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1.
Oncoimmunology ; 10(1): 1899671, 2021 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-33796411

RESUMO

Immunotherapy via interleukin-2 (IL-2) mediated activation of anti-tumor immune response is a promising approach for cancer treatment. The multi-potent cytokine, IL-2 has a central role in immune cell activation and homeostasis. Since IL-2 preferentially activates immunosuppressive T regulatory cells by IL-2Rα dependent manner, blocking IL-2:IL-2Rα interaction is a key to amplify the IL-2 activity in effector T cells toward anti-tumor response. Anti-IL-2 monoclonal antibodies are good candidates to control the IL-2:IL-2Rα interaction. In a previous study, we developed a new IL-2Rα mimetic antibody, TCB2, and showed that the human IL-2(hIL-2):TCB2 complex can stimulate T effector cells specifically and elicit potent anti-cancer immunotherapeutic effect, especially when administered in combination with immune checkpoint inhibitors. To understand the molecular mechanism, we determined the crystal structure of TCB2-Fab in a complex with hIL-2 at 2.5 Å resolution. Our structural analysis reveals that TCB2 binds to the central area of the hIL-2Rα binding region on hIL-2, and binding angle and epitope are different from previously known hIL-2Rα mimicking antibody NARA1 which recognizes the top part of hIL-2. TCB2 binding to hIL-2 also induces an allosteric effect that increases the affinity for the hetero-dimeric hIL-2 receptor, IL-2R(ß + Î³), on effector T cells.

2.
J Exp Med ; 218(6)2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-33822841

RESUMO

Gastric cancer (GC) is one of the most common deadly cancers in the world. Although patient genomic data have identified AT-rich interaction domain 1A (ARID1A), a key chromatin remodeling complex subunit, as the second most frequently mutated gene after TP53, its in vivo role and relationship to TP53 in gastric tumorigenesis remains unclear. Establishing a novel mouse model that reflects the ARID1A heterozygous mutations found in the majority of human GC cases, we demonstrated that Arid1a heterozygosity facilitates tumor progression through a global loss of enhancers and subsequent suppression of the p53 and apoptosis pathways. Moreover, mouse genetic and single-cell analyses demonstrated that the homozygous deletion of Arid1a confers a competitive disadvantage through the activation of the p53 pathway, highlighting its distinct dosage-dependent roles. Using this unique vulnerability of Arid1a mutated GC cells, our combined treatment with the epigenetic inhibitor, TP064, and the p53 agonist, Nutlin-3, inhibited growth of Arid1a heterozygous tumor organoids, providing a novel therapeutic option for GC.

3.
Ann Lab Med ; 41(5): 469-478, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-33824235

RESUMO

Background: Approximately 10%-20% of kidney transplant (KT) recipients suffer from acute rejection (AR); thus, sensitive and accurate monitoring of allograft status is recommended. We evaluated the clinical utility of donor-derived DNA (dd-DNA) detection in the urine of KT recipients as a non-invasive means for diagnosing AR. Methods: Urine samples serially collected from 39 KT recipients were tested for 39 single-nucleotide variant loci selected according to technical criteria (i.e., high minor allele frequency and low analytical error) using next-generation sequencing. The fraction of dd-DNA was calculated and normalized by the urine creatinine (UCr) level (%dd-DNA/UCr). The diagnostic performance of %dd-DNA/UCr for AR was assessed by ROC curve analysis. Results: There was an increasing trend of %dd-DNA/UCr in the AR group before subsequent graft injury, which occurred before (median of 52 days) histological rejection. The serum creatinine (SCr) level differed significantly between the AR and non-AR groups at two and four months of follow-up, whereas %dd-DNA/UCr differed between the groups at six months of follow-up. The combination of %dd-DNA/UCr, SCr, and spot urine protein (UPtn)/UCr showed high discriminating power, with an area under the ROC curve of 0.93 (95% confidence interval: 0.81-1.00) and a high negative predictive value of 100.0%. Conclusions: Although the dd-DNA-based test cannot eliminate the need for biopsy, the high negative predictive value of this marker could increase the prebiopsy probability of detecting treatable injury to make biopsy an even more effective diagnostic tool.

4.
Sci Rep ; 11(1): 7244, 2021 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-33790305

RESUMO

The screening rate of diabetic retinopathy (DR) is low despite the importance of early diagnosis. We investigated the predictive value of dietary glutamic acid and aspartic acid for diagnosis of DR using the Korea National Diabetes Program cohort study. The 2067 patients with type 2 diabetes without DR were included. The baseline intakes of energy, glutamic acid and aspartic acid were assessed using a 3-day food records. The risk of DR incidence based on intake of glutamic acid and aspartic acid was analyzed. The DR group was older, and had higher HbA1c, longer DM duration, lower education level and income than non-DR group (all p < 0.05). The intake of total energy, glutamic acid and aspartic acid were lower in DR group than non-DR group (p = 0.010, p = 0.025 and p = 0.042, respectively). There was no difference in the risk of developing DR according to the intake of glutamic acid and ascorbic acid. But, aspartic acid intake had a negative correlation with PDR. Hence, the intake of glutamic acid and aspartic acid did not affect in DR incidence. However, lower aspartic acid intake affected the PDR incidence.

5.
Med Image Anal ; 71: 102036, 2021 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-33827038

RESUMO

Image registration is a fundamental task in medical image analysis. Recently, many deep learning based image registration methods have been extensively investigated due to their comparable performance with the state-of-the-art classical approaches despite the ultra-fast computational time. However, the existing deep learning methods still have limitations in the preservation of original topology during the deformation with registration vector fields. To address this issues, here we present a cycle-consistent deformable image registration, dubbed CycleMorph. The cycle consistency enhances image registration performance by providing an implicit regularization to preserve topology during the deformation. The proposed method is so flexible that it can beapplied for both 2D and 3D registration problems for various applications, and can be easily extended to multi-scale implementation to deal with the memory issues in large volume registration. Experimental results on various datasets from medical and non-medical applications demonstrate that the proposed method provides effective and accurate registration on diverse image pairs within a few seconds. Qualitative and quantitative evaluations on deformation fields also verify the effectiveness of the cycle consistency of the proposed method.

7.
J Enzyme Inhib Med Chem ; 36(1): 856-868, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33771089

RESUMO

The present study describes evaluation of epigenetic regulation by a small molecule as the therapeutic potential for treatment of Huntington's disease (HD). We identified 5-allyloxy-2-(pyrrolidin-1-yl)quinoline (APQ) as a novel SETDB1/ESET inhibitor using a combined in silico and in vitro cell based screening system. APQ reduced SETDB1 activity and H3K9me3 levels in a HD cell line model. In particular, not only APQ reduced H3K9me3 levels in the striatum but it also improved motor function and neuropathological symptoms such as neuronal size and activity in HD transgenic (YAC128) mice with minimal toxicity. Using H3K9me3-ChIP and genome-wide sequencing, we also confirmed that APQ modulates H3K9me3-landscaped epigenomes in YAC128 mice. These data provide that APQ, a novel small molecule SETDB1 inhibitor, coordinates H3K9me-dependent heterochromatin remodelling and can be an epigenetic drug for treating HD, leading with hope in clinical trials of HD.

8.
Aging Cell ; 20(3): e13332, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33709472

RESUMO

We previously demonstrated that ibrutinib modulates LPS-induced neuroinflammation in vitro and in vivo, but its effects on the pathology of Alzheimer's disease (AD) and cognitive function have not been investigated. Here, we investigated the effects of ibrutinib in two mouse models of AD. In 5xFAD mice, ibrutinib injection significantly reduced Aß plaque levels by promoting the non-amyloidogenic pathway of APP cleavage, decreased Aß-induced neuroinflammatory responses, and significantly downregulated phosphorylation of tau by reducing levels of phosphorylated cyclin-dependent kinase-5 (p-CDK5). Importantly, tau-mediated neuroinflammation and tau phosphorylation were also alleviated by ibrutinib injection in PS19 mice. In 5xFAD mice, ibrutinib improved long-term memory and dendritic spine number, whereas in PS19 mice, ibrutinib did not alter short- and long-term memory but promoted dendritic spinogenesis. Interestingly, the induction of dendritic spinogenesis by ibrutinib was dependent on the phosphorylation of phosphoinositide 3-kinase (PI3K). Overall, our results suggest that ibrutinib modulates AD-associated pathology and cognitive function and may be a potential therapy for AD.

9.
Int J Mol Sci ; 22(5)2021 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-33668863

RESUMO

Lon protease 1 (LONP1) is a highly conserved serine peptidase that plays an important role in the protein quality control system in mammalian mitochondria. LONP1 catalyzes the degradation of oxidized, dysfunctional, and misfolded matrix proteins inside mitochondria and regulates mitochondrial gene expression and genome integrity. Therefore, LONP1 is up-regulated and suppresses cell death in response to oxidative stress, heat shock, and nutrient starvation. On the other hand, translocation of high mobility group box 1 (HMGB1) and active caspase-3 into mitochondria is involved in apoptosis of parvalbumin (PV) cells (one of the GABAergic interneurons) and necrosis of CA1 neurons in the rat hippocampus, respectively, following status epilepticus (SE). In the present study, we investigated whether LONP1 may improve neuronal viability to prevent or ameliorate translocation of active caspase-3 and HMGB1 in mitochondria within PV and CA1 neurons. Following SE, LONP1 expression was up-regulated in mitochondria of PV and CA1 neurons. LONP1 knockdown deteriorated SE-induced neuronal death with mitochondrial accumulation of active caspase-3 and HMGB1 in PV cells and CA1 neurons, respectively. LONP1 knockdown did not affect the aberrant mitochondrial machinery induced by SE. Therefore, our findings suggest, for the first time, that LONP1 may contribute to the alleviation of mitochondrial overloads of active caspase-3 and HMGB1, and the maintenance of neuronal viability against SE.

10.
Biomedicines ; 9(2)2021 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-33670708

RESUMO

Therapeutic applications of extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) have attracted considerable attention because of their immunomodulatory properties against immune-mediated, inflammatory diseases. Here, we demonstrated enhanced immunomodulatory properties of EVs secreted from endoplasmic reticulum (ER) stress inducer thapsigargin (TSG)-primed human Wharton's jelly-derived MSCs (WJ-MSCs). EVs from TSG-primed WJ-MSCs (TSG-EV) showed increased yield and expression of immunomodulatory factors, such as transforming growth factor-ß1 (TGFß), cyclooxygenase-2 (COX2), and especially indoleamine 2,3-dioxygenase (IDO), compared to control EVs. TSG-EV showed a significantly enhanced immunosuppressive effect on human peripheral blood-derived T cell proliferation and Th1 and Th17 differentiation, whereas Treg and M2-type macrophage were enriched compared to a control EV-treated group. Furthermore, TSG-EV substantially mitigated mouse experimental colitis by reducing the inflammatory response and maintaining intestinal barrier integrity. A significant increase of Tregs and M2-type macrophages in colitic colons of a TSG-EV-treated mouse suggests an anti-inflammatory effect of TSG-EV in colitis model, possibly mediated by Treg and macrophage polarization. These data indicate that TSG treatment promoted immunomodulatory properties of EVs from WJ-MSCs, and TSG-EV may provide a new therapeutic approach for treatment of colitis.

11.
J Dairy Sci ; 2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33685684

RESUMO

Human milk lipids provide not only energy but also indispensable bioactive components such as essential fatty acids. To establish the recommended daily intake value and guidelines for infant formula, a reference library of fatty acid composition has been generated from 4 Asian countries (Korea, China, Vietnam, and Pakistan). Regardless of country, palmitic acid (C16:0), linoleic acid (C18:1), and linolenic acid (C18:2) were the 3 most abundant fatty acids in human milk and account for more than 75% of total fatty acids (total FAtotal FA). However, there were several considerable differences between fatty acids, particularly n-3 and n-6 (omega-3 and omega-6) groups. Chinese mothers' milk had a high concentration of linoleic acid at 24.38 ± 10.02% of TOTAL FA, which may be due to maternal diet. Among the 4 countries, Pakistani mothers' milk contained a high amount of saturated fatty acid (56.83 ± 5.96% of total FA), and consequently, polyunsaturated fatty acids, including n-3 and n-6, were significantly lower than in other countries. It is noteworthy that docosahexaenoic acid (DHA) in Pakistani mothers' milk was 44.8 ± 33.3 mg/L, which is only 25 to 30% of the levels in the other 3 countries, suggesting the need for DHA supplementation for infants in Pakistan. Moreover, the ratio of n-6 to n-3 was also remarkably high in Pakistani mothers' milk (15.21 ± 4.96), being 1.4- to 1.7-fold higher than in other countries. The average DHA:ARA ratio in Asian human milk was 1.01 ± 0.79. Korean mothers' milk showed a high DHA:ARA ratio, with a value of 1.30 ± 0.98, but Pakistani mothers' milk had a significantly lower value (0.42 ± 0.12). The fatty acid compositions and anthropometric data of mother (body mass index, age) did not show any correlation. The obtained data might provide information about human milk compositions in the Asian region that could benefit from setting up recommended nutrient intake and infant formula for Asian babies.

12.
J Infect Chemother ; 2021 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-33642250

RESUMO

BACKGROUND: Community-acquired acute pyelonephritis (CA-APN) is relatively rare in men. This study aimed to compare the clinical characteristics of CA-APN between male and female patients. METHODS: We prospectively collected the clinical and microbiological data of hospitalized CA-APN patients aged ≥19 years in South Korea from March 2010 to February 2011 in 11 hospitals and from September 2017 to August 2018 in 8 hospitals. Only the first episodes of APN of each patient during the study period were included. RESULTS: From 2010 to 2011, 573 patients from 11 hospitals were recruited, and from 2017 to 2018, 340 patients were recruited from 8 hospitals. Among them, 5.9% (54/913) were male. Male patients were older (66.0 ± 15.2 vs. 55.3 ± 19.0 years, P < 0.001), had a higher Charlson comorbidity index (1.3 ± 1.5 vs. 0.7 ± 1.2, P = 0.027), and had a higher proportion of structural problems in the urinary tract (40.7% vs. 6.1%, P < 0.001) than female patients. Moreover, the total duration of antibiotic treatment was longer (21.8 ± 17.8 d vs. 17.3 ± 9.4 d, P = 0.001) and the proportion of carbapenem usage was higher (24.1% vs. 9.5%, P = 0.001) in men than in women. Male patients were hospitalized for longer durations than female patients (median, 10 d vs. 7 d, P < 0.001). CONCLUSIONS: Male CA-APN patients were older and had more comorbidities than female CA-APN patients. In addition, male patients received antibiotic treatment for a longer duration than female patients.

13.
Sci Rep ; 11(1): 5874, 2021 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-33712656

RESUMO

To characterize the carriage of antibiotic resistance genes (ARGs) in the gut microbiome of healthy individuals. Fecal carriage of ARGs was investigated in 61 healthy individuals aged 30 to 59 years through whole metagenome sequencing of the gut microbiome and a targeted metagenomic approach. The number of ARGs in the gut microbiome was counted and normalized per million predicted genes (GPM). In the Korean population, the resistome ranged from 49.7 to 292.5 GPM (median 89.7). Based on the abundance of ARGs, the subjects were categorised into high (> 120 GPM), middle (60‒120 GPM), and low (< 60 GPM) ARG groups. Individuals in the high ARG group tended to visit hospitals more often (P = 0.065), particularly for upper respiratory tract infections (P = 0.066), and carried more blaCTX-M (P = 0.008). The targeted metagenome approach for bla and plasmid-mediated quinolone resistance (PMQR) genes revealed a high fecal carriage rate; 23% or 13.1% of the subjects carried blaCTX-M or blaCMY-2, respectively. Regarding PMQR genes, 59% of the subjects carried PMQR, and 83% of them harboured 2‒4 PMQR genes (qnrB 44.3%, qnrS 47.5% etc.). The presence of blaCTX-M correlated with ARG abundance in the gut resistome, whereas PMQR genes were irrelevant to other ARGs (P = 0.176). Fecal carriage of blaCTX-M and PMQR genes was broad and multiplexed among healthy individuals.

14.
Ageing Res Rev ; 68: 101333, 2021 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-33774194

RESUMO

The responses of central nervous system (CNS) cells such as neurons and glia in neurodegenerative diseases (NDs) suggest that regulation of neuronal and glial functions could be a strategy for ND prevention and/or treatment. However, attempts to develop such therapeutics for NDs have been hindered by the challenge of blood-brain barrier (BBB) permeability and continued constitutive neuronal loss. These limitations indicate the need for additional perspectives for the prevention/treatment of NDs. In particular, the disruption of the blood-brain barrier (BBB) that accompanies NDs allows brain infiltration by peripheral factors, which may stimulate innate immune responses involved in the progression of neurodegeneration. The accumulation of blood factors like thrombin, fibrinogen, c-reactive protein (CRP) and complement components in the brain has been observed in NDs and may activate the innate immune system in the CNS. Thus, strengthening the integrity of the BBB may enhance its protective role to attenuate ND progression and functional loss. In this review, we describe the innate immune system in the CNS and the contribution of blood factors to the role of the CNS immune system in neurodegeneration and neuroprotection.

15.
J Glob Antimicrob Resist ; 24: 429-439, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33571708

RESUMO

OBJECTIVES: The optimal treatment option for carbapenem-resistant Acinetobacter baumannii (CRAB) is still limited. This study investigated the efficacy of three or more antibiotic types and regimens for treatment of CRAB infection in high CRAB endemic areas. METHODS: A multicentre retrospective study was conducted to evaluate the efficacy of treatment types and regimens of CRAB infections in 10 tertiary hospitals in the Republic of Korea. The outcomes comprised 7-day and 28-day mortality, and clinical and microbiological responses at 7 days, 28 days, and the end of treatment. Nephrotoxicity and hepatotoxicity were evaluated as drug adverse reactions. RESULTS: A total of 282 patients were included in the study. Among the CRAB strains, the two most susceptible antibiotics were colistin (99.6%) and minocycline (80.4%). A combination of colistin and carbapenem significantly reduced 7-day mortality, and a sulbactam-containing regimen significantly reduced 28-day mortality. Colistin monotherapy was significantly associated with increased 7-day and 28-day mortality. A minocycline-containing regimen showed the best microbiological responses at 7 days, 28 days, and the end of treatment. Colistin and tigecycline were associated with increased nephrotoxicity and hepatotoxicity, respectively. Subgroup analysis of patients with pneumonia showed similar results to the overall CRAB infection. CONCLUSIONS: A combination of colistin and carbapenem and sulbactam-containing regimen may contribute improved mortality in CRAB infections. Colistin monotherapy should be considered cautiously in severe CRAB infections or CRAB pneumonia. A minocycline-containing regimen showed the best microbiological responses, and further studies may be needed to evaluate improved mortality.

16.
AJR Am J Roentgenol ; 216(4): 1003-1013, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33566636

RESUMO

OBJECTIVE. The purpose of this study was to evaluate the diagnostic utility of dual-layer CT (DLCT) for evaluating wrist injuries and to compare it with MRI. MATERIALS AND METHODS. The cases of 62 patients with suspected wrist fractures who underwent imaging with both DLCT and MRI from January 2018 through February 2019 were retrospectively reviewed. By means of a calcium suppression algorithm, virtual noncalcium (VNCa) image reconstruction was performed, and the images were reviewed by two readers to identify fractures, bone contusions, and nontraumatic lesions in the radius, ulna, and carpal bones. Sensitivity, specificity, PPV, and NPV were calculated and compared between standard CT and VNCa images with a combination of standard CT and MRI as the reference standard. RESULTS. Use of DLCT with VNCa reconstruction increased the sensitivity of diagnosis of fractures in the radius and carpal bones over that of standard CT alone; occult fractures were detected that were not seen with standard CT. The sensitivity and specificity for detecting radius fracture were 98.1% and 93.8% for DLCT and 96.3% and 93.8% for standard CT. For detecting carpal bone fracture, sensitivity and specificity were 100% and 98.9% for DLCT and 93.8% and 100% for standard CT. VNCa reconstruction also had good diagnostic accuracy with regard to diagnosing nonfracture bone contusions in carpal bones. The accuracy was comparable to that of MRI with sensitivity of 92.9% and specificity of 94.5%. Interreader agreement in interpreting VNCa images was generally good to excellent. CONCLUSION. DLCT with VNCa reconstruction is a promising tool for identifying occult wrist fractures and nonfracture contusion injuries in patients with wrist trauma.

17.
Stem Cell Res ; 51: 102199, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33529979

RESUMO

Human induced pluripotent stem cells with indefinite propagation in vitro provide a potential donor source of cells including erythroid cells for human therapy. Since group O D-negative (RhD-) blood cells are considered as universal donors for transfusion, it is compelling to derive iPSC line from group O/RhD- sample as a new cellular source to generate universal RBCs. The resulting iPSC line derived from group O/RhD- somatic source showed typical features of pluripotent stem cells and could provide an unprecedented cellular tool to develop universal therapeutics for blood transfusion.

19.
Anat Sci Int ; 2021 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-33625718

RESUMO

Identifying of variations of renal vascular anatomy is important for radical surgery, endovascular intervention, and renal transplantation. While there are common normal variations of renal vascular anatomy, such as accessory renal arteries, a main renal artery that originates from the thoracic aorta (thoracic renal artery) is remarkably rare. The majority of reported cases of thoracic renal artery were right side, except two cases reported on 1980 and 2016. The author reports a rare case of left renal artery originating from the thoracic aorta.

20.
PLoS Negl Trop Dis ; 15(2): e0009128, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33606699

RESUMO

BACKGROUND: Severe fever with thrombocytopenia syndrome (SFTS) is an acute, febrile, and potentially fatal tick-borne disease caused by the SFTS Phlebovirus. Here, we evaluated the effects of steroid therapy in Korean patients with SFTS. METHODS: A retrospective study was performed in a multicenter SFTS clinical cohort from 13 Korean university hospitals between 2013 and 2017. We performed survival analysis using propensity score matching of 142 patients with SFTS diagnosed by genetic or antibody tests. RESULTS: Overall fatality rate was 23.2%, with 39.7% among 58 patients who underwent steroid therapy. Complications were observed in 37/58 (63.8%) and 25/83 (30.1%) patients in the steroid and non-steroid groups, respectively (P < .001). Survival analysis after propensity score matching showed a significant difference in mean 30-day survival time between the non-steroid and steroid groups in patients with a mild condition [Acute Physiology and Chronic Health Evaluation II (APACHE II) score <14; 29.2 (95% CI 27.70-30.73] vs. 24.9 (95% CI 21.21-28.53], P = .022]. Survival times for the early steroid (≤5 days from the start of therapy after symptom onset), late steroid (>5 days), and non-steroid groups, were 18.4, 22.4, and 27.3 days, respectively (P = .005). CONCLUSIONS: After steroid therapy, an increase in complications was observed among patients with SFTS. Steroid therapy should be used with caution, considering the possible negative effects of steroid therapy within 5 days of symptom onset or in patients with mild disease (APACHE II score <14).

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