Viral load and the duration of viral shedding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are important determinants of the transmission of coronavirus disease 2019.In this study, we examined the effects of viral doses on the lung and spleen of K18-hACE2 transgenic mice by temporal histological and transcriptional analyses. Approximately, 1×105 plaque-forming units (PFU) of SARS-CoV-2 induced strong host responses in the lungs from 2 days post inoculation (dpi) which did not recover until the mice died, whereas responses to the virus were obvious at 5 days, recovering to the basal state by 14 dpi at 1×102 PFU. Further, flow cytometry showed that number of CD8+ T cells continuously increased in 1×102 PFU-virusinfected lungs from 2 dpi, but not in 1×105 PFU-virus-infected lungs. In spleens, responses to the virus were prominent from 2 dpi, and number of B cells was significantly decreased at 1×105PFU; however, 1×102 PFU of virus induced very weak responses from 2 dpi which recovered by 10 dpi. Although the defense responses returned to normal and the mice survived, lung histology showed evidence of fibrosis, suggesting sequelae of SARS-CoV-2 infection. Our findings indicate that specific effectors of the immune response in the lung and spleen were either increased or depleted in response to doses of SARS-CoV-2. This study demonstrated that the response of local and systemic immune effectors to a viral infection varies with viral dose, which either exacerbates the severity of the infection or accelerates its elimination.

Background/Aims: The safety of direct oral anticoagulants (DOACs) compared with warfarin in patients with both nonvalvular atrial fibrillation (AF) and clinically confirmed liver cirrhosis (LC) has not been well studied. We compared the risk of a major bleeding event between DOAC and warfarin treatments in this patient population. Methods: A total of 238 cirrhotic patients with AF were retrospectively analyzed. The major bleeding event risk was compared between DOAC- and warfarin-treated groups. The median follow-up duration was 5.6 years. Results: Among the 238 study patients with LC and AF, 128 (53.8%) received DOACs and 110 (46.2%) received warfarin. The mean patient age was 68.8 years, and 78.2% were men. A major bleeding event occurred in 10 and 20 patients in the DOAC and warfarin groups, respectively, most commonly caused by gastrointestinal bleeding (70.0%). The cumulative risk of major bleeding did not differ between the groups by log-rank test (p = 0.12). This finding did not change when using 60 propensity score-matched pairs. A multivariable Cox regression model indicated that the concomitant use of antiplatelet agents (adjusted hazard ratio [aHR], 2.06; 95% confidence interval [CI], 1.00 to 4.30; p = 0.048) and presence of esophageal or gastric varices confirmed by endoscopic examination (aHR, 2.31; 95% CI, 1.03 to 5.17; p = 0.04) were associated with major bleeding in the entire cohort. Conclusions A major bleeding event risk is not increased by DOAC compared with warfarin treatment. Antiplatelet agent use and varices are independently associated with a higher risk of major bleeding during anticoagulation.

Objective: To analyze the differences in characteristics and outcomes between public bath (PB)- related and non-PB-related out-of-hospital cardiac arrest (OHCA) patients in South Korea. Methods: We performed a retrospective observational analysis of collected data from the Smart Advanced Cardiac Life Support (SALS) registry between September 2015 and December 2018. We included adult OHCA patients (aged >18 years) with presumed OHCA of non-traumatic etiology who were attended by dispatched emergency medical services. SALS is a field advanced life support with smartphone-based direct medical direction. The primary outcome was the survival to discharge rate measured at the time of discharge. Results: Of 38,995 cardiac arrest patients enrolled in the SALS registry, 11,889 were included in the final analysis. In total, 263 OHCAs occurred in PBs. Male sex and bystander cardiopulmonary resuscitation proportions appeared to be higher among PB patients than among non-PB patients. Percentages for shockable rhythm, witnessed rate, and number of underlying disease were lower in the PB group than in the non-PB group. Prehospital return of spontaneous circulation (11.4% vs. 19.5%, P=0.001), survival to discharge (2.3% vs. 9.9%, P<0.001), and favorable neurologic outcome (1.9% vs. 5.8%, P=0.007) in PB patients were significantly poorer than those in non-PB patients. Conclusion Patient characteristics and emergency medical services factors differed between PB and non-PB patients. All outcomes of PB-related OHCA were poorer than those of non-PB-related OHCA. Further treatment strategies should be developed to improve the outcomes of PBrelated cardiac arrest.

Myoblast fusion depends on mitochondrial integrity and intracellular Ca²⁺ signaling regulated by various ion channels. In this study, we investigated the ionic currents associated with [Ca²⁺]i regulation in normal and mitochondrial DNA-depleted (ρ0) L6 myoblasts. The ρ0 myoblasts showed impaired myotube formation. The inwardly rectifying K⁺ current (I(Kir)) was largely decreased with reduced expression of KIR2.1, whereas the voltage-operated Ca²⁺ channel and Ca²⁺-activated K⁺ channel currents were intact. Sustained inhibition of mitochondrial electron transport by antimycin A treatment (24 h) also decreased the I(Kir). The ρ0 myoblasts showed depolarized resting membrane potential and higher basal [Ca²⁺]ᵢ. Our results demonstrated the specific downregulation of I(Kir) by dysfunctional mitochondria. The resultant depolarization and altered Ca²⁺ signaling might be associated with impaired myoblast fusion in ρ0 myoblasts.
Antimycin A ; Down-Regulation ; Electron Transport ; Ion Channels ; Membrane Potentials ; Mitochondria ; Muscle Development ; Muscle Fibers, Skeletal ; Myoblasts* ; Oxidative Phosphorylation*

PURPOSE: KX-01 is a novel dual inhibitor of Src and tubulin. Unlike previous Src inhibitors that failed to show clinical benefit during treatment of breast cancer, KX-01 can potentially overcome the therapeutic limitations of current Src inhibitors through inhibition of both Src and tubulin. The present study further evaluates the activity and mechanism of KX-01 in vitro and in vivo. MATERIALS AND METHODS: The antitumor effect of KX-01 in triple negative breast cancer (TNBC) cell lines was determined by MTT assay. Wound healing and immunofluorescence assays were performed to evaluate the action mechanisms of KX-01. Changes in the cell cycle and molecular changes induced by KX-01 were also evaluated. A MDA-MB-231 mouse xenograft model was used to demonstrate the in vivo effects. RESULTS: KX-01 effectively inhibited the growth of breast cancer cell lines. The expression of phospho-Src and proliferative-signaling molecules were down-regulated in KX-01-sensitive TNBC cell lines. In addition, migration inhibition was observed by wound healing assay. KX-01-induced G2/M cell cycle arrest and increased the aneuploid cell population in KX-01-sensitive cell lines. Multi-nucleated cells were significantly increased after KX-01 treatment. Furthermore, KX-01 effectively delayed tumor growth in a MDA-MB-231 mouse xenograft model. CONCLUSION: KX-01 effectively inhibited cell growth and migration of TNBC cells. Moreover, this study demonstrated that KX-01 showed antitumor effects through the inhibition of Src signaling and the induction of mitotic catastrophe. The antitumor effects of KX-01 were also demonstrated in vivo using a mouse xenograft model.
Aneuploidy ; Animals ; Breast Neoplasms ; Cell Cycle ; Cell Cycle Checkpoints ; Cell Line ; Fluorescent Antibody Technique ; Heterografts ; In Vitro Techniques ; Mice ; Microtubules ; Mitosis* ; src-Family Kinases* ; Triple Negative Breast Neoplasms ; Tubulin ; Wound Healing

PURPOSE: Previously, we reported the presence of virus-encoded microRNAs (miRNAs) in the urine of prostate cancer (CaP) patients. In this study, we investigated the expression of two herpes virus-encoded miRNAs in prostate tissue. METHODS: A total of 175 tissue samples from noncancerous benign prostatic hyperplasia (BPH), 248 tissue samples from patients with CaP and BPH, and 50 samples from noncancerous surrounding tissues from these same patients were analyzed for the expression of two herpes virus-encoded miRNAs by real-time polymerase chain reaction (PCR) and immunocytochemistry using nanoparticles as molecular beacons. RESULTS: Real-time reverse transcription-PCR results revealed significantly higher expression of hsv1-miR-H18 and hsv2-miRH9- 5p in surrounding noncancerous and CaP tissues than that in BPH tissue (each comparison, P<0.001). Of note, these miRNA were expressed equivalently in the CaP tissues and surrounding noncancerous tissues. Moreover, immunocytochemistry clearly demonstrated a significant enrichment of both hsv1-miR-H18 and hsv2-miR-H9 beacon-labeled cells in CaP and surrounding noncancerous tissue compared to that in BPH tissue (each comparison, P<0.05 for hsv1-miR-H18 and hsv2- miR-H9). CONCLUSIONS: These results suggest that increased expression of hsv1-miR-H18 and hsv2-miR-H95p might be associated with tumorigenesis in the prostate. Further studies will be required to elucidate the role of these miRNAs with respect to CaP and herpes viral infections.
Carcinogenesis ; Herpesviridae ; Humans ; Hyperplasia* ; Immunohistochemistry ; MicroRNAs ; Nanoparticles ; Prostate* ; Prostatic Hyperplasia ; Prostatic Neoplasms ; Real-Time Polymerase Chain Reaction

In this article, a part of fund and grant supports was omitted unintentionally.

PURPOSE: The purpose of this study was to evaluate potential prognostic factors in patients with adenoid cystic carcinoma (ACC). MATERIALS AND METHODS: A total of 68 patients who underwent curative surgery and had available tissue were enrolled in this study. Their medical records and pathologic slides were reviewed and immunohistochemistry for basic fibroblast growth factor, fibroblast growth factor receptor (FGFR) 2, FGFR3, c-kit, Myb proto-oncogene protein, platelet-derived growth factor receptor beta, vascular endothelial growth factor (VEGF), and Ki-67 was performed. Univariate and multivariate analysis was performed for determination of disease-free survival (DFS) and overall survival (OS). RESULTS: In univariate analyses, primary site of nasal cavity and paranasal sinus (p=0.022) and Ki-67 expression of more than 7% (p=0.001) were statistically significant factors for poor DFS. Regarding OS, perineural invasion (p=0.032), high expression of VEGF (p=0.033), and high expression of Ki-67 (p=0.007) were poor prognostic factors. In multivariate analyses, primary site of nasal cavity and paranasal sinus (p=0.028) and high expression of Ki-67 (p=0.004) were independent risk factors for poor DFS, and high expression of VEGF (p=0.011) and Ki-67 (p=0.011) showed independent association with poor OS. CONCLUSION: High expression of VEGF and Ki-67 were independent poor prognostic factors for OS in ACC.
Adenoids* ; Carcinoma, Adenoid Cystic* ; Disease-Free Survival ; Fibroblast Growth Factor 2 ; Humans ; Immunohistochemistry ; Medical Records ; Multivariate Analysis ; Nasal Cavity ; Prognosis ; Proto-Oncogenes ; Receptors, Fibroblast Growth Factor ; Receptors, Platelet-Derived Growth Factor ; Risk Factors ; Vascular Endothelial Growth Factor A*

PURPOSE: The effect of different peritoneal dialysis (PD) modalities on the decline in residual renal function (RRF) is unclear due to inconsistencies among studies. In particular, the effect of automated peritoneal dialysis (APD) modalities [continuous cyclic peritoneal dialysis (CCPD) and nightly intermittent peritoneal dialysis (NIPD)] on RRF has not been examined in a large cohort. MATERIALS AND METHODS: We conducted a single-center retrospective study to investigate the association between PD modalities and decline in RRF in 142 incident PD patients [34 on CCPD, 36 on NIPD, and 72 on continuous ambulatory peritoneal dialysis (CAPD)]. RRF was measured within 2 months from PD start and at 1 year after PD initiation. RESULTS: The RRF at 1 year after PD initiation was 1.98+/-2.20 mL/min/1.73 m2 in CCPD patients and 3.63+/-3.67 mL/min/1.73 m2 in NIPD patients, which were moderately lower than 4.23+/-3.51 mL/min/1.73 m2 in CAPD patients (p=0.064). Moreover, there was no significant difference in the 1-year rate of decline of RRF between CCPD and NIPD patients, although APD patients had a faster 1-year RRF decline rate than CAPD patients (CCPD and NIPD vs. CAPD: -45.68 and -36.69 vs. 1.17%/year, p=0.045). APD was associated with a more rapid decline in RRF in patients with end-stage renal disease undergoing PD, although multivariate analysis attenuated the significance of this finding (beta=-31.50; 95% CI, -63.61 to 0.62; p=0.052). CONCLUSION: Our results suggest that CAPD might be more helpful than APD for preserving RRF during the first year of dialysis therapy, although there was no significant difference in the 1-year rate of decline of RRF between the two APD modalities.
Adult ; Female ; Glomerular Filtration Rate/physiology ; Humans ; Kidney/pathology/physiopathology ; Kidney Failure, Chronic/*therapy ; Male ; Middle Aged ; Peritoneal Dialysis/*adverse effects ; Retrospective Studies

OBJECTIVE: To evaluate the technical feasibility, performance, and interobserver agreement of a computer-aided classification (CAC) system for regional ventilation at two-phase xenon-enhanced CT in patients with chronic obstructive pulmonary disease (COPD). MATERIALS AND METHODS: Thirty-eight patients with COPD underwent two-phase xenon ventilation CT with resulting wash-in (WI) and wash-out (WO) xenon images. The regional ventilation in structural abnormalities was visually categorized into four patterns by consensus of two experienced radiologists who compared the xenon attenuation of structural abnormalities with that of adjacent normal parenchyma in the WI and WO images, and it served as the reference. Two series of image datasets of structural abnormalities were randomly extracted for optimization and validation. The proportion of agreement on a per-lesion basis and receiver operating characteristics on a per-pixel basis between CAC and reference were analyzed for optimization. Thereafter, six readers independently categorized the regional ventilation in structural abnormalities in the validation set without and with a CAC map. Interobserver agreement was also compared between assessments without and with CAC maps using multirater kappa statistics. RESULTS: Computer-aided classification maps were successfully generated in 31 patients (81.5%). The proportion of agreement and the average area under the curve of optimized CAC maps were 94% (75/80) and 0.994, respectively. Multirater kappa value was improved from moderate (kappa = 0.59; 95% confidence interval [CI], 0.56-0.62) at the initial assessment to excellent (kappa = 0.82; 95% CI, 0.79-0.85) with the CAC map. CONCLUSION: Our proposed CAC system demonstrated the potential for regional ventilation pattern analysis and enhanced interobserver agreement on visual classification of regional ventilation.
Aged ; Area Under Curve ; Feasibility Studies ; Female ; Humans ; Male ; Middle Aged ; Observer Variation ; Pulmonary Disease, Chronic Obstructive/physiopathology/*radiography ; Pulmonary Emphysema/physiopathology/radiography ; *Respiration ; Retrospective Studies ; Tomography, X-Ray Computed/*methods ; Xenon/*diagnostic use