The Cancer Genome Atlas (TCGA) project recently uncovered four molecular subtypes of gastric cancer: Epstein-Barr virus (EBV), microsatellite instability (MSI), genomically stable (GS), and ...chromosomal instability (CIN). However, their clinical significances are currently unknown. We aimed to investigate the relationship between subtypes and prognosis of patients with gastric cancer.
Gene expression data from a TCGA cohort (
= 262) were used to develop a subtype prediction model, and the association of each subtype with survival and benefit from adjuvant chemotherapy was tested in 2 other cohorts (
= 267 and 432). An integrated risk assessment model (TCGA risk score) was also developed.
EBV subtype was associated with the best prognosis, and GS subtype was associated with the worst prognosis. Patients with MSI and CIN subtypes had poorer overall survival than those with EBV subtype but better overall survival than those with GS subtype (
= 0.004 and 0.03 in two cohorts, respectively). In multivariate Cox regression analyses, TCGA risk score was an independent prognostic factor HR, 1.5; 95% confidence interval (CI), 1.2-1.9;
= 0.001. Patients with the CIN subtype experienced the greatest benefit from adjuvant chemotherapy (HR, 0.39; 95% CI, 0.16-0.94;
= 0.03) and those with the GS subtype had the least benefit from adjuvant chemotherapy (HR, 0.83; 95% CI, 0.36-1.89;
= 0.65).
Our prediction model successfully stratified patients by survival and adjuvant chemotherapy outcomes. Further development of the prediction model is warranted.
Instillation of highly soluble nanoparticles (NPs) into the lungs of rodents can cause acute eosinophilia without any previous sensitizations by the role of dissolved ions. However, whether gradually ...dissolving NPs can cause the same type of eosinophilia remains to be elucidated. We selected nickel oxide (NiO) as a gradually dissolving NP and evaluated the time course pulmonary inflammation pattern as well as its mechanisms.
NiO NPs were intratracheally instilled into female Wistar rats at various concentrations (50, 100, and 200 cm(2)/rat) and the lung inflammation was evaluated at various time-points (1, 2, 3, and 4 days). As positive controls, NiCl2 and the ovalbumin-induced allergic airway inflammation model was applied. NiCl2 was instilled at 171.1 μg Ni/rat, which is equivalent nickel concentration of 200 cm(2)/rat of NiO NPs. Cytological analysis and biochemical analysis including lactate dehydrogenase (LDH), total protein, and pro-inflammatory cytokines were measured in bronchoalveolar lavage fluid (BALF). The levels of total immunoglobulin E (IgE) and anaphylatoxins (C3a and C5a) were measured in BALF and serum. The levels of eotaxin were measured in the alveolar macrophages and normal lung tissue before and after addition of cell lysis buffer to evaluate whether the direct lysis of cells can release intracellular eotaxin.
NiO NPs produced acute neutrophilic inflammation throughout the study. However, eosinophils were recruited at 3 and 4 days post-instillation of NiO NPs and the magnitude and pattern of inflammation was similar with NiCl2 at 24 h post-instillation. The eosinophil recruitment by NiO NPs was not related with either the levels of total IgE or anaphylatoxins. The lysis of alveolar macrophages and normal lung tissue showed high levels of intracellular eotaxin and the levels of LDH showed positive correlation with the levels of eotaxin.
Instillation of NiO NPs produced neutrophilia at 1 and 2 days after instillation, while the mixed type of neutrophilic and eosinophilic inflammation was produced at 3 and 4 days post-instillation, which was consistent with NiCl2. The mechanism of the eosinophilia involves the direct release of intracellular eotaxin due to the rupture of cells by the accumulated solubilized nickel ions in the phagolysosome.
Serum uromodulin in dogs with chronic kidney disease Seo, Dansong; Yang, Yeseul; Hwang, Sung‐Hyun ...
Journal of veterinary internal medicine,
November/December 2022, 2022-11-00, 20221101, 2022-11-01, Volume:
36, Issue:
6
Journal Article
Peer reviewed
Open access
Background
Serum uromodulin concentration has been described as a novel biomarker of chronic kidney disease (CKD) in humans but not dogs.
Objective
To evaluate the serum uromodulin concentration in ...dogs with CKD and assess its diagnostic performance in distinguishing dogs with CKD from healthy dogs.
Animals
Forty‐nine dogs with CKD (International Renal Interest Society IRIS Stage 1, n = 23; Stage 2, n = 20; Stage 3‐4, n = 6) and 25 healthy controls.
Methods
Prospective, observational study. Serum uromodulin concentration was measured using a canine‐specific enzyme‐linked immunosorbent assay (ELISA), and its correlation with conventional renal markers was analyzed.
Results
Serum uromodulin concentrations were significantly lower in the CKD group than in the control group (P < .001), but no significant difference was observed among stages of CKD. A negative correlation was observed between serum uromodulin concentration and conventional renal markers (blood urea nitrogen concentration, r = −.60, P < .0001; serum creatinine concentration, r = −.46, P < .0001; serum symmetric dimethylarginine concentration SDMA, r = −.65, P < .0001). In receiver operating characteristic analysis, the area under the curve (AUC) of uromodulin (AUC, 0.97; 95% confidence interval CI, 0.94‐1.00) was higher than that of SDMA (AUC, 0.87; 95% CI, 0.79‐0.95) for CKD diagnosis (P = .01). The AUC of uromodulin (AUC, 0.95; 95% CI, 0.89‐1.00) also was higher than that of SDMA (AUC, 0.72; 95% CI, 0.58‐0.87) in distinguishing dogs with Stage 1 CKD from controls (P = .001).
Conclusions and Clinical Importance
Serum uromodulin concentration is decreased in dogs with CKD. Thus, serum uromodulin may be a valuable diagnostic marker for CKD in dogs, particularly in identifying early‐stage CKD.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Metformin, a drug for type 2 diabetes mellitus, has shown therapeutic effects for various cancers. However, it had no beneficial effects on the survival rate of human malignant mesothelioma (HMM) ...patients. The present study was performed to elucidate the underlying mechanism of metformin resistance in HMM cells. Glucose‐starved HMM cells had enhanced resistance to metformin, demonstrated by decreased apoptosis and autophagy and increased cell survival. These cells showed abnormalities in mitochondria, such as decreased ATP synthesis, morphological elongation, altered mitochondrial permeability transition pore and hyperpolarization of mitochondrial membrane potential (MMP). Intriguingly, Mdr1 was significantly upregulated in mitochondria but not in cell membrane. The upregulated mitochondrial Mdr1 was reversed by treatment with carbonyl cyanide m‐chlorophenyl hydrazone, an MMP depolarization inducer. Furthermore, apoptosis and autophagy were increased in multidrug resistance protein 1 knockout HMM cells cultured under glucose starvation with metformin treatment. The data suggest that mitochondrial Mdr1 plays a critical role in the chemoresistance to metformin in HMM cells, which could be a potential target for improving its therapeutic efficacy.
This study illustrated that glucose‐deficient conditions facilitated resistance to metformin in human malignant mesothelioma (HMM) cells through Mdr1 increasing in defected mitochondria. It also increased through mitochondrial membrane potential hyperpolarization and mitochondrial dysfunction rescued glucose‐starved HMM cells as a result of metformin treatment.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
It is widely accepted that strong ties exist between land uses and the water quality of adjacent aquatic systems within a watershed. Recently, studies of the relationships between land uses and water ...quality have also begun to consider the spatial configuration of land uses. Here we investigated the spatial configuration of land uses within watersheds in South Korea and examined how spatial patterns of urban, agricultural, and forest land uses measured at both landscape and class levels, related to water quality in adjacent reservoirs from landscape ecological perspective. The results indicate that water quality of reservoirs is closely associated with both the proportions of land use and the configurations of urban, agricultural, and forest areas. Water quality is more likely to be degraded when there is high interspersion of various land use types and when a large number of different land use types exist within a watershed. For urban land uses, high patch and edge densities, and urban land use as the largest patch, were also associated with water quality degradation, as were higher degrees of patch density and edge density for agricultural land uses. Water quality is likely better if forest patches are unfragmented, have a high value for the largest patch proportion, have complex patch shape, and are aggregated.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
•The immunogenicity of KVAC103 was compared to the CJ-50300 vaccine immunogenicity.•Binding and neutralizing-antibody titers rose in a concentration-dependent manner after second ...inoculation.•Compared to CJ-50300 after the first injection, the T-cell immune response of KVAC103 increased after the second injection.•KVAC103 administered intramuscular, subcutaneous, or intradermal had similar levels of neutralizing antibody titers and antigen-specific IgG levels.•KVAC103 might be a powerful smallpox vaccine.
Smallpox, caused by the variola virus belonging to the genus Orthopoxvirus, is an acute contagious disease that killed 300 million people in the 20th century. Since it was declared to be eradicated and the national immunization program against it was stopped, the variola virus has become a prospective bio-weapon. It is necessary to develop a safe vaccine that protects people from terrorism using this biological weapon and that can be administered to immunocompromised people. Our previous study reported on the development of an attenuated smallpox vaccine (KVAC103). This study evaluated cellular and humoral immune responses to various doses, frequencies, and routes of administration of the KVAC103 strain, compared to CJ-50300 vaccine, and its protective ability against the wild-type vaccinia virus Western Reserve (VACV-WR) strain was evaluated. The binding and neutralizing-antibody titers increased in a concentration-dependent manner in the second inoculation, which increased the neutralizing-antibody titer compared to those after the single injection. In contrast, the T-cell immune response (interferon-gamma positive cells) increased after the second inoculation compared to that of CJ-50300 after the first inoculation. Neutralizing-antibody titers and antigen-specific IgG levels were comparable in all groups administered KVAC103 intramuscularly, subcutaneously, and intradermally. In a protective immunity test using the VACV-WR strain, all mice vaccinated with CJ-50300 or KVAC103 showed 100% survival. KVAC103 could be a potent smallpox vaccine that efficiently induces humoral and cellular immune responses to protect mice against the VACV-WR strain.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Transforming growth factor-β (TGF-β) signaling and microRNAs (miRNAs) are important gene regulatory components in cancer. Usually in advanced malignant stages, TGF-β signaling is elevated but global ...miRNA expression is suppressed. Such a gene expression signature is well illustrated in a fibrosis (or mesenchymal) subtype of ovarian cancer (OC) that is of poor prognosis. However, the interplay between the two pathways in the OC subtype has not yet been elucidated. nc886 is a recently identified non-coding RNA implicated in several malignancies. The high expression of nc886 is associated with poor prognosis in 285 OC patients. Herein, we find that in OC nc886 expression is induced by TGF-β and that nc886 binds to Dicer to inhibit miRNA maturation. By preventing the miRNA pathway, nc886 emulates TGF-β in gene expression patterns and potentiates cell adhesion, migration, invasion, and drug resistance. Here we report nc886 to be a molecular link between the TGF-β and miRNA pathways.
Hypoxia is a hallmark of the solid tumor microenvironment and is associated with poor outcomes in cancer patients. The present study was performed to investigate mechanisms underlying the ...hypoxia-induced phenotypic changes using human malignant mesothelioma (HMM) cells.
Hypoxic conditions were achieved by incubating HMM cells in the air chamber. The effect of hypoxia on phenotype changes in HMM cells was investigated by performing in vitro clonogenicity, drug resistance, migration, and invasion assays. Signaling pathways and molecules involved in the more aggressive behaviors of HMM cells under hypoxia were investigated. A two-tailed unpaired Student's t-test or one-way ANOVA with Bonferroni post-test correction was used in this study.
Hypoxic conditions upregulated hypoxia-inducible factor 1 alpha (HIF-1α) and HIF-2α in parallel with the upregulation of its target, Glut-1, in HMM cells. In vitro clonogenicity of HMM cells was significantly increased in hypoxic conditions, but the proliferation of cells at a high density in hypoxia was lower than that in normoxic conditions. The expression levels of HIF-2α and Oct4 were increased in hypoxic HMM cells. The percentage of cells with high CD44 expression was significantly higher in HMM cells cultured in hypoxia than those cultured in normoxia. Hypoxia significantly enhanced the resistance of HMM cells to cisplatin, which occurred through cytoprotection against cisplatin-induced apoptosis. While cisplatin treatment decreased the ratio of Bcl-2 to Bax in normoxic condition, hypoxia conversely increased the ratio in HMM cells treated with cisplatin. Hypoxia increased the mobility and invasiveness of HMM cells. Epithelial to mesenchymal transition was promoted, which was indicated by the repression of E-cadherin and the concomitant increase of vimentin in HMM cells.
The data illustrated that hypoxic conditions augmented the aggressive phenotypes of HMM cells at the biological and molecular levels. The present study provides valuable background information beginning to understand aggressiveness of HMM in tumor microenvironments, suggesting that a control measure for tumor hypoxia may be an effective therapeutic strategy to reduce the aggressiveness of cancer cells in HMM patients.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Cancer-associated fibroblasts (CAFs) coordinate the malignancy of cancer cells via secretory materials. Reprogrammed lipid metabolism and signaling play critical roles in cancer biology. Oleic acid ...(OA) serves as a source of energy under glucose-deficient conditions, but its function in cancer progression remains unclear. The present study investigated that CAFs in xenografted tumors had higher amounts of fatty acids, particularly OA, compared to normal fibroblasts, and promoted the cancer cell stemness in lung adenocarcinoma cells under glucose-deficient condition.
Xenografts were established in immunodeficient mice by injection of NCI-H460 (H460) cells. Lipids and fatty acids were evaluated using the BODIPY staining and fatty-acid methyl esters analysis. The expression levels of markers for lipid metabolism and cancer stemness were determined by western blot, flow cytometry, and real-time PCR. Cancer cell subclones against stearoyl-CoA desaturase (SCD) were produced by lentiviral vector and CRISPR/cas9 systems. The expression of SCD was examined immunochemically in human adenocarcinoma tissues, and its clinical relevance to survival rate in lung adenocarcinoma patients was assessed by Kaplan-Meier analysis.
Transferred CAF-derived OA through lipid transporter upregulated SCD in cancer cells under glucose-deficient conditions, resulting in enhanced lipid metabolism and autophagosome maturation. By OA treatment under glucose deficient condition, cancer cell stemness was significantly enhanced through sequential activation of SCD, F-actin polymerization and nuclear translocation of yes-associated protein. These findings were confirmed by experiments using chemical inhibitors, SCD-overexpressing cells and SCD-knockout (KO) cells. When xenografted, SCD-overexpressing cells produced larger tumors compared with parental cells, while SCD-KO cells generated much smaller tumors. Analysis of tumor tissue microarray from lung adenocarcinoma patients revealed that SCD expression was the marker for poor prognosis involving tumor grade, clinical stage and survival rate.
Our data indicate that CAFs-derived OA activated lipid metabolism in lung adenocarcinoma cells under glucose-deficient conditions, subsequently enhancing stemness and progression toward malignancy.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Diagnostic ureterorenoscopy is powerful tool to confirm upper tract urothelial cancer (UTUC). However, URS and associated manipulation may be related to the risk of intravesical recurrence (IVR) ...following radical nephroureterectomy (RNU). We aimed to investigate whether preoperative ureterorenoscopy would increase IVR after RNU in patients with UTUC. We performed a retrospective analysis of 630 patients who had RNU with bladder cuff excision due to UTUC. Diagnostic URS was performed in 282 patients (44.7%). Patients were divided into two groups according to the URS. Survival analysis and multivariate Cox regression model were performed to address risk factors for the IVR. The interval from URS to RNU was measured. During URS, manipulation such as biopsy and resection was determined. The median age was 64 (IQR 56-72) years with follow-up duration of 34.3 (15.7-64.9) months. Median time from URS to RNU was 16 (0-38) days. The IVR developed in 42.5% (n = 268) patients at 8.2 (4.9-14.7) months. The five-year IVR-free survival rate was 42.6 ± 8.0% and 63.6 ± 6.9% in patients with and without preoperative URS, respectively (P < 0.001). In multivariate analysis, previous history of bladder tumour, extravesical excision of distal ureter, multifocal tumour, and URS (HR, 95% CI; 1.558, 1.204-2.016, P = 0.001) were independent predictors for higher IVR. The IVR rate in patients without manipulation during URS was not different to those with manipulation (P = 0.658). The duration from URS to RNU was not associated with IVR (P = 0.799). Diagnostic URS for UTUC increased IVR rate after RNU. However, the lessening of interval from URS to radical surgery or URS without any manipulation could not reduce the IVR rate.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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