Publications by authors named "Young-Ho Lee"

727 Publications

Characterization of alfalfa mosaic virus capsid protein using Cryo-EM.

Biochem Biophys Res Commun 2021 Apr 30;559:161-167. Epub 2021 Apr 30.

BioApplications Inc., Pohang Techno Park Complex, 394 Jigok-ro Nam-gu, Pohang, 37668, South Korea. Electronic address:

VLPs are virus-like particles that comprise viral capsid proteins that can self-assemble and mimic the shape and size of real viral particles; however, because they do not contain genetic material they cannot infect host cells. VLPs have great potential as safe drug/vehicle candidates; therefore, they are gaining popularity in the field of preventive medicine and therapeutics. Indeed, extensive studies are underway to examine their role as carriers for immunization and as vehicles for delivery of therapeutic agents. Here, we examined the possibility of developing VLP-utilizing technology based on an efficient VLP production process and high-resolution structural analysis. Nicotiana benthamiana was used as an expression platform to produce the coat protein of the alfalfa mosaic virus (AMV-CP). About 250 mg/kg of rAMV-CP was produced from Nicotiana benthamiana leaves. Structural analysis revealed that the oligomeric status of rAMV-CP changed according to the composition and pH of the buffer. Size exclusion chromatography and electron microscopy analysis confirmed the optimal conditions for rAMV-CP VLP formation, and a 2.4 Å resolution structure was confirmed by cryo-EM analysis. Based on the efficient protein production, VLP manufacturing technology, and high-resolution structure presented herein, we suggest that rAMV-CP VLP is a useful platform for development of various new drugs.
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http://dx.doi.org/10.1016/j.bbrc.2021.04.060DOI Listing
April 2021

Suppressed estrogen supply extra-ovarian progesterone receptor membrane component 1 in menopause.

J Biomed Res 2021 Jan 29:1-10. Epub 2021 Jan 29.

College of Veterinary Medicine, Chungnam National University, Daejeon 34134, Republic of Korea.

In post-menopausal women, intra-mammary estrogen, which is converted from extra-ovarian estrone (E1), promotes the growth of breast cancer. Since the aromatase inhibitor letrozole does not suppress 17β-estradiol (E2) production from E1, high intra-mammary E1 concentrations impair letrozole's therapeutic efficacy. Progesterone receptor membrane component 1 (Pgrmc1) is a non-classical progesterone receptor associated with breast cancer progression. In the present study, we introduced a heterozygous knockout (hetero KO) murine model exhibiting low Pgrmc1 expression, and observed estrogen levels and steroidogenic gene expression. Naïve hetero KO mice exhibited low estrogen (E2 and E1) levels and low progesterone receptor (PR) expression, compared to wild-type mice. In contrast, hetero KO mice that have been ovariectomized (OVX), including letrozole-treated OVX mice (OVX-letrozole), exhibited high estrogen levels and PR expression. Increased extra-ovarian estrogen production in hetero KO mice was observed with the induction of steroid sulfatase (STS). In MCF-7 cell, letrozole suppressed PR expression, but knockdown increased PR and STS expression. Our presented results highlight the important role of in modulating estrogen production when ovary-derived estrogen is limited, thereby suggesting a potential therapeutic approach for letrozole resistance.
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http://dx.doi.org/10.7555/JBR.35.20200172DOI Listing
January 2021

Comparison of the efficacy and safety of tofacitinib and mavrilimumab in patients with active rheumatoid arthritis: A Bayesian network meta-analysis of randomized controlled trials.

Int J Clin Pharmacol Ther 2021 Apr 16. Epub 2021 Apr 16.

Objectives: The relative efficacy and safety of tofacitinib and mavrilimumab were assessed in patients with rheumatoid arthritis (RA) presenting an inadequate response to disease-modifying antirheumatic drugs (DMARDs).

Materials And Methods: We performed a Bayesian network meta-analysis combining direct and indirect evidence from randomized controlled trials (RCTs) to examine the efficacy and safety of tofacitinib and mavrilimumab combined with DMARDs in patients with an inadequate response to DMARDs.

Results: In total, 8 RCTs with 2,965 patients met inclusion criteria. 21 pairwise comparisons were performed, including 12 direct comparisons of 7 interventions. In patients with active RA and an inadequate DMARD response, mavrilimumab 150 mg+methotrexate (MTX) and mavrilimumab 100 mg+MTX were the most effective treatments. Compared with placebo+MTX, all tofacitinib and mavrilimumab doses, except mavrilimumab 50 mg+MTX, achieved significant ACR20 responses. The ranking probability based on the surface under the cumulative ranking curve indicated that mavrilimumab 150 mg+MTX had the highest probability for best treatment outcome in terms of the ACR20 response rate, followed by mavrilimumab 100 mg+MTX, tofacitinib 10 mg+MTX, tofacitinib 5 mg+MTX, mavrilimumab 30 mg+MTX, mavrilimumab 50 mg+MTX, and placebo+MTX. No significant differences were noted in the incidence of serious adverse events (SAEs) after tofacitinib+MTX, mavrilimumab+MTX, or placebo+MTX.

Conclusion: In patients with RA showing inadequate DMARD response, mavrilimumab 150 mg+MTX and mavrilimumab 100 mg+MTX, followed by tofacitinib 10 mg+MTX and tofacitinib 5 mg+MTX, were the most efficacious interventions and were not associated with a significant risk of SAEs.
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http://dx.doi.org/10.5414/CP203979DOI Listing
April 2021

Relative efficacy and safety of secukinumab and guselkumab for the treatment of active psoriatic arthritis: A network meta-analysis.

Int J Clin Pharmacol Ther 2021 Apr 16. Epub 2021 Apr 16.

Objective: To determine the relative effectiveness and safety of doses of secukinumab and guselkumab in patients with active psoriatic arthritis (PsA).

Materials And Methods: A Bayesian network meta-analysis was performed incorporating data from randomized controlled trials (RCTs) to evaluate the effectiveness and safety of secukinumab 150 mg, secukinumab 300 mg, and guselkumab 100 mg every 4 weeks (Q4W) and guselkumab every 8 weeks (Q8W).

Results: Six RCTs, including 2,385 patients, fulfilled the inclusion criteria. The surface under the cumulative ranking curve (SUCRA) revealed that secukinumab 300 mg had the highest probability of reaching a 20% American College of Rheumatology (ACR20) response rate, followed by secukinumab 150 mg, guselkumab 100 mg Q4W, guselkumab 100 mg Q8W, and placebo. The ACR50 response rate revealed the same distribution pattern as the ACR20 response rate. The SUCRA rating, dependent on the psoriasis area and severity index of at least 75% (PASI75) response rate, showed that guselkumab 100 mg Q4W had the highest possibility of achieving the PASi75 response, followed by guselkumab 100 mg Q8W, secukinumab 300 mg, secukinumab 150 mg, and placebo. Safety analyses focused on serious adverse events (SAEs), adverse events (AEs), and withdrawals attributable to AEs that did not have statistically relevant variation in the respective intervention categories.

Conclusion: Based on the ACR20 and ACR50 response rates, secukinumab 300 mg had the strongest response effectiveness, whereas guselkumab 100 mg Q4W was the most effective treatment strategy for PsA based on PASI75. However, there was little disparity between the treatment options with regard to SAEs.
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http://dx.doi.org/10.5414/CP203906DOI Listing
April 2021

A unique leucine-valine adhesive motif supports structure and function of protein disulfide isomerase P5 via dimerization.

Structure 2021 Apr 9. Epub 2021 Apr 9.

Institute of Multidisciplinary Research for Advanced Materials, Tohoku University, 2-1-1 Katahira, Aoba-ku, Sendai, Miyagi 980-8577, Japan. Electronic address:

P5, also known as PDIA6, is a PDI family member involved in the ER quality control. Here, we revealed that P5 dimerizes via a unique adhesive motif contained in the N-terminal thioredoxin-like domain. Unlike conventional leucine zipper motifs with leucine residues every two helical turns on ∼30-residue parallel α helices, this adhesive motif includes periodic repeats of leucine/valine residues at the third or fourth position spanning five helical turns on 15-residue anti-parallel α helices. The P5 dimerization interface is further stabilized by several reciprocal salt bridges and C-capping interactions between protomers. A monomeric P5 mutant with the impaired adhesive motif showed structural instability and local unfolding, and behaved as aberrant proteins that induce the ER stress response. Disassembly of P5 to monomers compromised its ability to inactivate IRE1α via intermolecular disulfide bond reduction and its Ca-dependent regulation of chaperone function in vitro. Thus, the leucine-valine adhesive motif supports structure and function of P5.
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http://dx.doi.org/10.1016/j.str.2021.03.016DOI Listing
April 2021

Crystal structure of higher plant heme oxygenase-1 and its mechanism of interaction with ferredoxin.

J Biol Chem 2020 Dec 24;296:100217. Epub 2020 Dec 24.

Institute for Protein Research, Osaka University, Suita, Osaka, Japan; Department of Macromolecular Science, Osaka University, Toyonaka, Osaka, Japan. Electronic address:

Heme oxygenase (HO) converts heme to carbon monoxide, biliverdin, and free iron, products that are essential in cellular redox signaling and iron recycling. In higher plants, HO is also involved in the biosynthesis of photoreceptor pigment precursors. Despite many common enzymatic reactions, the amino acid sequence identity between plant-type and other HOs is exceptionally low (∼19.5%), and amino acids that are catalytically important in mammalian HO are not conserved in plant-type HOs. Structural characterization of plant-type HO is limited to spectroscopic characterization by electron spin resonance, and it remains unclear how the structure of plant-type HO differs from that of other HOs. Here, we have solved the crystal structure of Glycine max (soybean) HO-1 (GmHO-1) at a resolution of 1.06 Å and carried out the isothermal titration calorimetry measurements and NMR spectroscopic studies of its interaction with ferredoxin, the plant-specific electron donor. The high-resolution X-ray structure of GmHO-1 reveals several novel structural components: an additional irregularly structured region, a new water tunnel from the active site to the surface, and a hydrogen-bonding network unique to plant-type HOs. Structurally important features in other HOs, such as His ligation to the bound heme, are conserved in GmHO-1. Based on combined data from X-ray crystallography, isothermal titration calorimetry, and NMR measurements, we propose the evolutionary fine-tuning of plant-type HOs for ferredoxin dependency in order to allow adaptation to dynamic pH changes on the stroma side of the thylakoid membrane in chloroplast without losing enzymatic activity under conditions of fluctuating light.
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http://dx.doi.org/10.1074/jbc.RA120.016271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948506PMC
December 2020

Comparative efficacy and safety of secukinumab, ixekizumab, and tofacitinib in patients with active psoriatic arthritis showing insufficient response to tumor necrosis factor inhibitors.

Int J Clin Pharmacol Ther 2021 Apr 9. Epub 2021 Apr 9.

Objective: This study aimed to determine the relative effectiveness and safety of secukinumab, ixekizumab, and tofacitinib in patients with psoriatic arthritis (PsA) showing insufficient responses to tumor necrosis factor (TNF) inhibitors.

Materials And Methods: A Bayesian network meta-analysis was conducted using direct and indirect data from five randomized controlled trials that examined the efficacy and safety of secukinumab 150 mg or 300 mg every 4 weeks, subcutaneously injected ixekizumab 80 mg every 2 weeks (Q2W) or every 4 weeks (Q4W), and tofacitinib 5 mg or 10 mg twice orally in active PsA patients responding insufficiently to TNF inhibitors.

Results: Six RCTs, including 1,279 patients, fulfilled the inclusion criteria. Secukinumab 300 mg, listed at the top left of the league table diagonal, was associated with the most favorable American College of Rheumatology 20 (ACR20) response rate. Contrastingly, the placebo, listed at the bottom right of the league table diagonal, showed the least favorable results. The ixekizumab 80 mg Q2W or Q4W, secukinumab 150 mg, and tofacitinib 5 or 10 mg groups exhibited significantly higher ACR20 responses than the placebo group. The surface under the cumulative ranking curve (SUCRA)-based ranking probability suggested that secukinumab 300 mg was most likely the best treatment to achieve the ACR20 response rate, followed by ixekizumab 80 mg Q2W, secukinumab 150 mg, ixekizumab 80 mg Q4W, tofacitinib 5 and 10 mg, and the placebo.

Conclusion: Secukinumab, ixekizumab, and tofacitinib were effective in PsA patients with inadequate response to TNF inhibitors, without serious adverse event risks.
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http://dx.doi.org/10.5414/CP203944DOI Listing
April 2021

Absence of progesterone receptor membrane component 1 reduces migration and metastasis of breast cancer.

Cell Commun Signal 2021 Apr 8;19(1):42. Epub 2021 Apr 8.

College of Veterinary Medicine, Chungnam National University, Suite 401, Veterinary Medicine Bldg., 99, Daehak-ro, Yuseong-gu, Daejeon, 34134, Republic of Korea.

Background: Progesterone receptor membrane component 1 (Pgrmc1) is a non-classical progesterone receptor associated with the development of the mammary gland and xenograft-induced breast cancer. Importantly, Pgrmc1 is associated with the expression of estrogen receptor alpha and can be used for predicting the prognosis of breast cancer. Whether the genetic deletion of Pgrmc1 affects the progression of breast cancer is still unclear.

Methods: We used MMTV-PyMT transgenic mice that spontaneously develop breast tumors. In backcrossed FVB Pgrmc1 knockout (KO) mice, we monitored the development of the primary tumor and lung metastasis. In MCF-7 and MDA-MB-231 tumor cell lines, the migratory activity was evaluated after Pgrmc1 knockdown.

Results: There was no significant difference in the development of breast cancer in terms of tumor size at 13 weeks of age between WT and Pgrmc1 KO mice. However, Pgrmc1 KO mice had a significantly longer survival duration compared with WT mice. Furthermore, Pgrmc1 KO mice exhibited a significantly lower degree of lung metastasis. Compared with those of WT mice, the tumors of Pgrmc1 KO mice had a low expression of focal adhesion kinase and epithelial-mesenchymal transition markers. PGRMC1 knockdown resulted in a significantly reduced migration rate in breast cancer cell lines.

Conclusions: Pgrmc1 KO mice with breast cancer had a prolonged survival, which was accompanied by a low degree of lung metastasis. PGRMC1 showed a significant role in the migration of breast cancer cells, and may serve as a potential therapeutic target in breast cancer. Video Abstract.
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http://dx.doi.org/10.1186/s12964-021-00719-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034092PMC
April 2021

COVID-19 pandemic: a double-edged sword for cord blood banking.

Authors:
Young-Ho Lee

Blood Res 2021 Mar;56(1):1-3

Department of Pediatrics, Hanyang University Medical Center, Hanyang University College of Medicine, Seoul, Korea.

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http://dx.doi.org/10.5045/br.2021.2021021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987473PMC
March 2021

Molecular mechanism of negative cooperativity of ferredoxin-NADP+ reductase by ferredoxin and NADP(H): involvement of a salt bridge between Asp60 of ferredoxin and Lys33 of FNR.

Biosci Biotechnol Biochem 2021 Mar;85(4):860-865

Department of Biological Chemistry, College of Agriculture, Graduate School of Sciences and Technology for Innovation, Yamaguchi University, Yoshida, Japan.

Ferredoxin-NADP+ reductase (FNR) in plants receives electrons from ferredoxin (Fd) and converts NADP+ to NADPH at the end of the photosynthetic electron transfer chain. We previously showed that the interaction between FNR and Fd was weakened by the allosteric binding of NADP(H) on FNR, which was considered as a part of negative cooperativity. In this study, we investigated the molecular mechanism of this phenomenon using maize FNR and Fd, as the three-dimensional structure of this Fd:FNR complex is available. NMR chemical shift perturbation analysis identified a site (Asp60) on Fd molecule which was selectively affected by NADP(H) binding on FNR. Asp60 of Fd forms a salt bridge with Lys33 of FNR in the complex. Site-specific mutants of FdD60 and FNRK33 suppressed the negative cooperativity (downregulation of the interaction between FNR and Fd by NADPH), indicating that a salt bridge between FdD60 and FNRK33 is involved in this negative cooperativity.
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http://dx.doi.org/10.1093/bbb/zbaa102DOI Listing
March 2021

Serum GDF15 Level Is Independent of Sarcopenia in Older Asian Adults.

Gerontology 2021 Mar 9:1-7. Epub 2021 Mar 9.

Division of Endocrinology and Metabolism, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.

Background: Growth differentiation factor 15 (GDF15), induced by tissue inflammation and mitochondrial stress, has received significant attention as a biomarker of mitochondrial dysfunction and has been implicated in various age-related diseases. However, the association between circulating GDF15 and sarcopenia-associated outcomes in older adults remains to be established.

Aim: To validate previous experimental data and to investigate the possible role of GDF15 in aging and muscle physiology in humans, this study examined serum GDF15 levels in relation to sarcopenia-related parameters in a cohort of older Asian adults.

Methods: Muscle mass and muscle function-related parameters, such as grip strength, gait speed, chair stands, and short physical performance battery score were evaluated by experienced nurses in 125 geriatric participants with or without sarcopenia. Sarcopenia was diagnosed using the Asian-specific cutoff points. Serum GDF15 levels were measured using an enzyme immunoassay kit.

Results: Serum GDF15 levels were not significantly different according to sarcopenia status, muscle mass, muscle strength, and physical performance and were not associated with the skeletal muscle index, grip strength, gait speed, time to complete 5 chair stands, and short physical performance battery score, regardless of adjustments for sex, age, and BMI.

Conclusions: These findings indicate that the definite role of GDF15 on muscle metabolism observed in animal models might not be evident in humans and that elevated GDF15 levels might not predict the risk for sarcopenia, at least in older Asian adults.
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http://dx.doi.org/10.1159/000513600DOI Listing
March 2021

Placebo and nocebo responses in randomized controlled trials of Janus kinase inhibitor monotherapy for rheumatoid arthritis : A meta-analysis.

Z Rheumatol 2021 Mar 9. Epub 2021 Mar 9.

Division of Rheumatology, Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, 73, Goryeodae-ro, Seongbuk-gu, 02841, Seoul, Korea (Republic of).

Objective: The goal of this meta-analysis was to assess the frequency and magnitude of placebo and nocebo responses in placebo-controlled randomized controlled trials (RCTs) of Janus kinase (JAK) inhibitor monotherapy for rheumatoid arthritis (RA) METHODS: We performed a meta-analysis on the rates of placebo response, adverse effects (AEs), severe AEs (SAEs) and withdrawal due to AEs in placebo-controlled randomized clinical trials (RCTs) of JAK inhibitor therapy for RA.

Results: Five RCTs contained a total of 1422 patients (746 trial participants and 676 controls). The pooled incidence of an American College of Rheumatology 20% (ACR20) response rate was 33.0% (95% CI 19.6-44.9%) in placebo-treated patients and 68.3% (95% CI 61.4-74.1%) in active drug-treated patients. A strong negative correlation was observed between drug efficacies (ACR20 response) and AE rates in the placebo arm, indicating that the stronger the placebo response, the weaker the nocebo response (r = -0.906, P = 0.034). The pooled estimate of at least one AE was 54.1% (95% CI 44.6-63.4%) in placebo-treated patients and 54.5% (95% CI 46.2-62.6%) in active drug-treated patients. The pooled SAE rate was 3.9% (95% CI 2.7-5.7%) in placebo-treated patients and 3.8% (95% CI 2.5-5.7%) in active comparator-treated patients. The pooled estimate of withdrawal owing to an AE was 4.1% (95% CI 1.4-11.3%) in placebo-treated patients and 2.1% (95% CI 0.8-5.4%) in active drug-treated patients. However, there were no differences in the pooled risk of AE, SAEs, or withdrawal owing to AEs between the active comparator and placebo groups. A strong positive correlation was observed in AE rates between the placebo and active arms, indicating that the stronger the nocebo response, the higher the AE rate in the active arm (r = 0.957, P = 0.012).

Conclusion: The frequency of placebo and nocebo responses was 33.0 and 54.1%, respectively, in JAK monotherapy trials for RA. The findings indicated that the strengths of placebo and nocebo responses are inversely proportional and that clinically significant differences were absent between AE, SAE, and dropout owing to AEs.
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http://dx.doi.org/10.1007/s00393-021-00969-6DOI Listing
March 2021

Comparative effectiveness and safety of non-tumour necrosis factor biologics and Janus kinase inhibitors in patients with active rheumatoid arthritis showing insufficient response to tumour necrosis factor inhibitors: A Bayesian network meta-analysis of randomized controlled trials.

J Clin Pharm Ther 2021 Feb 18. Epub 2021 Feb 18.

Department of Rheumatology, Korea University College of Medicine, Seoul, Korea.

What Is Known And Objective: Both biologic and Janus kinase (JAK) inhibitor therapies have demonstrated substantial effectiveness in placebo-controlled studies in patients with active rheumatoid arthritis (RA) showing inadequate responses to tumour necrosis factor (TNF) inhibitors. The purpose of this study was to determine the relative effectiveness and safety of non-TNF biologics and JAK inhibitors in patients with RA showing insufficient response to TNF inhibitors.

Methods: A Bayesian network meta-analysis incorporating direct and indirect data from randomized controlled trials (RCTs) was used to investigate the effectiveness and safety of non-TNF biologics (abatacept, rituximab, tocilizumab, salirumab and sirukumab) and JAK inhibitors (tofacitinib, baricitinib, upadacitinib and filgotinib) in patients with RA showing insufficient response to TNF inhibitors.

Results: Nine RCTs, evaluating 3577 patients for 12 weeks fulfilled the inclusion requirements. JAK inhibitors and non-TNF biologics achieved a significant American College of Rheumatology 20% (ACR20) response relative to the placebo. The ranking probability based on the surface under the cumulative ranking curve (SUCRA) showed that JAK inhibitor treatment was most likely to achieve the highest ACR20 response rate, followed by non-TNF biologics and placebo. The ACR50 rate displayed similar patterns as the ACR20 response rate, but non-TNF biologics have a higher value than JAK inhibitors based on the ACR70 response rate. Adverse events did not reach statistical significance nor did serious adverse events when looking at safety over 12 weeks. The confidence intervals overlap, and there is no clinical significance to these safety data, even compared with placebo.

What Is New And Conclusion: Both non-TNF biologics and JAK inhibitors have similar effects in patients with active RA that are refractory to anti-TNF treatment, and there were no differences with regard to safety among the treatments.
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http://dx.doi.org/10.1111/jcpt.13380DOI Listing
February 2021

Treatment Outcomes of Pediatric Acute Myeloid Leukemia in the Yeungnam Region: A Multicenter Retrospective Study of the Study Alliance of Yeungnam Pediatric Hematology-Oncology (SAYPH).

Children (Basel) 2021 Feb 5;8(2). Epub 2021 Feb 5.

Department of Pediatrics, Pusan National University Children's Hospital, Pusan National University, School of Medicine, Yangsan 50612, Korea.

Acute myeloid leukemia (AML) is the second most common pediatric leukemia, with a survival rate of 70%. In this retrospective study, we evaluated the treatment outcomes of pediatric AML among 144 patients diagnosed between 2000 and 2013. After induction, 80.6% of patients achieved complete remission (CR). The 5-year overall survival (OS) and event-free survival (EFS) rates were 58.8 ± 4.2% and 49.8 ± 4.2%, respectively. Based on the response to induction therapy, the 5-year OS was 66.9 ± 5.7% in patients with CR ( < 0.001). Ninety-nine patients with CR after induction therapy were examined, and their 5-year OS and EFS were 66.4 ± 4.9% and 56.3 ± 5.1%, respectively. The 5-year OS rates according to treatment were 59.9 ± 7.4% in the chemotherapy group and 72.3 ± 6.3% in the hematopoietic stem cell transplantation (HSCT) group ( = 0.089). The EFS was 50.1 ± 7.4% in the chemotherapy group and 61.7 ± 6.9% in the HSCT group ( = 0.098). OS and EFS according to cytogenetics were insignificant. Our findings confirmed that the response to induction treatment was important for survival and HSCT had no significant survival benefits compared with those of chemotherapy. Moreover, many early induction deaths under the age of 2 years were observed.
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http://dx.doi.org/10.3390/children8020109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7915354PMC
February 2021

Correspondence on 'Prevalence and clinical outcomes of COVID-19 in patients with autoimmune diseases: a systematic review and meta-analysis'.

Authors:
Young Ho Lee

Ann Rheum Dis 2021 Jan 27. Epub 2021 Jan 27.

Rheumatology, Korea University, Seoul, Seongbuk-gu, Korea (the Republic of)

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http://dx.doi.org/10.1136/annrheumdis-2021-219904DOI Listing
January 2021

Methotrexate for treating polymyalgia rheumatica: A meta-analysis of randomized controlled trials.

Int J Clin Pharmacol Ther 2021 Jan 22. Epub 2021 Jan 22.

Objective: The objective of this study was to evaluate the efficacy and steroid-sparing effect of methotrexate (MTX) in patients with active polymyalgia rheumatica (PMR) undergoing prednisone therapy.

Materials And Methods: A meta-analysis of randomized controlled trial (RCT) was conducted to compare the efficacy and steroid-sparing effect of MTX with those of placebo in patients with PMR.

Results: Four RCTs (97 patients and 97 controls) were used in this meta-analysis. The remission rate was significantly higher in the MTX group than in the placebo group (odds ratio (OR) = 5.699, 95% confidence interval (CI) = 2.401 - 13.53, p < 0.001). The relapse rate appeared lower in the MTX group than in the placebo group, albeit without significance (OR = 0.377, 95% CI = 0.093 - 1.526, p = 0.171). The cumulative steroid dosage was also significantly lower in the MTX group than in the placebo group (standard mean difference (SMD) = -1.636, 95% CI = -2.864 - 0.407, p = 0.009), which suggested the steroid-sparing role of MTX in PMR therapy. All studies showed the same pattern of SMDs in the cumulative steroid dose, but there was variability in the meta-analysis results for the cumulative steroid dose owing to the disparity in the extent of the effect.

Conclusion: MTX in conjunction with prednisone was more successful than prednisone alone for treating PMR, and the use of MTX was correlated with a decreased average steroid dose.
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http://dx.doi.org/10.5414/CP203901DOI Listing
January 2021

Graphene Quantum Dots Alleviate Impaired Functions in Niemann-Pick Disease Type C in Vivo.

Nano Lett 2021 03 20;21(5):2339-2346. Epub 2021 Jan 20.

Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul 08826, Korea.

While the neuropathological characteristics of Niemann-Pick disease type C (NPC) result in a fatal diagnosis, the development of clinically available therapeutic agent remains a challenge. Here we propose graphene quantum dots (GQDs) as a potential candidate for the impaired functions in NPC in vivo. In addition to the previous findings that GQDs exhibit negligible long-term toxicity and are capable of penetrating the blood-brain barrier, GQD treatment reduces the aggregation of cholesterol in the lysosome through expressed physical interactions. GQDs also promote autophagy and restore defective autophagic flux, which, in turn, decreases the atypical accumulation of autophagic vacuoles. More importantly, the injection of GQDs inhibits the loss of Purkinje cells in the cerebellum while also demonstrating reduced activation of microglia. The ability of GQDs to alleviate impaired functions in NPC proves the promise and potential of the use of GQDs toward resolving NPC and other related disorders.
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http://dx.doi.org/10.1021/acs.nanolett.0c03741DOI Listing
March 2021

Deep-learning-based three-dimensional label-free tracking and analysis of immunological synapses of CAR-T cells.

Elife 2020 12 17;9. Epub 2020 Dec 17.

Department of Physics, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea.

The immunological synapse (IS) is a cell-cell junction between a T cell and a professional antigen-presenting cell. Since the IS formation is a critical step for the initiation of an antigen-specific immune response, various live-cell imaging techniques, most of which rely on fluorescence microscopy, have been used to study the dynamics of IS. However, the inherent limitations associated with the fluorescence-based imaging, such as photo-bleaching and photo-toxicity, prevent the long-term assessment of dynamic changes of IS with high frequency. Here, we propose and experimentally validate a label-free, volumetric, and automated assessment method for IS dynamics using a combinational approach of optical diffraction tomography and deep learning-based segmentation. The proposed method enables an automatic and quantitative spatiotemporal analysis of IS kinetics of morphological and biochemical parameters associated with IS dynamics, providing a new option for immunological research.
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http://dx.doi.org/10.7554/eLife.49023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817186PMC
December 2020

Biophysical processes underlying cross-seeding in amyloid aggregation and implications in amyloid pathology.

Biophys Chem 2021 Feb 19;269:106507. Epub 2020 Nov 19.

Biophysics, University of Michigan, Ann Arbor, MI 48109, USA; Department of Chemistry, University of Michigan, Ann Arbor, MI 48109, USA; Macromolecular Science and Engineering, University of Michigan, Ann Arbor, MI 48109, USA; Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address:

Abnormal aggregation of proteins into filamentous aggregates commonly associates with many diseases, such as Alzheimer's disease, Parkinson's disease and type-2 diabetes. These filamentous aggregates, also known as amyloids, can propagate their abnormal structures to either the same precursor molecules (seeding) or other protein monomers (cross-seeding). Cross-seeding has been implicated in the abnormal protein aggregation and has been found to facilitate the formation of physiological amyloids. It has risen to be an exciting area of research with a high volume of published reports. In this review article, we focus on the biophysical processes underlying the cross-seeding for some of the most commonly studied amyloid proteins. Here we will discuss the relevant literature related to cross-seeded polymerization of amyloid-beta, human islet amyloid polypeptide (hIAPP, or also known as amylin) and alpha-synuclein. SEVI (semen-derived enhancer of viral infection) amyloid formation by the cross-seeding between the bacterial curli protein and PAP is also briefly discussed.
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http://dx.doi.org/10.1016/j.bpc.2020.106507DOI Listing
February 2021

Relative efficacy and safety of tofacitinib for treating psoriasis: A Bayesian network meta-analysis of randomized controlled trials.

Int J Clin Pharmacol Ther 2021 Apr;59(4):308-314

Objective: To assess the relative efficacy and safety of tofacitinib administration (5 and 10 mg) twice daily in psoriasis patients.

Materials And Methods: Randomized controlled trials (RCTs) examining the efficacy and safety of tofacitinib in psoriasis patients were included in this network meta-analysis. A Bayesian network meta-analysis was performed to combine the direct and indirect evidence from the RCTs.

Results: Five RCTs, including 3,265 patients, met the inclusion criteria. The 75% or more reduction in Psoriasis Area and Severity Index (PASI75) response rate was significantly higher in the 10-mg tofacitinib group than in the placebo group (OR, 20.53; 95% credible interval (CrI), 13.98 - 32.69). Similarly, the PASI75 response rate was significantly higher in the 50-mg etanercept and 5-mg tofacitinib groups than in the placebo group (OR, 18.39; 95% CrI, 10.19 - 36.97 and OR, 8.87; 95% CrI, 6.02 - 13.55, respectively). However, 10 mg tofacitinib tended to be more efficacious than 50 mg etanercept and 5 mg tofacitinib. Ranking probability based on Surface under the cumulative ranking curve (SUCRA) indicated that 10 mg tofacitinib had the highest probability of being the best treatment for achieving the PASI75 response rate, followed by 50 mg etanercept, 5 mg tofacitinib, and placebo. The Physician's Global Assessment (PGA) and PASI75 response rates showed similar distribution patterns. In contrast, the number of patients with serious adverse events (SAEs) or withdrawals due to AEs did not differ significantly among the 4 treatment options.

Conclusion: Tofacitinib (10 mg) showed the highest efficacy for the intervention for psoriasis, followed by 50 mg etanercept and 5 mg tofacitinib, and was not associated with a significant risk for SAEs or AE-induced withdrawals.
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http://dx.doi.org/10.5414/CP203831DOI Listing
April 2021

Comparison of the efficacy and safety of biological agents in patients with systemic juvenile idiopathic arthritis: A Bayesian network meta-analysis of randomized controlled trials.

Int J Clin Pharmacol Ther 2021 Mar;59(3):239-246

Objective: To assess the relative efficacy and safety of biological agents in patients with systemic juvenile idiopathic arthritis (sJIA).

Materials And Methods: We performed a Bayesian network meta-analysis to combine direct and indirect evidence from randomized controlled trials (RCTs) to examine the efficacy and safety of canakinumab, anakinra, tocilizumab, and rilonacept in patients with sJIA.

Results: Five RCTs that included 286 patients met the inclusion criteria. Canakinumab was the most effective treatment for sJIA (odds ratio, 55.04; 95% credible interval, 15.52 - 253.29). A greater efficacy was observed with canakinumab than with tocilizumab and rilonacept. All interventions achieved a significant modified American College of Rheumatology Pediatric 30 (ACRpedi30) response compared to the placebo. The ranking probability, based on the surface under the cumulative ranking curve, indicated that canakinumab had the highest probability of being the best treatment in terms of the modified ACRpedi30 response rate, followed by anakinra, tocilizumab, rilonacept, and the placebo. However, no significant differences were observed in the incidence of serious adverse events after treatment with canakinumab, anakinra, tocilizumab, rilonacept, or the placebo.

Conclusion: In patients with sJIA, canakinumab had the highest probability of being the best treatment in terms of the modified ACRpedi30 response rate; neither of the tested biological agents were associated with a significant risk of serious adverse events.
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http://dx.doi.org/10.5414/CP203791DOI Listing
March 2021

Development of a Polo-like Kinase-1 Polo-Box Domain Inhibitor as a Tumor Growth Suppressor in Mice Models.

J Med Chem 2020 12 3;63(23):14905-14920. Epub 2020 Nov 3.

Division of Magnetic Resonance, Korea Basic Science Institute (KBSI), Ochang, Chung Buk 28119, Republic of Korea.

Polo-like kinase-1 (Plk1) plays a key role in mitosis and has been identified as an attractive anticancer drug target. Plk1 consists of two drug-targeting sites, namely, N-terminal kinase domain (KD) and C-terminal polo-box domain (PBD). As KD-targeting inhibitors are associated with severe side effects, here we report on the pyrazole-based Plk1 PBD inhibitor, KBJK557, which showed a remarkable anticancer effect by inducing Plk1 delocalization, mitotic arrest, and apoptosis in HeLa cells. Further, optical imaging analysis and antitumorigenic activities in mouse xenograft models demonstrate that KBJK557 preferentially accumulates in cancer cells and selectively inhibits cancer cell proliferation. Pharmacokinetic profiles and partition coefficients suggest that KBJK557 was exposed in the blood and circulated through the organs with an intermediate level of clearance (, 7.73 h). The present investigation offers a strategy for specifically targeting cancer using a newly identified small-molecule inhibitor that targets the Plk1 PBD.
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http://dx.doi.org/10.1021/acs.jmedchem.0c01451DOI Listing
December 2020

Relative efficacy and tolerability of 2.5, 5, and 10 mg tanezumab for the treatment of osteoarthritis: A Bayesian network meta-analysis of randomized controlled trials based on patient withdrawal.

Int J Clin Pharmacol Ther 2021 Feb;59(2):147-155

Aims: To assess the relative efficacy and tolerability of tanezumab (2.5, 5, and 10 mg) in osteoarthritis (OA) patients.

Materials And Methods: Six randomized controlled trials (RCTs) including 3,813 patients and examining the efficacy and tolerability of tanezumab (2.5, 5, 10 mg), naproxen (1,000 mg), and placebo, based on the number of withdrawals among osteoarthritis patients, were included in this Bayesian random-effects network meta-analysis, which combined direct and indirect evidence.

Results: Tanezumab (5, 2.5, 10 mg) and 1,000 mg naproxen were more efficacious than placebo (odds ratio (OR): 0.34, 95% credible interval (CrI): 0.26 - 0.43; OR: 0.35, 95% CrI: 0.24 - 0.48; OR: 0.364, 95% CrI: 0.28 - 0.45; and OR: 0.44, 95% CrI: 0.32 - 0.61, respectively). The number of withdrawals due to lack of efficacy were lower in the tanezumab groups than in the naproxen group, and the difference was not significant. Ranking probability based on the cumulative ranking curve (SUCRA) indicated that 5 mg tanezumab had the highest probability of being the best treatment based on the number of withdrawals due to lack of efficacy, followed by 2.5 mg tanezumab, 10 mg tanezumab, 1,000 mg naproxen, and placebo. Ranking probability based on SUCRA indicated that 2.5 mg tanezumab and placebo had the highest probability of being the most tolerable treatment, followed by 5 mg tanezumab, 1,000 mg naproxen, and 10 mg tanezumab.

Conclusion: Tanezumab (5 mg) had the highest probability of being the best treatment based on the number of withdrawals due to lack of efficacy among the medications, while 2.5 mg tanezumab and placebo had the highest probability of being the most tolerable treatment.
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http://dx.doi.org/10.5414/CP203812DOI Listing
February 2021

Small molecule induced toxic human-IAPP species characterized by NMR.

Chem Commun (Camb) 2020 Nov 2;56(86):13129-13132. Epub 2020 Oct 2.

Department of Chemistry, University of Michigan, Ann Arbor, MI, USA.

In this study, the effect of CurDAc, a water-soluble curcumin derivative, on the formation and stability of amyloid fibers is revealed. CurDAc interaction with amyloid is structurally selective, which is reflected in a strong interference with hIAPP aggregation while showing weaker interactions with human-calcitonin and amyloid-β in comparison. Remarkably, CurDAc also exhibited potent fiber disaggregation for hIAPP generating a toxic oligomeric species.
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http://dx.doi.org/10.1039/d0cc04803hDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641245PMC
November 2020

The novel DYRK1A inhibitor KVN93 regulates cognitive function, amyloid-beta pathology, and neuroinflammation.

Free Radic Biol Med 2020 11 5;160:575-595. Epub 2020 Sep 5.

Department of Neural Development and Disease, Korea Brain Research Institute (KBRI), 61, Cheomdan-ro, Dong-gu, Daegu, 41062, South Korea; Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science & Technology, Daegu, 42988, South Korea. Electronic address:

Regulating amyloid beta (Aβ) pathology and neuroinflammatory responses holds promise for the treatment of Alzheimer's disease (AD) and other neurodegenerative and/or neuroinflammation-related diseases. In this study, the effects of KVN93, an inhibitor of dual-specificity tyrosine phosphorylation-regulated kinase-1A (DYRK1A), on cognitive function and Aβ plaque levels and the underlying mechanism of action were evaluated in 5x FAD mice (a mouse model of AD). KVN93 treatment significantly improved long-term memory by enhancing dendritic synaptic function. In addition, KVN93 significantly reduced Aβ plaque levels in 5x FAD mice by regulating levels of the Aβ degradation enzymes neprilysin (NEP) and insulin-degrading enzyme (IDE). Moreover, Aβ-induced microglial and astrocyte activation were significantly suppressed in the KVN-treated 5xFAD mice. KVN93 altered neuroinflammation induced by LPS in microglial cells but not primary astrocytes by regulating TLR4/AKT/STAT3 signaling, and in wild-type mice injected with LPS, KVN93 treatment reduced microglial and astrocyte activation. Overall, these results suggest that the novel DYRK1A inhibitor KVN93 is a potential therapeutic drug for regulating cognitive/synaptic function, Aβ plaque load, and neuroinflammatory responses in the brain.
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http://dx.doi.org/10.1016/j.freeradbiomed.2020.08.030DOI Listing
November 2020

The MAO Inhibitor Tranylcypromine Alters LPS- and Aβ-Mediated Neuroinflammatory Responses in Wild-type Mice and a Mouse Model of AD.

Cells 2020 08 28;9(9). Epub 2020 Aug 28.

Department of Neural Development and Disease, Korea Brain Research Institute (KBRI), 61, Cheomdan-ro, Dong-gu, Daegu 41062, Korea.

Monoamine oxidase (MAO) has been implicated in neuroinflammation, and therapies targeting MAO are of interest for neurodegenerative diseases. The small-molecule drug tranylcypromine, an inhibitor of MAO, is currently used as an antidepressant and in the treatment of cancer. However, whether tranylcypromine can regulate LPS- and/or Aβ-induced neuroinflammation in the brain has not been well-studied. In the present study, we found that tranylcypromine selectively altered LPS-induced proinflammatory cytokine levels in BV2 microglial cells but not primary astrocytes. In addition, tranylcypromine modulated LPS-mediated TLR4/ERK/STAT3 signaling to alter neuroinflammatory responses in BV2 microglial cells. Importantly, tranylcypromine significantly reduced microglial activation as well as proinflammatory cytokine levels in LPS-injected wild-type mice. Moreover, injection of tranylcypromine in 5xFAD mice (a mouse model of AD) significantly decreased microglial activation but had smaller effects on astrocyte activation. Taken together, our results suggest that tranylcypromine can suppress LPS- and Aβ-induced neuroinflammatory responses in vitro and in vivo.
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http://dx.doi.org/10.3390/cells9091982DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563969PMC
August 2020

Epidemiological Study of Hereditary Hemolytic Anemia in the Korean Pediatric Population during 1997-2016: a Nationwide Retrospective Cohort Study.

J Korean Med Sci 2020 Aug 24;35(33):e279. Epub 2020 Aug 24.

Department of Pediatrics, Korea University Ansan Hospital, Korea University College of Medicine, Ansan, Korea.

Background: Hereditary hemolytic anemia (HHA) is a rare disease characterized by premature red blood cell (RBC) destruction due to intrinsic RBC defects. The RBC Disorder Working Party of the Korean Society of Hematology established and updated the standard operating procedure for making an accurate diagnosis of HHA since 2007. The aim of this study was to investigate a nationwide epidemiology of Korean HHA.

Methods: We collected the data of a newly diagnosed pediatric HHA cohort (2007-2016) and compared this cohort's characteristics with those of a previously surveyed pediatric HHA cohort (1997-2006) in Korea. Each participant's information was retrospectively collected by a questionnaire survey.

Results: A total of 369 children with HHA from 38 hospitals distributed in 16 of 17 districts of Korea were investigated. RBC membranopathies, hemoglobinopathies, RBC enzymopathies, and unknown etiologies accounted for 263 (71.3%), 59 (16.0%), 23 (6.2%), and 24 (6.5%) of the cases, respectively. Compared to the cohort from the previous decade, the proportions of hemoglobinopathies and RBC enzymopathies significantly increased ( < 0.001 and = 0.008, respectively). Twenty-three of the 59 hemoglobinopathy patients had immigrant mothers, mostly from South-East Asia.

Conclusion: In Korea, thalassemia traits have increased over the past 10 years, reflecting both increased awareness of this disease and increased international marriages. The enhanced recognition of RBC enzymopathies is due to advances in diagnostic technique; however, 6.5% of HHA patients still do not have a clear diagnosis. It is necessary to improve accessibility of diagnosing HHA.
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http://dx.doi.org/10.3346/jkms.2020.35.e279DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7445306PMC
August 2020

Comparison of treatment response and serious infection using tacrolimus, tacrolimus with mycophenolate mofetil, in comparison to cyclophosphamide as induction treatment for lupus nephritis.

Int J Clin Pharmacol Ther 2020 Oct;58(10):550-556

Aims: This study evaluated the relative efficacy and safety of tacrolimus, tacrolimus+mycophenolate mofetil (MMF), and cyclophosphamide (CYC) for lupus nephritis.

Materials And Methods: Randomized controlled trials (RCTs) were included to investigate the effectiveness and safety of tacrolimus, tacrolimus+MMF, and CYC as a lupus induction therapy. We performed a Bayesian network meta-analysis of the random effects to incorporate direct and indirect data from RCTs.

Results: Four RCTs met the inclusion criteria, giving a sample size of 543 patients. Tacrolimus+MMF had a significantly higher overall response rate (complete plus partial remission) than CYC (OR 4.22, 95% credible interval (CrI) 11.02 - 29.23) and was more efficacious than tacrolimus (OR 2.02, 95% CrI 0.24 - 28.51). Tacrolimus had higher overall response than CYC (OR 2.14, 95% CrI 0.38 - 12.33). Ranking the treatments based on the surface under the cumulative ranking curve (SUCRA) suggested that tacrolimus+MMF was the best treatment by the overall response (SUCRA = 0.876), followed by tacrolimus (SUCRA = 0.533) and CYC (SUCRA = 0.091). Tacrolimus was the least likely to cause serious infections (-SUCRA = 0.758), followed by CYC (SUCRA = 0.398) and tacrolimus+MMF (SUCRA = 0.345).

Conclusion: Tacrolimus+MMF was the most effective induction treatment for patients with lupus nephritis, and tacrolimus was the least likely to cause severe infections.
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http://dx.doi.org/10.5414/CP203736DOI Listing
October 2020

Vasodilatory Effect of Extract in Rat Mesenteric Arteries.

Molecules 2020 Jul 10;25(14). Epub 2020 Jul 10.

Department of Physiology, College of Medicine, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University, 50 Yeonseiro, Seodaemun-gu, Seoul 03722, Korea.

is a well-known medicinal mushroom that is widely used in Asian countries. In several experimental models, extracts were reported to have various biological effects, including anti-inflammatory, anti-cancer, hepatoprotective, anti-diabetic, neuroprotective, and anti-angiogenic activity. In the present study, several bioactive compounds, including palmitic acid ethyl ester and linoleic acid, were identified in . The intermediate-conductance calcium-activated potassium channel (IK) plays an important role in the regulation of the vascular smooth muscle cells' (VSMCs) contraction and relaxation. The activation of the IK channel causes the hyperpolarization and relaxation of VSMCs. To examine whether extract causes vasodilation in the mesenteric arteries of rats, we measured the isometric tension using a wire myograph. After the arteries were pre-contracted with U46619 (a thromboxane analogue, 1 µM), extract was administered. The extract induced vasodilation in a dose-dependent manner, which was independent of the endothelium. To further investigate the mechanism, we used the non-selective K channel blocker tetraethylammonium (TEA). TEA significantly abolished extract-induced vasodilation. Thus, we tested three different types of K channel blockers: iberiotoxin (BK channel blocker), apamin (SK channel blocker), and charybdotoxin (IK channel blocker). Charybdotoxin significantly inhibited extract-induced relaxation, while there was no effect from apamin and iberiotoxin. Membrane potential was measured using the voltage-sensitive dye bis-(1,3-dibutylbarbituric acid)-trimethine oxonol (DiBAC(3)) in the primary isolated vascular smooth muscle cells (VSMCs). We found that the extract induced hyperpolarization of VSMCs, which is associated with a reduced phosphorylation level of 20 KDa myosin light chain (MLC).
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http://dx.doi.org/10.3390/molecules25143160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7397296PMC
July 2020