Autophagy is a biological process that maintains cellular homeostasis and regulates the internal cellular environment. Hyperactivating autophagy to trigger cell death has been a suggested therapeutic ...strategy for cancer treatment. Mechanistic target of rapamycin (mTOR) is a crucial protein kinase that regulates autophagy; therefore, using a structure-based virtual screen analysis, we identified lomitapide, a cholesterol-lowering drug, as a potential mTOR complex 1 (mTORC1) inhibitor. Our results showed that lomitapide directly inhibits mTORC1 in vitro and induces autophagy-dependent cancer cell death by decreasing mTOR signaling, thereby inhibiting the downstream events associated with increased LC3 conversion in various cancer cells (e.g., HCT116 colorectal cancer cells) and tumor xenografts. Lomitapide also significantly suppresses the growth and viability along with elevated autophagy in patient-derived colorectal cancer organoids. Furthermore, a combination of lomitapide and immune checkpoint blocking antibodies synergistically inhibits tumor growth in murine MC38 or B16-F10 preclinical syngeneic tumor models. These results elucidate the direct, tumor-relevant immune-potentiating benefits of mTORC1 inhibition by lomitapide, which complement the current immune checkpoint blockade. This study highlights the potential repurposing of lomitapide as a new therapeutic option for cancer treatment.
There have been reports on regional variation in prevalence of hepatitis B and C, and Clonorchis sinensis (C. sinensis) infection, which indicates potential of spatial variation in liver cancer and ...gallbladder cancer incidence in Korea. Therefore, we aimed to assess the regional variation of liver and gallbladder cancer incidence and its determinants based on the regional distribution of risk factors, including hepatitis B infection in Korea.
This study used an ecological study design and district-level cancer incidence statistics generated by the National Cancer Center. Spatial clusters of liver and gallbladder cancer incidence were detected based on spatial scan statistics using SaTScan™ software. We set the size of maximum spatial scanning window of 25 and 35% of the population at risk for analyses of liver and gallbladder cancer, respectively. Significance level of 0.05 was used to reject the null hypothesis of no cluster. We fitted the Besag-York-Mollie model using integrated nested Laplace approximations to assess factors that influence the regional variation in cancer incidence.
Spatial clusters with high liver cancer incidence rates were detected in the southwestern and southeastern regions of Korea. High gallbladder cancer incidence rates are clustered in the southeastern region. Regional liver cancer incidence can be accounted for the prevalence of high household income (coefficient, - 0.10; 95% credible interval CI, - 0.18 to - 0.02), marital status (coefficient, - 0.14; 95% CI, - 0.25 to - 0.03), the incidence of hepatitis B (coefficient, 0.87; 95% CI, 0.29 to 1.44), and liver cancer screening (coefficient, 0.06; 95% CI, 0.00 to 0.12), while gallbladder cancer incidence was related to the prevalence of high household income (coefficient, - 0.03; 95% CI, - 0.05 to 0.00) and living close to a river with a high prevalence of liver fluke infection (coefficient, 0.55; 95% CI, 0.14 to 0.96).
This study demonstrated geographic variation in liver and gallbladder cancer incidence, which can be explained by determinants such as hepatitis B, income, marital status, and living near a river.
We evaluated the spatial variation in thyroid cancer incidence and its determinants in Korea considering its importance in cancer prevention and control. This study was based on the ecological design ...with cancer incidence data by administrative district from the National Cancer Center and regional characteristics generated from the Korea Community Health Survey Data. We identified spatial clusters of thyroid cancer incidences based on spatial scan statistics. Determinants of regional variation in thyroid cancer incidence were assessed using the Besag-York-Mollie model with integrated nested Laplace approximations. Spatial clusters for low and high thyroid cancer incidences were detected in the northeastern and southwestern regions, respectively. Regional variations in thyroid cancer incidence can be attributed to the prevalence of recipients of basic livelihood security (coefficient, - 1.59; 95% credible interval CI, - 2.51 to - 0.67), high household income (coefficient, 0.53; 95% CI, 0.31 to 0.76), heavy smoking (coefficient, - 0.91; 95% CI, - 1.59 to - 0.23), thyroid dysfunction (coefficient, 3.24; 95% CI, 1.47 to 5.00), and thyroid cancer screening (coefficient, 0.38; 95% CI, 0.09 to 0.67). This study presented the spatial variations in thyroid cancer incidence, which can be explained by the prevalence of socioeconomic factors, thyroid cancer screening, thyroid dysfunction, and smoking.
Background:This study investigated the consequences of recurrent mitral regurgitation (MR) after mitral valve (MV) repair in patients with degenerative MR and risk factors for recurrence.Methods and ...Results:From January 1990 to December 2015, 792 patients underwent MV repair due to degenerative MR. Recurrent MR was defined as moderate-to-severe MR on follow-up echocardiography. Mean follow-up duration was 8.71±5.58 years. During the follow-up period, MR recurred in 133 (16.8%) patients, and the MR recurrence-free rate at 20 years was 77.5±2.0%. In the recurrence group, the degree of MR decreased in 8 (6.0%) patients and was aggravated in 46 (34.6%) patients. Recurrent MR was associated with increased mortality and adverse left ventricular (LV) remodeling. Independent risk factors for MR recurrence were MV repair performed before 2000, preoperative atrial fibrillation, high LV end-diastolic dimension (LVEDD), prolapse of the isolated anterior leaflet or multiple segments, and absence of ring annuloplasty. Predictors of MR progression were high LVEDD and repair without artificial chordae implantation.Conclusions:Recurrent MR after MV repair in patients with degenerative MR showed a tendency to progress and was associated with increased mortality and adverse LV remodeling. Early referral for MV repair before development of atrial fibrillation and LV enlargement may reduce the risk of MR recurrence. Moreover, artificial chordae implantation and ring annuloplasty may assure the long-term durability of MV repair.
Background The effect of prosthesis–patient mismatch (PPM) on clinical outcomes after aortic valve replacement remains controversial. We evaluated effect of PPM on long-term clinical outcomes after ...isolated aortic valve replacement in patients with predominant aortic stenosis. Methods We analyzed data from patients with predominant aortic stenosis who underwent isolated aortic valve replacement between January 1995 and July 2010. The indexed effective orifice area, obtained by dividing the in vivo effective orifice area by the patient’s body surface area, was used to define PPM as clinically nonsignificant (group I, 224 patients), mild (group II, 52 patients), moderate (group III, 39 patients), and severe (group IV, 36 patients). Results Early survival was not significantly different among the groups, but overall survival was decreased gradually in group IV. Overall survival at 12 years was lower in group IV than in group I (92.8% ± 2.7% vs 67.0 ± 10.1, respectively; P = .001). Cardiac-related-death-free survival at 12 years was lower in patients with severe PPM. Left ventricular mass index decreased during the follow-up period in all groups. But left ventricular mass index was less decreased in group IV compared with groups I, II, and III. Age, severe PPM, and ejection fraction <40%, and New York Heart Association Functional Class IV were independent risk factors of overall survival on multivariate analysis. Severe PPM was an independent risk factor for cardiac-related death. Conclusions Severe PPM showed an adverse effect on long-term survival, and was an independent risk factor for cardiac-related death. In addition, patients with severe PPM showed less decreasing left ventricular mass index during follow-up.
Chronic kidney disease (CKD) is a major public health problem and a leading cause of cardiovascular disease and death. Early recognition and management of CKD risk factors are necessary to prevent ...its onset and progression. Neck circumference (NC) is a non-invasive and easily accessible anthropometric measure associated with central obesity and subcutaneous fat accumulation in the upper body. Our study aimed to explore the relationship between NC and the prevalence of CKD using data from the nationally representative Korea National Health and Nutrition Examination Survey (2019-2021). We analyzed data from 10,219 subjects (age > 19 years, no missing values). CKD was defined as an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m
. Logistic regression analysis was performed, which revealed a significant association between NC and CKD prevalence even after adjusting for confounding factors, both when NC was considered a continuous variable (OR 95% CI, 1.11 1.03-1.19) and in quartiles (Q1 as reference; Q2 OR 95% CI, 1.23 0.91-1.67; Q3 OR 95% CI, 1.59 1.16-2.18; Q4 OR 95% CI, 1.70 1.16-2.50). Our findings suggest that NC could be a simple and effective anthropometric measurement for identifying individuals at risk for CKD.
Low-pathogenicity avian influenza H9N2 remains an endemic disease worldwide despite continuous vaccination, indicating the need for an improved vaccine strategy. Bacillus subtilis (B. subtilis), a ...gram-positive and endospore-forming bacterium, is a non-pathogenic species that has been used in probiotic formulations for both animals and humans. The objective of the present study was to elucidate the effect of B. subtilis spores as adjuvants in chickens administered inactivated avian influenza virus H9N2. Herein, the adjuvanticity of B. subtilis spores in chickens was demonstrated by enhancement of H9N2 virus-specific IgG responses. B. subtilis spores enhanced the proportion of B cells and the innate cell population in splenocytes from chickens administered both inactivated H9N2 and B. subtilis spores (Spore + H9N2). Furthermore, the H9N2 and spore administration induced significantly increased expression of the pro-inflammatory cytokines IL-1β and IL-6 compared to that in the H9N2 only group. Additionally, total splenocytes from chickens immunized with inactivated H9N2 in the presence or absence of B. subtilis spores were re-stimulated with inactivated H9N2. The subsequent results showed that the extent of antigen-specific CD4
and CD8
T cell proliferation was higher in the Spore + H9N2 group than in the group administered only H9N2. Taken together, these data demonstrate that B. subtilis spores, as adjuvants, enhance not only H9N2 virus-specific IgG but also CD4
and CD8
T cell responses, with an increase in pro-inflammatory cytokine production. This approach to vaccination with inactivated H9N2 together with a B. subtilis spore adjuvant in chickens produces a significant effect on antigen-specific antibody and T cell responses against avian influenza virus.
Graphene quantum dots attenuate intestinal inflammation by modulating immune homeostasis.
While graphene and its derivatives have been suggested as a potential nanomedicine in several biomimetic ...models, their specific roles in immunological disorders still remain elusive. Graphene quantum dots (GQDs) may be suitable for treating intestinal bowel diseases (IBDs) because of their low toxicity in vivo and ease of clearance. Here, GQDs are intraperitoneally injected to dextran sulfate sodium (DSS)–induced chronic and acute colitis model, and its efficacy has been confirmed. In particular, GQDs effectively prevent tissue degeneration and ameliorate intestinal inflammation by inhibiting T
H
1/T
H
17 polarization. Moreover, GQDs switch the polarization of macrophages from classically activated M1 to M2 and enhance intestinal infiltration of regulatory T cells (T
regs
). Therefore, GQDs effectively attenuate excessive inflammation by regulating immune cells, indicating that they can be used as promising alternative therapeutic agents for the treatment of autoimmune disorders, including IBDs.
Patients with chronic hepatitis B (CHB) who were administered tenofovir disoproxil fumarate (TDF)-based combination therapy after receiving multiple drugs are frequently switched to TDF monotherapy ...in South Korea. We evaluated the efficacy and safety of switching to TDF monotherapy from TDF-based combination therapy over 5 years. This was a retrospective study of multidrug-experienced CHB patients who switched from TDF-based combination therapy to TDF monotherapy after achieving a virologic response (VR; <20 IU/mL) at Konkuk University Hospital and Sanggye Paik Hospital. The biochemical response was defined as a normalized serum ALT level during follow-up. Each patient was assessed from the date of switching to TDF monotherapy to the date of the last follow-up over 5 years. A total of 39 patients who received at least one antiviral therapy before TDF-based combination therapy were analyzed. The median duration of VR before switching to TDF monotherapy was 18 months and the median duration of TDF monotherapy was 55 months. In this study, except for one patient who had poor compliance, all patients maintained a VR. Three patients had a temporarily increased HBV DNA level and 91.2% of the patients showed a biochemical response. Switching multidrug-experienced patients to TDF monotherapy is generally safe and effective.
The model for end-stage liver disease (MELD) serves as an indicator for short-term mortality among patients diagnosed with liver cirrhosis (LC) and is used to prioritize patients for liver ...transplantation. In 2021, the updated version of MELD, MELD-3.0, was introduced to improve the accuracy of the mortality prediction of MELD. Therefore, this study aimed to compare the efficacy of MELD 3.0 and MELD-Na in predicting mortality among Korean patients with LC.
A retrospective review was conducted using the medical records of patients diagnosed with LC who were admitted to Konkuk University Hospital From 2011 to 2021. The study calculated the predictive values of MELD-Na and MELD-3.0 for 3- and 6-months mortality using the area under the receiver operating curve (AUROC) and compared the results using the DeLong test.
Of the 3,034 patients enrolled in the study, 339 (11.2%) died within 3 months and 421 (14.4%) died within 6 months. The AUROCs values for predicting 3 months mortality were 0.846 for MELD-Na and 0.851 for MELD-3.0. The corresponding AUROC values for predicting 6 months mortality were 0.843 for MELD-Na and 0.848 for MELD-3.0. MELD-3.0 exhibited better discrimination ability than MELD-Na for both 3 (p = 0.03) and 6 months mortality (p = 0.01).
Our study found a significant difference between the performance of MELD-3.0 and MELD-Na in Korean patients with LC.
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