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1.
Statin therapy in individuals with intermediate cardiovascular risk.
Kim, J, Kim, H, Park, SH, Kang, Y, Han, K, Lee, SH
Metabolism: clinical and experimental. 2024;:155723
Abstract
BACKGROUND As intermediate cardiovascular risk group accounts for a large part of the total population, determining appropriate cholesterol target in this population is critical. Herein, we investigated the optimal low-density lipoprotein cholesterol (LDL-C) level in individuals with intermediate cardiovascular risk after statin therapy. METHODS This was a nationwide observational and validation cohort study (median duration of follow-up: 7.5 and 8.7 years, respectively), using data from the Korean National Health Insurance Service and a tertiary hospital database. Among individuals who underwent regular health examinations, those with ≥2 cardiovascular risk factors except diabetes mellitus, LDL-C 100-189 mg/dL, and newly used statins were enrolled. Of the 358,694 screened people, 57,594 met the inclusion criteria, of whom 27,793 were finally analyzed. The study population was stratified according to post-treatment LDL-C levels as follows: <100, 100-119, 120-139, and ≥ 140 mg/dL. The primary outcome variable was composite cardiovascular events (myocardial infarction, coronary revascularization, and ischemic stroke). From the patients screened of Severance Hospital cohort, 1859 meeting inclusion criteria were used for validation. RESULTS The rates of composite events ranged from 7.74 to 9.10 (mean 8.38)/1000 person-years in the three lower LDL-C groups. Adjusted hazard ratios (aHRs) ranged from 0.78 to 0.95 in the three groups with lower LDL-C, and a lower event risk was more evident in the groups that achieved LDL-C levels <120 mg/dL (p = 0.001-0.009). The total mortality risk did not differ between groups. In the validation cohort, the mean rate of composite events was 10.83/1000 person-years. aHRs ranged from 0.52 to 0.78 in the groups with lower LDL-C, and a lower risk was more obvious in patients who achieved LDL-C levels <100 mg/dL (p = 0.006-0.03). CONCLUSIONS Individuals with intermediate cardiovascular risk who achieved LDL-C levels <120 mg/dL after statin therapy had lower event risk. This result provides clinically useful evidence on target LDL-C levels in this population.
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2.
Engineering Strategies to Modulate the Gut Microbiome and Immune System.
Han, K, Xu, J, Xie, F, Crowther, J, Moon, JJ
Journal of immunology (Baltimore, Md. : 1950). 2024;(2):208-215
Abstract
The gut microbiota, predominantly residing in the colon, is a complex ecosystem with a pivotal role in the host immune system. Dysbiosis of the gut microbiota has been associated with various diseases, and there is an urgent need to develop new therapeutics that target the microbiome and restore immune functions. This Brief Review discusses emerging therapeutic strategies that focus on oral delivery systems for modulating the gut microbiome. These strategies include genetic engineering of probiotics, probiotic-biomaterial hybrids, dietary fibers, and oral delivery systems for microbial metabolites, antimicrobial peptides, RNA, and antibiotics. Engineered oral formulations have demonstrated promising outcomes in reshaping the gut microbiome and influencing immune responses in preclinical studies. By leveraging these approaches, the interplay between the gut microbiota and the immune system can be harnessed for the development of novel therapeutics against cancer, autoimmune disorders, and allergies.
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3.
Establishing a Clinical Care Pathway to Expedite Rehabilitation Transitions for Stroke Patients With Dysphagia and Enteral Feeding Needs.
Braun, R, Han, K, Arata, J, Gourab, K, Hearn, J, Gonzalez-Fernandez, M
American journal of physical medicine & rehabilitation. 2024;(5):390-394
Abstract
OBJECTIVE The aim of the study is to evaluate the safety and efficacy of a physiatrist-led clinical pathway to expedite rehabilitation transitions for stroke patients with dysphagia requiring nasogastric tube or percutaneous endoscopic gastrostomy. DESIGN This is a retrospective single-center observational study in 426 adults with stroke and dysphagia admitted to the acute hospital. Physican Medicine and Rehabilitation (PM&R) was consulted to determine dysphagia prognosis and candidacy for rehabilitation admission with nasogastric tube or percutaneous endoscopic gastrostomy. The proportion of patients accepted with nasogastric tube versus percutaneous endoscopic gastrostomy, progression to total oral diet during rehabilitation, and lengths of stay were tracked. RESULTS The rate of recovery to total oral diet for patients accepted with nasogastric tube was 38/44 = 86.3% versus 29/75 = 38.6% with percutaneous endoscopic gastrostomy. There was a significant difference in mean time to total oral diet with nasogastric tube (20.37 days) versus percutaneous endoscopic gastrostomy (34.46 days): t (43) = 4.49, P < 0.001. The acute hospital length of stay was significantly shorter with nasogastric tube (12.9 days) versus percutaneous endoscopic gastrostomy (20.4 days): t (117) = 4.16, P < 0.001. Rehabilitation length of stay did not differ significantly between groups (26.9 vs. 32.0 days). CONCLUSION Physiatrist-led initiatives to evaluate stroke patients with dysphagia can expedite rehabilitation transitions, prevent unnecessary invasive procedures, and reduce acute hospital length of stay.
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4.
Managing ferroptosis-related diseases with indirect dietary modulators of ferroptosis.
Cao, L, Zhao, S, Han, K, Fan, L, Zhao, C, Yin, S, Hu, H
The Journal of nutritional biochemistry. 2023;:109427
Abstract
Ferroptosis is an iron-dependent form of programmed cell death driven by excessive oxidation of polyunsaturated phospholipids on cellular membranes. Accumulating evidence suggests that ferroptosis has been implicated in the pathological process of various diseases, such as cardiovascular diseases, neurological diseases, liver diseases, kidney injury, lung injury, diabetes, and cancer. Targeting ferroptosis is therefore considered to be a reasonable strategy to fight against ferroptosis-associated diseases. Many dietary bioactive agents have been identified to be able to either suppress or promote ferroptosis, indicating that ferroptosis-based intervention by dietary approach may be an effective strategy for preventing and treating diseases associated with ferroptosis dysregulation. In this review, we summarize the present understanding of the functional role of ferroptosis in the pathogenesis of aforementioned diseases with an emphasis on the evidence of managing ferroptosis-related diseases with indirect dietary modulators of ferroptosis and propose issues that need to be addressed to promote practical application of dietary approach targeting ferroptosis.
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5.
Postoperative delirium after transcatheter aortic valve replacement: An updated systematic review and meta-analysis.
Ma, X, Chu, H, Han, K, Shao, Q, Yu, Y, Jia, S, Wang, D, Wang, Z, Zhou, Y
Journal of the American Geriatrics Society. 2023;(2):646-660
Abstract
AIMS: To perform an updated systematic review and meta-analysis of postoperative delirium (POD) after transcatheter aortic valve replacement (TAVR). METHODS We conducted a systematic literature search of PubMed, Embase, and Cochrane Library databases from the time of the first human TAVR procedure in 2002 until December 24, 2021, which was supplemented by manual searches of bibliographies. Data were collected on incidence rates, risk factors, and/or associated mortality of POD after TAVR. Pooled analyses were conducted using random effects models to yield mean differences, odds ratios, hazard ratios, and risk ratios, with 95% confidence intervals. RESULTS A total of 70 articles (69 studies) comprising 413,389 patients were included. The study heterogeneity was substantial. The pooled mean incidence of POD after TAVR in all included studies was 9.8% (95% CI: 8.7%-11.0%), whereas that in studies using validated tools to assess for delirium at least once a day for at least 2 consecutive days after TAVR was 20.7% (95% CI: 17.8%-23.7%). According to the level of evidence and results of meta-analysis, independent preoperative risk factors with a high level of evidence included increased age, male sex, prior stroke or transient ischemic attack, atrial fibrillation/flutter, weight loss, electrolyte abnormality, and impaired Instrumental Activities of Daily Living; intraoperative risk factors included non-transfemoral access and general anesthesia; and acute kidney injury was a postoperative risk factor. POD after TAVR was associated with significantly increased mortality (pooled unadjusted RR: 2.20, 95% CI: 1.79-2.71; pooled adjusted RR: 1.62, 95% CI: 1.25-2.10), particularly long-term mortality (pooled unadjusted HR: 2.84, 95% CI: 1.91-4.23; pooled adjusted HR: 1.88, 95% CI: 1.30-2.73). CONCLUSIONS POD after TAVR is common and is associated with an increased risk of mortality. Accurate identification of risk factors for POD after TAVR and implementation of preventive measures are critical to improve prognosis.
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6.
Association between fatty liver index and risk of end-stage renal disease stratified by kidney function in patients with type 2 diabetes: A nationwide population-based study.
Chung, GE, Han, K, Lee, KN, Bae, JH, Yang, SY, Choi, SY, Yim, JY, Heo, NJ
Diabetes & metabolism. 2023;(4):101454
Abstract
OBJECTIVE The effects of nonalcoholic fatty liver disease on the risk of end-stage renal disease (ESRD) remain unclear. We investigated the association between the fatty liver index (FLI) and risk of ESRD in patients with type 2 diabetes. METHODS This population-based observational cohort study enrolled patients with diabetes who underwent health screening between 2009 and 2012 and utilized data from the Korean National Health Insurance Services. The FLI functioned as a surrogate marker for the presence of hepatic steatosis. Chronic kidney disease (CKD) was defined as an estimated glomerular filtration rate < 60 ml/min/1.73 m² calculated using the Modification of Diet in Renal Disease equation. We performed Cox proportional hazards regression. RESULTS Incident ESRD developed in 19,476 of 1,900,598 patients with type 2 diabetes during a median follow-up of 7.2 years. After adjusting for conventional risk factors, patients with high FLI scores had a higher risk for ESRD FLI, 30-59 [hazard ratio (HR) = 1.124; 95% confidence interval (CI), 1.083-1.166]; FLI ≥ 60 [HR = 1.278; 95% CI, 1.217-1.343] compared with those with FLI < 30. The association between a high FLI score (≥ 60) and incident ESRD was more prominent in women than in men (male, FLI ≥60: HR, 1.106; 95% CI = 1.041-1.176 and female, FLI ≥ 60: HR, 1.835; 95% CI = 1.689-1.995). The association between a high FLI score (≥ 60) and the risk of ESRD differed according to baseline kidney function. High FLI scores increased the risk of ESRD (HR = 1.268; 95% CI, 1.198-1.342) in patients with CKD at baseline. CONCLUSION High FLI scores are associated with a greater risk of ESRD in patients with type 2 diabetes with CKD at baseline. Close monitoring and appropriate management of hepatic steatosis may aid in preventing the progression of kidney dysfunction in patients with type 2 diabetes and CKD.
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7.
Cuproptosis-Related MiR-21-5p/FDX1 Axis in Clear Cell Renal Cell Carcinoma and Its Potential Impact on Tumor Microenvironment.
Xie, M, Cheng, B, Yu, S, He, Y, Cao, Y, Zhou, T, Han, K, Dai, R, Wang, R
Cells. 2022;(1)
Abstract
As a newly identified type of programmed cell death, cuproptosis may have an impact on cancer development, including clear cell renal cell carcinoma (ccRCC). Herein, we first noticed that the expression levels of cuproptosis regulators exhibited a tight correlation with the clinicopathological characteristics of ccRCC. The cuproptosis-sensitive sub-type (CSS), classified via consensus clustering analysis, harbored a higher overall survival rate compared to the cuproptosis-resistant sub-type (CRS), which may have resulted from the differential infiltration of immune cells. FDX1, the cuproptosis master regulator, was experimentally determined as a tumor suppressor in ccRCC cells by suppressing the cell growth and cell invasion of ACHN and OSRC-2 cells in a cuproptosis-dependent and -independent manner. The results from IHC staining also demonstrated that FDX1 expression was negatively correlated with ccRCC tumor initiation and progression. Furthermore, we identified the miR-21-5p/FDX1 axis in ccRCC and experimentally verified that miR-21-5p directly binds the 3'-UTR of FDX1 to mediate its degradation. Consequently, a miR-21-5p inhibitor suppressed the cell growth and cell invasion of ACHN and OSRC-2 cells, which could be compensated by FDX1 knockdown, reinforcing the functional linkage between miR-21-5p and FDX1 in ccRCC. Finally, we evaluated the ccRCC tumor microenvironment under the miR-21-5p/FDX1 axis and noted that this axis was strongly associated with the infiltration of immune cells such as CD4+ T cells, Treg cells, and macrophages, suggesting that this signaling axis may alter microenvironmental components to drive ccRCC progression. Overall, this study constructed the miR-21-5p/FDX1 axis in ccRCC and analyzed its potential impact on the tumor microenvironment, providing valuable insights to improve current ccRCC management.
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8.
Neuronal mitochondrial morphology is significantly affected by both fixative and oxygen level during perfusion.
Kim, SY, Strucinska, K, Osei, B, Han, K, Kwon, SK, Lewis, TL
Frontiers in molecular neuroscience. 2022;:1042616
Abstract
Neurons in the brain have a uniquely polarized structure consisting of multiple dendrites and a single axon generated from a cell body. Interestingly, intracellular mitochondria also show strikingly polarized morphologies along the dendrites and axons: in cortical pyramidal neurons (PNs), dendritic mitochondria have a long and tubular shape, while axonal mitochondria are small and circular. Mitochondria play important roles in each compartment of the neuron by generating adenosine triphosphate (ATP) and buffering calcium, thereby affecting synaptic transmission and neuronal development. In addition, mitochondrial shape, and thereby function, is dynamically altered by environmental stressors such as oxidative stress or in various neurodegenerative diseases including Alzheimer's disease and Parkinson's disease. Although the importance of altered mitochondrial shape has been claimed by multiple studies, methods for studying this stress-sensitive organelle have not been standardized. Here we address pertinent steps that influence mitochondrial morphology during experimental processes. We demonstrate that fixative solutions containing only paraformaldehyde (PFA), or that introduce hypoxic conditions during the procedure, induce dramatic fragmentation of mitochondria both in vitro and in vivo. This disruption was not observed following the use of glutaraldehyde (GA) addition or oxygen supplementation, respectively. Finally, using pre-formed fibril α-synuclein treated neurons, we show fixative choice can alter experimental outcomes. Specifically, α-synuclein-induced mitochondrial remodeling could not be observed with PFA only fixation as fixation itself caused mitochondrial fragmentation. Our study provides optimized methods for examining mitochondrial morphology in neurons and demonstrates that fixation conditions are critical when investigating the underlying cellular mechanisms involving mitochondria in physiological and neurodegenerative disease models.
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9.
Voltage-gated sodium channel Nav1.5 promotes tumor progression and enhances chemosensitivity to 5-fluorouracil in colorectal cancer.
Sui, Q, Peng, J, Han, K, Lin, J, Zhang, R, Ou, Q, Qin, J, Deng, Y, Zhou, W, Kong, L, et al
Cancer letters. 2021;:119-131
Abstract
Nav1.5, encoded by SCN5A, has been associated with metastasis in colorectal cancer (CRC). Here, we investigated the mechanism by which Nav1.5 regulates tumor progression and whether Nav1.5 influences chemosensitivity to 5-fluorouracil (5-FU) in CRCs. CRC cases were evaluated for Nav1.5 expression. Elevated Nav1.5 expression was associated with poor prognosis in CRCs, whereas stage II/III patients with upregulated SCN5A expression could have better survival after receiving 5-FU-based adjuvant chemotherapy. In CRC cells, SCN5A knockdown reduced the proliferation, migration and invasion. According to RNA sequencing, SCN5A knockdown inhibited both the cell cycle and epithelial-mesenchymal transition. In addition, Nav1.5 stabilized the KRas-calmodulin complex to modulate Ras signaling, promoting Ca2+ influx through the Na+-Ca2+ exchanger and Ca2+ release-activated calcium channel. Meanwhile, SCN5A knockdown increased the 50% inhibitory concentration to 5-FU by upregulating 5-FU-stimulated apoptosis in CRCs. In conclusion, Nav1.5 could progress to proliferation and metastasis through Ca2+/calmodulin-dependent Ras signaling in CRC, and it could also enhance 5-FU-stimulated apoptosis. Clinically, patients with stage II/III CRCs with elevated SCN5A expression demonstrated poor prognosis, yet those patients could benefit more from 5-FU-based chemotherapy than patients with lower SCN5A expression.
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10.
Association of anthropometric and nutrition status indicators with cognitive functions in centenarians.
Tai, P, Yang, S, Liu, W, Wang, S, Chen, K, Jia, W, Han, K, Liu, M, He, Y
Clinical nutrition (Edinburgh, Scotland). 2021;(4):2252-2258
Abstract
BACKGROUND & AIMS How anthropometric and nutrition status indicators relate to cognitive function in the oldest old adults is an issue that needs to be explored. This study aimed to analyze the association of parameters and nutrition status indicators (waist circumference, BMI, calf circumference, and waist-calf circumference ratio [WCR]) with cognitive functions in centenarians. METHODS A cross-sectional observational study was conducted with the full sample of 1002 centenarians from Hainan. The mini-mental state examination (MMSE) was used to identify cognitive impairment. Multiple logistic regression analysis was used to examine the strength of association between each anthropometric index and the risk of cognitive impairment or severe cognitive impairment identified by MMSE. Locally Weighted Scatterplot Smoothing (LOWESS) curve was used to visualize the linear or non-linear relationship of each pair. RESULTS The risk of cognitive impairment identified by MMSE for centenarians was reduced by 12% for every 1 cm thickening of the calf circumference (OR = 0.88, 95% CI: 0.81-0.95) and the increase in each unit of WCR increased cognitive impairment the risk by 1.60 times (OR = 2.60, 95% CI: 1.31-5.13) after adjusting for demographic characteristics (i.e., gender, age, ethnicity, marital status, education level, and type of residence) and lifestyle (i.e., smoking, drinking, and exercise) related variables. CONCLUSIONS Results suggest that calf circumference is negatively associated with the risk of cognitive impairment identified by MMSE in centenarians. Older adults with lower calf circumference should pay attention to their cognitive function.