Comparative analysis of genetic testing utilization rates among people with and without disabilities in South Korea from 2016 to 2019, focusing on malignant neoplasms: A national population-based study.

INTRODUCTION: Oncogene testing is widely used to detect or direct cancer treatments. Compared to people without disabilities, people with disabilities in Korea have a lower cancer incidence rate but a fivefold higher cancer mortality rate, implying delayed detection. METHODS: We used an administrative database combining disability status and care utilization to analyze every case of cancer-related genetic testing paid for by the National Health Insurance Services of Korea between 2016 and 2019. We first compared percentages of individuals who had taken a registered genetic test by their disability statuses. We then compared the most frequently utilized tests between individuals with and without disabilities. RESULTS: Korean citizens, 175,000 in total, underwent at least one of the 192 registered cancer-related genetic tests between 2016 and 2019. People with disabilities utilized these genetic tests at higher rates than those without disabilities, regardless of sex or age. Among people aged ≥40 years, lung and colorectal cancer-related tests were most frequently utilized, regardless of disability status. CONCLUSION: Although the cancer-related genetic test uptake rate is higher among people with disabilities than among those without disabilities, it is still possible that information on these tests is not as readily available to people with disabilities. Therefore, it is imperative for the government to actively devise strategies to enhance national cancer screening rates among people with disabilities.

Design, synthesis, and evaluation of purine and pyrimidine-based KRAS G12D inhibitors: Towards potential anticancer therapy.

Oncogenic RAS mutations, commonly observed in human tumors, affect approximately 30% of cancer cases and pose a significant challenge for effective cancer treatment. Current strategies to inhibit the KRAS G12D mutation have shown limited success, emphasizing the urgent need for new therapeutic approaches. In this study, we designed and synthesized several purine and pyrimidine analogs as inhibitors for the KRAS G12D mutation. Our synthesized compounds demonstrated potent anticancer activity against cell lines with the KRAS G12D mutation, effectively impeding their growth. They also exhibited low toxicity in normal cells, indicating their selective action against cancer cells harboring the KRAS G12D mutation. Notably, the lead compound, PU1-1 induced the programmed cell death of KRAS G12D-mutated cells and reduced the levels of active KRAS and its downstream signaling proteins. Moreover, PU1-1 significantly shrunk the tumor size in a pancreatic xenograft model induced by the KRAS G12D mutation, further validating its potential as a therapeutic agent. These findings highlight the potential of purine-based KRAS G12D inhibitors as candidates for targeted cancer therapy. However, further exploration and optimization of these compounds are essential to meet the unmet clinical needs of patients with KRAS-mutant cancers.

Development of chimeric antigen receptor (CAR)-T cells targeting A56 viral protein implanted by oncolytic virus.

To address the challenge of solid tumor targeting in CAR-T therapy, we utilized the A56 antigen, which is uniquely expressed on a diverse range of cancer cells following the systemic administration of an oncolytic vaccinia virus (OVV). Immunohistochemical assays precisely confirmed exclusive localization of A56 to tumor tissues. In vitro studies demonstrated a distinct superiority of A56-dependent CAR-T cytotoxicity across multiple cancer cell lines. Building on these in vitro observations, we strategically administered A56 CAR-T cells, OVV, and hydroxyurea (HU) combination in HCT-116 tumor-bearing non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice, leading to a significant reduction in tumor size and an extended time to progression. Consequently, A56-targeting combinatorial immunotherapy provides the benefit of reducing inadvertent CAR-T effects on normal cells while preserving its effectiveness against cancer cells. Furthermore, our approach of implanting A56 via OVV on tumors facilitates a wide therapeutic application of CAR-T cells across various solid tumors.

Pre-pandemic physical activity as a predictor of infection and mortality associated with COVID-19: Evidence from the National Health Insurance Service.

Introduction: During the coronavirus disease 2019 (COVID-19) pandemic, many populations have experienced reduced physical activity (PA) levels, weight gain, and increased anxiety and depression. However, according to a previous study, engaging in PA has a positive effect on damages caused by COVID-19. Therefore, this study aimed to investigate the association between PA and COVID-19 using the National Health Insurance Sharing Service Database in South Korea. Methods: Logistic regression analysis was used to analyze the association of PA with COVID-19 and mortality. The analysis was adjusted for body mass index, sex, age, insurance type, comorbidity, and region of residence at baseline. Disability and lifestyle (weight, smoking, and drinking status) were adjusted consecutively. Results: The results indicated that engaging in insufficient PA as per the WHO guidelines predicts a higher risk of COVID-19 when controlling for personal characteristics, comorbidity, lifestyle, disability, and mortality. Discussion: This study revealed the need to engage in PA and manage weight to reduce the risk of infection and mortality associated with COVID-19. Because engaging in PA is an important component of weight management and can help restore physical and mental health after the COVID-19 pandemic, it should be emphasized as a pillar of recovery after COVID-19.

Clinical big-data-based design of GLUT2-targeted carbon nanodots for accurate diagnosis of hepatocellular carcinoma.

Despite advances in diagnostic and therapeutic methods, the prognosis of patients with hepatocellular carcinoma (HCC) remains poor due to the delay in diagnosis. Herein, we aimed to discover a highly sensitive and specific biomarker for HCC based on genomic big data analysis and create an HCC-targeted imaging probe using carbon nanodots (CNDs) as contrast agents. In genomic analysis, we selected glucose transporter 2 (GLUT2) as a potential imaging target for HCC. We confirmed the target suitability by immunohisto-chemistry tests of 339 patient samples, where 81.1% of the patients exhibited underexpression of GLUT2, i.e., higher GLUT2 intensity in non-tumor tissues than in tumor tissues. To visualize GLUT2, we conjugated CNDs with glucosamine (GLN) as a targeting ligand to yield glucosamine-labeled CNDs (GLN-CNDs). A series of in vitro and in vivo experiments were conducted on GLUT2-modified HepG2 cells to confirm the specificity of the GLN-CNDs. Since the GLUT2 expression is higher in hepatocytes than in HCC cells, the GLUT2-targeted contrast agent is highly attached to normal cells. However, it is possible to produce images in the same form as the images obtained with a cancer cell-targeted contrast agent by inverting color scaling. Our results indicate that GLUT2 is a promising target for HCC and that GLN-CNDs may potentially be used as targeted imaging probes for diagnosing HCC.

Measuring Trends in the Socioeconomic Burden of Disease in Korea, 2007-2015.

This study estimated the direct and indirect socioeconomic costs of 238 diseases and 22 injuries from a social perspective in Korea from 2007 to 2015. The socioeconomic cost of each disease group was calculated based on the Korean Standard Disease Classification System. Direct costs were estimated using health insurance claims data provided by the National Health Insurance Service. The numbers of outpatients and inpatients with the main diagnostic codes for each disease were selected as a proxy indicator for estimating patients' medical use behavior by disease. The economic burden of disease from 2007 to 2015 showed an approximately 20% increase in total costs. From 2007 to 2015, communicable diseases (including infectious, maternal, pediatric, and nutritional diseases) accounted for 8.9-12.2% of the socioeconomic burden, while non-infectious diseases accounted for 65.7-70.7% and injuries accounted for 19.1-22.8%. The top 5 diseases in terms of the socioeconomic burden were self-harm (which took the top spot for 8 years), followed by cirrhosis of the liver, liver cancer, ischemic heart disease, and upper respiratory infections in 2007. Since 2010, the economic burden of conditions such as low back pain, falls, and acute bronchitis has been included in this ranking. This study expanded the scope of calculating the burden of disease at the national level by calculating the burden of disease in Koreans by gender and disease. These findings can be used as indicators of health equality and as useful data for establishing community-centered (or customized) health promotion policies, projects, and national health policy goals.

Health-related factors leading to disabilities in Korea: Survival analysis.

The purpose of this study is to analyze (a) population and socioeconomic factors affecting disability, excluding the occurrence of disability due to accidents and congenital diseases, and (b) health-related behavioral factors and factors that can prevent and reduce the cause of disability due to disease in Korea. This study was a longitudinal research. Data were obtained from The 2018 Korean Health Panel (KHP) is a survey jointly conducted by the Korea Institute of Health and Social Affairs and the National Health Insurance Service. A total of 7, 372 (Mage = 52.14, SD = 21.39; Male = 47.52%) were analyzed in this study. People with Higher education attainments and more income levels were associated with lower hazard of developing new disabilities (all p < 0.05). In this study, the health factors that could be related to the occurrence of new disabilities were smoking, alcohol consumption, physical activity, and stress (all p < 0.0001). However, physical activity was negatively associated with the risk of developing a disability at all follow-ups (p < 0.05). Higher scores on the number of chronic diseases (valid scores = 0, 1, 2, 3, or more) represented a greater level of newly developing disability present at all follow-ups (all p < 0.0001). This longitudinal study confirmed the relationship between health-related factors and specific chronic diseases. Its findings can be used as a crucial foundation for establishing healthcare policies and services that can lower and prevent disability by preventing and reducing specific negative health behaviors and unhealthy behavioral factors, and alleviating chronic diseases in Korea.

A National Study of Life-Sustaining Treatments in South Korea: What Factors Affect Decision-Making?

PURPOSE: This cross-sectional study investigated the status of life-sustaining treatment (LST) practices and identified characteristics and factors influencing decision-making practices. MATERIALS AND METHODS: The National Agency for Management of Life-sustaining Treatment retains records provided by doctors regarding patients subject to LST implementation. A total of 71,327 patients receiving LST were identified. We analyzed all nationally reported data between February 2018 and October 2019. Indicators such as the proportion of deaths, records for decision to terminate LST, implementation of LST records, and registration of Advance Statements on LST were analyzed. RESULTS: A total of 67,252 (94.3%) end-of life decisions were implemented in South Korea. The proportion of deaths preceded by a LST plan, non-self-determination LST decision, and any advance statements was 33.5% (23,891/71,327), 66.5% (47,436/71,327), and 1.2% (890/71,327), respectively. The logistic regression model revealed that self-determination to terminate LST was more frequent for men than for women and higher for those aged 30-69. Disability (odds ratio [OR], 0.59; 95% confidence interval [CI], 0.56 to 0.61), living in non-metropolitan areas (OR, 0.84; 95% CI, 0.81 to 0.86), and disease comorbidity was independently associated with a low level of self-determination. CONCLUSION: After the implementation of the new LST Act, about a third of patients in end-of-life process made decisions regarding their medical LST. However, family members still play a major role in LST decisions where the patient's intention cannot be verified. Decisions related to LST are predominantly made when death is imminent. Thus, it is necessary to increase awareness of end-of-life LST decision-making among medical staff and the public.

HIV Screening and Early Referral in the Trauma Population: The Experience of a Large Safety Net Hospital.

BACKGROUND: While the prevalence of HIV infection in the population is 0.5%, it is higher among trauma patients as are rates of unknown seropositivity. Routine HIV screening for all trauma evaluations was implemented at our urban level I center in 2009. We aimed to evaluate use and results of the program in our trauma population. METHODS: This was a retrospective analysis of all trauma evaluations between July 2015 and February 2018. After passage of legislation rescinding the requirement for consent to perform HIV testing, our trauma service instituted an order set which automatically tested for HIV unless the ordering physician opted out. Patients found to be infected with HIV were to be counseled and referred to specialty care. RESULTS: Of 6175 consecutive trauma evaluations during the study period, 449 (7.3%) patients had been screened within the prior year and were excluded. Of the remaining cohort, 2024 (35.3%) patients were screened with 27 (1.3%) testing positive. Among those testing positive for infection, 100% were male, 77% white, 63% non-Hispanic, and 70% lacked insurance. Twenty-five (92.6%) patients received counseling and 19 were referred to specialty care. Age, gender, race, ethnicity, Injury Severity Score, trauma activation level, and payor type were not significant predictors for positive HIV screen on logistic regression analysis. CONCLUSIONS: Despite a significantly higher rate of HIV in the trauma population, only a third of patients are screened. Such high infection rates justify the existence of this screening program but steps must be taken to increase screening rate. LEVEL OF EVIDENCE: Level 3.

Transfer Is Associated with a Higher Mortality Rate in Necrotizing Soft Tissue Infections.

Background: Necrotizing soft tissue infections (NSTI) are a surgical emergency with significant morbidity and mortality rates. It has been thought that NSTIs are best treated in large tertiary centers. However, the effect of transfer has been under-studied. We examined whether transfer status is associated with a higher mortality rate in NSTIs. Methods: We conducted a retrospective review of patients with an International Classification of Disease (ICD) code associated with NSTI seen from 2012-2015 at two tertiary care institutions. Patients transferred to a tertiary center (T-NSTI) were compared with those who were treated initially at a tertiary center (P-NSTI). The primary endpoint was in-hospital death. Results: A total of 138 patients with NSTI met our study criteria, 39 transfer patients (28.0%) and 99 (72.0%) who were treated primarily at our institutions. The mortality rate was significantly higher for T-NSTI patients than P-NSTI patients (35.9% versus 14.1%; p < 0.01) with an adjusted odds ratio of 5.33 (95% confidence interval 1.02-28.30; p = 0.04). The need for hemodialysis was an independent predictor of in-hospital death. Treatment at a Level 1 trauma center and current smoking status were independent protectors???? of in-hospital death. For the transfer patients, the timing of transfer and debridement status were not different in survivors and non-survivors. However, there was a trend toward a lower in-hospital mortality rate if patients were transferred early without prior debridement than in all other transfers (21.4% versus 40.0%; p = 0.21). The in-hospital mortality rate was significantly lower at the Level 1 trauma center than at the non-trauma tertiary center (15.5% versus 34.3%; p = 0.02). Conclusion: Transfer status is an independent predictor of in-hospital death in patients with NSTI. Larger, multi-institutional studies are needed to elucidate further what factors contribute to the higher mortality rate in these patients.

Effect of Statin Use on Liver Cancer Mortality Considering Hypercholesterolemia and Obesity in Patients with Non-Cirrhotic Chronic Hepatitis B.

Little is known about the benefits of statin use on liver cancer mortality among patients with chronic hepatitis B (CHB) considering hypercholesterolemia and obesity. A nationwide retrospective cohort study was conducted using data from a Health Examination Cohort of the National Health Insurance Service of Korea. Data on CHB patients with no other concurrent liver disease were acquired, and statin use was defined as a cumulative daily dose ≥28. A 3-year landmark analysis was performed to avoid immortal time bias. Patients who started statin therapy within the landmark date were considered statin users. A Cox regression analysis was applied to assess associations between statin use and liver cancer mortality considering hypercholesterolemia and obesity. Among 13063 patients, 193 (1.5%) died of liver cancer during the mean follow-up period of 10.6 years. After adjusting for demographic and metabolic factors, statin use [hazard ratio (HR), 0.17; 95% confidence interval (CI), 0.04-0.70] and hypercholesterolemia (HR, 0.46; 95% CI, 0.24-0.88 for total cholesterol ≥240 mg/dL) were associated with a decreased risk of liver cancer mortality, whereas body mass index (BMI) ≥30 kg/m² was associated with an increased risk of liver cancer mortality (HR, 2.46; 95% CI, 1.20-5.06). This study showed that statin use was associated with decreased liver cancer mortality when adjusting for cholesterol levels and BMI. This study found that hypercholesterolemia was independently associated with decreased liver cancer mortality regardless of statin use.

Latent Profiles Based on Light Physical Activity, Sedentary Behavior, Perceived Body Shape, and Body Mass Index in Patients with Dyslipidemia Influence Their Quality of Life.

Despite the increasing prevalence and economic burden of dyslipidemia in South Korea, we have little data on the physical activity of patients. Thus, we aimed to investigate how quality of life among patients with dyslipidemia is influenced by a combination of the following variables: light physical activity (PA), sedentary behavior (SB), perceived body shape, and body mass index (BMI). We examined data from the Sixth Korean National Health and Nutrition Examination Survey (KNHANES VI 2015), collected in 2015 by the Korean Centers for Disease Control and Prevention. The analysis included 534 individuals with dyslipidemia out of 7380 survey participants. Latent profile analysis identified three latent classes of individuals based on their physical profiles. Class 1 patients (active; n = 48) were more active, possessed more positive views of their body shape, were less sedentary, and had a lower BMI than Class 3 patients (inactive; n = 154). Class 2 patients (moderate; n = 331) had profiles in between the other two classes. Additionally, Class 1 and 2 patients had better quality of life than Class 3 patients. Our results suggest that promoting light PA and altering perceived body shape through counselling may improve quality of life in patients with dyslipidemia.

Factors of Physical Activity and Sedentary Behavior in Elderly Koreans.

Objectives: In this study, we examined factors of moderate-to-vigorous physical activity (MVPA) and sedentary behavior (SB) in elderly Koreans. Methods: We used 2015 data from the Sixth National Health and Nutrition Examination Survey. To analyze physical activity (PA), we categorized participants were into those who met MVPA recommendations (150 minutes/week of moderate PA or 75 minutes/week of vigorous PA) or those who did not. We also categorized them into high SB (620-1200 minutes/day of sitting) and low SB (30-600 minutes/day). Results: Final analyses included 1501 adults over 60 years old (mean: 69.2 ± 6.2). We performed multiple logistic regressions examining impacts of grip strength and body mass index, along with self-reports of perceived health, sleep duration, and demographics on PA and SB. We found positive associations between meeting MVPA guidelines and self-perceived health and urban living, but negative associations with sleep duration and education. A strong grip, high self-perceived health, long sleep duration (8-14 hours), and living with a partner were factors of being less sedentary. High annual income was a factor of being more sedentary. Conclusion: Our findings support efforts that develop interventions promoting active lifestyles among elderly Koreans.

Multitarget-based cotreatment with cilostazol and celecoxib synergistically suppresses collagen-induced arthritis in mice by enhancing interleukin-10 expression.

Cilostazol exerts potent anti-inflammatory effects and celecoxib, a COX-2 specific inhibitor, improves the unsatisfactory profile of NSAIDs. It was aimed to assess the anti-arthritic potential of celecoxib add-on for cilostazol therapy in collagen induced arthritis (CIA), and to elucidate the implication of interleukin (IL)-10 in the action of cilostazol and celecoxib cotreatment. Cotreatment of RAW 264.7 cells with 10 µM cilostazol and 0.3 µM celecoxib synergistically suppressed RANKL-induced increases in RANK mRNA and protein levels. When cultured in the presence of RANKL for 5 days, RANKL-stimulated expressions of osteoclastogenic genes (OSCAR, DC-STAMP, and cathepsin K mRNA) and the expression of RANK mRNA were markedly elevated. Furthermore, these gene expressions, including that of RANK, were significantly suppressed by cotreatment with cilostazol (10 µM) and celecoxib (0.3 µM). In addition, this co-treatment strongly down-regulated RANKL-induced NFATc1 protein and TRAP activity (key osteoclastogenic factors), and these down-regulations were significantly prevented by pretreating cells with IL-10 neutralizing antibody. Furthermore, increased osteoclast formation and extensive resorption pit formation by bone marrow-derived monocytes obtained from C57BL/6 mice cultured in the presence of M-CSF/RANKL were markedly suppressed by cilostazol and celecoxib cotreatment. Consequently, hindlimb paw thicknesses in DBA/1J CIA mice were significantly reduced by cilostazol (10 mg/kg/d) and celecoxib (5 mg/kg/d) cotreatment. These results were accompanied by synergistic suppression of cartilage depletion and bone erosion and reductions in arthritis scores in the CIA mice. In conclusion, serum IL-10 levels in these mice were markedly increased by cilostazol and celecoxib cotreatment, whereas elevated serum IL-1ß levels were markedly reduced. Cotreatment with low-dose cilostazol and celecoxib may ensure the synergistic anti-arthritic potential.

Comparative Research for the Healthcare Budget and Burden of Disease in Perspective Resource Allocation.

BACKGROUND: Burden of disease can be used to prioritize the healthcare budget allocation. We analyzed the research and development (R&D) budget of the Ministry of Health and Welfare (MOHW) in 2018 and compared the results with those of the 2015 Korean National Burden of Disease (KNBD) study. METHODS: The 2018 MOHW R&D Project integrated implementation plan was used to analyze the R&D budget of the MOHW. The budget was allocated according to the KNBD disease group and according to the budget lines. The allocated budget was compared with the economic burden and the disability adjusted life years (DALYs) in 2015. Also, for budget targets for risk factors, DALYs of attributable risk factors were compared with corresponding budgets. RESULTS: In 2018, the MOHW major R&D budget of USD 435.1 million accounted for 3% of the total government budget. Within the disease specific R&D budget, 35.9% was allocated to communicable disease groups, 64.1% to non-communicable diseases, and 0% to injury and violence. Among level 2 disease groups, neoplasm was ranked first. Among risk factors, climate change and behavioral risk were targeted for R&D. CONCLUSIONS: It would be difficult to say that current R&D allocations focus to minimize the burden of disease. A mismatch was observed between the R&D budget and the burden of disease in terms of economic burden and DALYs. There was a similar finding for risk factors R&D. A novel approach for allocating government R&D funding that is based on the goal of minimizing the disease burden in the Korean population should be considered.

Serum alanine aminotransferase level and liver-related mortality in patients with chronic hepatitis B: A large national cohort study.

BACKGROUND: The serum alanine aminotransferase (ALT) level has been used to identify at-risk patients with chronic hepatitis B (CHB) who need antiviral therapy. However, the level associated with increased liver-related mortality requiring active treatment is still unclear. METHODS: We used a Health Examination Cohort of the National Health Insurance Service of Korea that included approximately 0.5 million individuals aged 40-79 years. In total, 12 486 patients with CHB and no other concurrent liver disease were enrolled, and patients' liver-related mortality, including that owing to liver cancer, was investigated over 9 years. RESULTS: The serum ALT level was correlated positively with liver-related mortality. The rates in men were 0.14, 0.17, 0.24, 0.57, 0.63 and 0.85 per 100 person-years (%) for serum ALT levels of <20, 20-29, 30-39, 40-49, 50-79 and ≥80 U/L, respectively, and the corresponding liver-related mortality rates in women were 0.03%, 0.09%, 0.12%, 0.63%, 0.65% and 0.32%. In patients with ALT levels of 40-79 U/L, the liver-related mortality rates were 0.60% in men and 0.64% in women, which were similar to the overall mortality rate of age- and sex-matched subjects without CHB (0.69%). The best cut-off values for liver-related mortality prediction were >34 U/L in men and >30 U/L in women. CONCLUSIONS: The liver-related mortality rate increased significantly, even in CHB patients with relatively low serum ALT levels. Careful monitoring or earlier antiviral therapy should be considered for patients aged >40 years with serum ALT levels above the upper limit of normal.

Targeting the epitope spreader Pep19 by naïve human CD45RA+ regulatory T cells dictates a distinct suppressive T cell fate in a novel form of immunotherapy.

PURPOSE: Beyond the limited scope of non-specific polyclonal regulatory T cell (Treg)-based immunotherapy, which depends largely on serendipity, the present study explored a target Treg subset appropriate for the delivery of a novel epitope spreader Pep19 antigen as part of a sophisticated form of immunotherapy with defined antigen specificity that induces immune tolerance. METHODS: Human polyclonal CD4+CD25+CD127lo- Tregs (127-Tregs) and naïve CD4+CD25+CD45RA+ Tregs (45RA-Tregs) were isolated and were stimulated with target peptide 19 (Pep19)-pulsed dendritic cells in a tolerogenic milieu followed by ex vivo expansion. Low-dose interleukin-2 (IL-2) and rapamycin were added to selectively exclude the outgrowth of contaminating effector T cells (Teffs). The following parameters were investigated in the expanded antigen-specific Tregs: the distinct expression of the immunosuppressive Treg marker Foxp3, epigenetic stability (demethylation in the Treg-specific demethylated region), the suppression of Teffs, expression of the homing receptors CD62L/CCR7, and CD95L-mediated apoptosis. The expanded Tregs were adoptively transferred into an NOD/scid/IL-2Rγ-/- mouse model of collagen-induced arthritis. RESULTS: Epitope-spreader Pep19 targeting by 45RA-Tregs led to an outstanding in vitro suppressive T cell fate characterized by robust ex vivo expansion, the salient expression of Foxp3, high epigenetic stability, enhanced T cell suppression, modest expression of CD62L/CCR7, and higher resistance to CD95L-mediated apoptosis. After adoptive transfer, the distinct fate of these T cells demonstrated a potent in vivo immunotherapeutic capability, as indicated by the complete elimination of footpad swelling, prolonged survival, minimal histopathological changes, and preferential localization of CD4+CD25+ Tregs at the articular joints in a mechanistic and orchestrated way. CONCLUSIONS: We propose human naïve CD4+CD25+CD45RA+ Tregs and the epitope spreader Pep19 as cellular and molecular targets for a novel antigen-specific Treg-based vaccination against collagen-induced arthritis.

SIRT1/Adenosine Monophosphate-Activated Protein Kinase α Signaling Enhances Macrophage Polarization to an Anti-inflammatory Phenotype in Rheumatoid Arthritis.

Macrophages are crucially involved in the pathogenesis of rheumatoid arthritis (RA). Macrophages of the M1 phenotype act as pro-inflammatory mediators in synovium, whereas those of the M2 phenotype suppress inflammation and promote tissue repair. SIRT1 is a class 3 histone deacetylase with anti-inflammatory characteristics. However, the role played by SIRT1 in macrophage polarization has not been defined in RA. We investigated whether SIRT1 exerts anti-inflammatory effects by modulating M1/M2 polarization in macrophages from RA patients. In this study, SIRT1 activation promoted the phosphorylation of an adenosine monophosphate-activated protein kinase (AMPK) α/acetyl-CoA carboxylase in macrophages exposed to interleukin (IL)-4, and that this resulted in the expressions of M2 genes, including MDC, FcεRII, MrC1, and IL-10, at high levels. Furthermore, these expressions were inhibited by sirtinol (an inhibitor of SIRT1) and compound C (an inhibitor of AMPK). Moreover, SIRT1 activation downregulated LPS/interferon γ-mediated NF-κB activity by inhibiting p65 acetylation and the expression of M1 genes, such as CCL2, iNOS, IL-12 p35, and IL-12 p40. Macrophages from SIRT1 transgenic (Tg)-mice exhibited enhanced polarization of M2 phenotype macrophages and reduced polarization of M1 phenotype macrophages. In line with these observations, SIRT1-Tg mice showed less histological signs of arthritis, that is, lower TNFα and IL-1ß expressions and less severe arthritis in the knee joints, compared to wild-type mice. Taken together, the study shows activation of SIRT1/AMPKα signaling exerts anti-inflammatory activities by regulating M1/M2 polarization, and thereby reduces inflammatory responses in RA. Furthermore, it suggests that SIRT1 signaling be viewed as a therapeutic target in RA.

5-Lipoxygenase in monocytes emerges as a therapeutic target for intimal hyperplasia in a murine wire-injured femoral artery.

Given the importance of leukotrienes in vascular inflammation induced by local tissue injury, this study investigated the role for 5-lipoxygenase (5-LO) in monocytes in the development of intimal hyperplasia. As a mechanistic study, the importance of monocyte 5-LO in monocyte-macrophage differentiation with subsequent infiltration in neointima was evaluated. In a mouse model of wire-injured femoral artery, intimal hyperplasia started as early as 2wks after injury, and luminal area and blood flow were reduced due to increased neointima formation. Time-dependent increases in macrophage infiltration were observed in neointima and showed a positive relationship with neointima volume. In 5-LO-deficient (KO) mice or wild-type (WT) mice treated with an inhibitor of 5-LO activating protein (MK886, 1 and 10mg/kg), intimal hyperplasia and macrophage infiltration into neointima were reduced, but monocyte adhesion to injured luminal surface was not inhibited, which suggested 5-LO participates in monocyte-macrophage differentiation. In an in vitro study, monocyte-macrophage differentiation was found to be increased by high mobility group box 1 protein (HMGB1), but this effect was attenuated in cells isolated from 5-LO-KO mice. Furthermore, macrophage infiltration and intimal hyperplasia were more prominent in 5-LO-KO mice transplanted with monocytes from WT mice than in 5-LO-KO mice transplanted with monocytes from 5-LO-KO mice. Taken together, it was suggested that 5-LO in monocytes played a pivotal role in monocyte-macrophage differentiation and subsequent infiltration of macrophage in neointima, leading to vascular remodeling after vascular injury.

Application of a Modified Garbage Code Algorithm to Estimate Cause-Specific Mortality and Years of Life Lost in Korea.

Years of life lost (YLLs) are estimated based on mortality and cause of death (CoD); therefore, it is necessary to accurately calculate CoD to estimate the burden of disease. The garbage code algorithm was developed by the Global Burden of Disease (GBD) Study to redistribute inaccurate CoD and enhance the validity of CoD estimation. This study aimed to estimate cause-specific mortality rates and YLLs in Korea by applying a modified garbage code algorithm. CoD data for 2010-2012 were used to calculate the number of deaths. The garbage code algorithm was then applied to calculate target cause (i.e., valid CoD) and adjusted CoD using the garbage code redistribution. The results showed that garbage code deaths accounted for approximately 25% of all CoD during 2010-2012. In 2012, lung cancer contributed the most to cause-specific death according to the Statistics Korea. However, when CoD was adjusted using the garbage code redistribution, ischemic heart disease was the most common CoD. Furthermore, before garbage code redistribution, self-harm contributed the most YLLs followed by lung cancer and liver cancer; however, after application of the garbage code redistribution, though self-harm was the most common leading cause of YLL, it is followed by ischemic heart disease and lung cancer. Our results showed that garbage code deaths accounted for a substantial amount of mortality and YLLs. The results may enhance our knowledge of burden of disease and help prioritize intervention settings by changing the relative importance of burden of disease.