.