Publications by authors named "Mihee Kim"

38 Publications

Source Analysis and Effective Control of a COVID-19 Outbreak in a University Teaching Hospital during a Period of Increasing Community Prevalence of COVID-19.

J Korean Med Sci 2021 Jun 21;36(24):e179. Epub 2021 Jun 21.

Department of Infectious Diseases, Chonnam National University Medical School, Gwangju, Korea.

Background: South Korea has been experiencing a third wave of coronavirus disease 2019 (COVID-19) since mid-November 2020. Our hospital in Gwangju metropolitan city experienced a healthcare-associated COVID-19 outbreak early in the third wave. The first confirmed COVID-19 patient was a symptomatic neurosurgery resident with high mobility throughout the hospital. We analyzed the transmission routes of nosocomial COVID-19 and discussed infection control strategies.

Methods: We retrospectively analyzed the severe acute respiratory syndrome coronavirus 2 reverse transcription-polymerase chain reaction (RT-PCR) testing results according to time point and evaluated transmission routes.

Results: Since COVID-19 was first confirmed in a healthcare worker (HCW) on 11/13/2020, we performed RT-PCR tests for all patients and caregivers and four complete enumeration surveys for all HCWs. We detected three clusters of nosocomial spread and several sporadic cases. The first cluster originated from the community outbreak spot, where an asymptomatic HCW visited, which led to a total of 22 cases. The second cluster, which included patient-to-patient transmission, originated from a COVID-19 positive caregiver before diagnosis and the third cluster involved a radiologist and a banker. We took measures to isolate Building 1 of the hospital for 17 days and controlled the outbreak during a period of increasing community COVID-19 prevalence. Universal screening of all inpatients upon admission and resident caregivers was made mandatory and hospital-related employees are now screened monthly.

Conclusion: Infection control strategies to prevent the nosocomial transmission of emerging infectious diseases must correspond with community disease prevalence. Our data reinforce the importance of multi-time point surveillance of asymptomatic HCWs and routine surveillance of patients and caregivers during an epidemic.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3346/jkms.2021.36.e179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8216991PMC
June 2021

Expanded natural killer cells augment the antimyeloma effect of daratumumab, bortezomib, and dexamethasone in a mouse model.

Cell Mol Immunol 2021 Jul 12;18(7):1652-1661. Epub 2021 May 12.

Research Center for Cancer Immunotherapy, Chonnam National University Hwasun Hospital and Chonnam National University Medical School, Gwangju, Korea.

The use of natural killer (NK) cells is a promising and safe immunotherapeutic approach in the field of cancer immunotherapy. However, combination treatments are required to enhance the effector functions and therapeutic efficacy of NK cells. In this study, we investigated the potential of daratumumab (Dara), bortezomib, and dexamethasone (Dvd) to augment the antitumor effects of NK cells in a multiple myeloma (MM) xenograft mouse model. NK cells were expanded and activated using the K562-OX40 ligand and membrane-bound IL-18 and IL-21 in the presence of IL-2 and IL-15 from peripheral blood mononuclear cells from MM patients. A human MM xenograft model was established using human RPMI8226-RFP-FLuc cells in NOD/SCID IL-2Rγ (NSG) mice. Tumor-bearing mice were divided into six treatment groups: no treatment, expanded NK cells (eNKs), Dara, Dara + eNKs, Dvd, and Dvd + eNKs. Dvd treatment strongly enhanced the cytotoxicity of eNKs by upregulating expression of NK cell activation ligands, downregulating expression of NK cell inhibitory ligands, and promoting antibody-dependent cellular cytotoxicity. The combination of eNKs with Dvd significantly prolonged mouse survival and reduced the tumor burden and serum M-protein level. Furthermore, Dvd pretreatment significantly increased eNK persistence and homing to MM sites. Our findings suggest that Dvd treatment potentiates the antimyeloma effects of NK cells expanded and activated ex vivo by modulating immune responses in MM-bearing mice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41423-021-00686-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8245645PMC
July 2021

Allogeneic transplant can abrogate the risk of relapse in the patients of first remission acute myeloid leukemia with detectable measurable residual disease by next-generation sequencing.

Bone Marrow Transplant 2021 05 5;56(5):1159-1170. Epub 2020 Dec 5.

Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University of Toronto, Toronto, Canada.

In patients with acute myeloid leukemia (AML) consolidation treatment options are between allogeneic hematopoietic stem cell transplantation (HCT) and chemotherapy, based on disease risk at the time of initial presentation and age. Measurable residual disease (MRD) following induction chemotherapy could be incorporated as a useful parameter for treatment decisions. The present study evaluated treatment outcomes according to the next-generation sequencing (NGS)-based MRD status and the type of consolidation therapy in patients with normal karyotype (NK)-AML. By sequencing 278 paired samples collected at diagnosis and first remission (CR1), we identified 361 mutations in 124 patients at diagnosis and tracked these at CR1. After excluding mutations associated with age-related clonal hematopoiesis, 82 mutations in 50 of the 124 patients (40.3%) were detected at CR1. Survival benefit was observed in favor of allogeneic HCT over chemotherapy consolidation in the MRD subgroup with respect to overall survival (HR 0.294, p = 0.003), relapse-free survival (HR 0.376, p = 0.015) and cumulative incidence of relapse (HR 0.279, p = 0.004) in multivariate analysis, but not in the MRD subgroup. In summary, these data support allogeneic HCT in NK-AML patients with detectable MRD by NGS in CR1. Randomized clinical trials will be required to confirm this observation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41409-020-01165-xDOI Listing
May 2021

Adrenal insufficiency in hospitalized patients with multiple myeloma.

Leuk Lymphoma 2021 02 2;62(2):501-503. Epub 2020 Nov 2.

Department of Hematology-Oncology, Chonnam National University Hwasun Hospital, Hwasun, Republic of Korea.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/10428194.2020.1834095DOI Listing
February 2021

Endothelial activation and stress index (EASIX) is a reliable predictor for overall survival in patients with multiple myeloma.

BMC Cancer 2020 Aug 24;20(1):803. Epub 2020 Aug 24.

Department of Hematology-Oncology, Chonnam National University Hwasun Hospital, 322 Seoyangro, Hwasun, Jeollanamdo, 519-763, Republic of Korea.

Background: Recently, the endothelial Activation and Stress Index (EASIX) score has been reported to predict overall survival (OS) after allogeneic stem cell transplantation. This study evaluated the prognostic role of EASIX score in patients with newly diagnosed multiple myeloma (MM).

Methods: This retrospective study analyzed the records of 1177 patients with newly diagnosed MM between February 2003 and December 2017 from three institutions in the Republic of Korea. Serum lactate dehydrogenase (LDH), creatinine, and platelet count at diagnosis were measured in all included patients. EASIX scores were calculated using the formula-LDH (U/L) × Creatinine (mg/dL) / platelet count (10/L) and were evaluated based on log2 transformed values.

Results: The median age of patients was 63 years (range, 22-92), and 495 patients (42.1%) underwent autologous stem cell transplantation (ASCT). The median log2 EASIX score at diagnosis was 1.1 (IQR 0.3-2.3). Using maximally selected log-rank statistics, the optimal EASIX cutoff value for OS was 1.87 on the log2 scale (95% CI 0.562-0.619, p < 0.001). After median follow-up for 50.0 months (range, 0.3-184.1), the median OS was 58.2 months (95% CI 53.644-62.674). Overall, 372 patients (31.6%) showed high EASIX scores at diagnosis, and had significantly inferior OS compared to those with low EASIX (log2 EASIX ≤1.87) (39.1 months vs. 67.2 months, p < 0.001). In multivariate Cox analysis, high EASIX was significantly associated with poor OS (HR 1.444, 95% CI 1.170-1.780, p = 0.001). In the subgroup analysis of patients who underwent ASCT, patients with high EASIX showed significantly inferior OS compared to those with low EASIX (52.8 months vs. 87.0 months, p < 0.001). In addition, in each group of ISS I, II, and III, high EASIX was associated with significantly inferior OS (ISS 1, 45.2 months vs. 76.0 months, p = 0.001; ISS 2, 42.3 months vs. 66.5 months, p = 0.002; ISS 3, 36.8 months vs. 55.1 months, p = 0.001).

Conclusion: EASIX score at diagnosis is a simple and strong predictor for OS in patients with newly diagnosed MM.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12885-020-07317-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446202PMC
August 2020

Spatial Distribution of PEO-PPO-PEO Block Copolymer and PEO Homopolymer in Lipid Bilayers.

Langmuir 2020 04 27;36(13):3393-3403. Epub 2020 Mar 27.

Department of Chemical Engineering and Materials Science, University of Minnesota, Minneapolis, Minnesota 55455, United States.

Maintaining the integrity of cell membranes is indispensable for cellular viability. Poloxamer 188 (P188), a poly(ethylene oxide)--poly(propylene oxide)--poly(ethylene oxide) (PEO-PPO-PEO) triblock copolymer with a number-average molecular weight of 8700 g/mol and containing 80% by mass PEO, protects cell membranes from various external injuries and has the potential to be used as a therapeutic agent in diverse applications. The membrane protection mechanism associated with P188 is intimately connected with how this block copolymer interacts with the lipid bilayer, the main component of a cell membrane. Here, we report the distribution of P188 in a model lipid bilayer comprising 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine (POPC) using neutron reflectivity (NR) and atomic force microscopy (AFM). We also investigated the association of a PEO homopolymer (PEO8.4K; = 8400 g/mol) that does not protect living cell membranes. These experiments were conducted following incubation of a 4.5 mmol/L polymer solution in a buffer that mimics physiological conditions with supported POPC bilayer membranes followed by washing with the aqueous medium. In contrast to previous reports, which dealt with P188 and PEO in salt-free solutions, both P188 and PEO8.4K penetrate into the inner portion of the lipid bilayer as revealed by NR, with approximately 30% by volume occupancy across the membrane without loss of bilayer structural integrity. These results indicate that PEO is the chemical moiety that principally drives P188 binding to bilayer membranes. No defects or phase-separated domains were observed in either P188- or PEO8.4K-incubated lipid bilayers when examined by AFM, indicating that polymer chains mingle homogeneously with lipid molecules in the bilayer. Remarkably, the breakthrough force required for penetration of the AFM tip through the bilayer membrane is unaffected by the presence of the large amount of P188 and PEO8.4K.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.langmuir.9b03208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8097911PMC
April 2020

The Effect of the Congruence between Job Characteristics and Personality on Job Crafting.

Int J Environ Res Public Health 2019 12 19;17(1). Epub 2019 Dec 19.

School of Business, Hanyang University, Seoul 04763, Korea.

This study examined the effect of the fit between personality (i.e., openness to experience) and core job characteristics (i.e., skill variety, task significance, and task identity) on job crafting. We collected survey data from 200 college students who were assigned a team project during the semester. Using polynomial regression analysis, we tested the effects of the fit between personality and job characteristics on job crafting. The results revealed that a high level of openness to experience was significantly associated with a high level of job crafting (i.e., task, relational, and cognitive crafting). Furthermore, when both openness to experience and job characteristics were congruent at a high level, the tendency to proactively perform one's tasks was also high. These findings enhance our understanding of the effect of the fit between openness to experience and three core job characteristics on job crafting.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijerph17010052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6981784PMC
December 2019

Interteam Cooperation and Competition and Boundary Activities: The Cross-Level Mediation of Team Goal Orientations.

Int J Environ Res Public Health 2019 07 31;16(15). Epub 2019 Jul 31.

College of Business Administration, Inha University, 100 Inha-ro, Michuhol-gu, Incheon 22212, Korea.

Drawing on Dragoni's cross-level model of state goal orientation, this research aims to examine the cross-level mediating effect of team goal orientation on the relationships between interteam cooperation and competition and three forms of boundary activities. Study 1 tested the proposed mediating relationships by collecting survey data from 249 members of 45 South Korean work teams. Additionally, we conducted a two-wave longitudinal study (Study 2) on 188 undergraduate students to replicate the relationships between three types of team goal orientation and their relevant forms of boundary activities. In Study 1, we found positive associations between interteam cooperation and team learning goal orientation, and between interteam competition and team performance-prove and performance-avoid goal orientations. Team learning and performance-prove goal orientations were positively related to boundary spanning and reinforcement. As predicted, team learning goal orientation had a stronger relationship with boundary spanning than team performance-prove goal orientation, whereas team performance-prove goal orientation had a stronger relationship with boundary reinforcement than team learning goal orientation. While team learning goal orientation mediated the relationship between interteam cooperation and boundary spanning and reinforcement, team performance-prove goal orientation mediated the relationship between interteam competition and boundary spanning and reinforcement. The results of Study 2 demonstrated the positive lagged effects of team performance-prove goal orientation on boundary reinforcement and of team performance-avoid goal orientation on boundary buffering.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijerph16152738DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6695722PMC
July 2019

Evaluation of Compound Activity in Primary Human Intestinal Organoids Using Gene Expression and Histology.

Curr Protoc Pharmacol 2019 06 28;85(1):e54. Epub 2019 Mar 28.

Discovery Immunology, Janssen Research and Development, San Diego, California.

Human intestinal organoids have enabled performance of functional epithelial studies and modeling of human diseases of the intestine. This unit describes 1) a method to isolate and culture crypts from human intestinal tissue, 2) use of combinatorial methods to expand stem cell-enriched spheroids and differentiate them into organoids composed of various intestinal epithelial cell types, and 3) methods to stimulate these organoids with and measure their responsiveness to external stimuli. To validate the differentiation, organoids can be stained to qualitatively evaluate the presence of colonic crypt morphology and specialized epithelial cell markers. These organoids are responsive to challenge with tumor necrosis factor α (TNFα), resulting in cytokine-induced apoptosis. TNFα-driven apoptosis can be blocked by a small-molecule inhibitor of Ire1α (4μ8C), an endoplasmic-reticulum stress sensor. This is one example of how the human intestinal organoid model can be a powerful tool to elucidate important biological pathways involved in human disease in intestinal epithelial cells. © 2019 by John Wiley & Sons, Inc.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cpph.54DOI Listing
June 2019

Surface Plasmon Resonance Study of the Binding of PEO-PPO-PEO Triblock Copolymer and PEO Homopolymer to Supported Lipid Bilayers.

Langmuir 2018 06 1;34(23):6703-6712. Epub 2018 Jun 1.

Poloxamer 188 (P188), a poly(ethylene oxide)- b-poly(propylene oxide)- b-poly(ethylene oxide) triblock copolymer, protects cell membranes against various external stresses, whereas poly(ethylene oxide) (PEO; 8600 g/mol) homopolymer lacks protection efficacy. As part of a comprehensive effort to elucidate the protection mechanism, we used surface plasmon resonance (SPR) to obtain direct evidence of binding of the polymers onto supported lipid bilayers. Binding kinetics and coverage of P188 and PEO were examined and compared. Most notably, PEO exhibited membrane association comparable to that of P188, evidenced by comparable association rate constants and coverage. This result highlights the need for additional mechanistic understanding beyond simple membrane association to explain the differential efficacy of P188 in therapeutic applications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.langmuir.8b00873DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6055929PMC
June 2018

Chemical End Group Modified Diblock Copolymers Elucidate Anchor and Chain Mechanism of Membrane Stabilization.

Mol Pharm 2017 07 12;14(7):2333-2339. Epub 2017 Jun 12.

Integrative Biology and Physiology, University of Minnesota Medical School , Minneapolis, Minnesota 55455, United States.

Block copolymers can be synthesized in an array of architectures and compositions to yield diverse chemical properties. The triblock copolymer Poloxamer 188 (P188), the family archetype, consisting of a hydrophobic poly(propylene oxide) core flanked by hydrophilic poly(ethylene oxide) chains, can stabilize cellular membranes during stress. However, little is known regarding the molecular basis of membrane interaction by copolymers in living organisms. By leveraging diblock architectural design, discrete end-group chemistry modifications can be tested. Here we show evidence of an anchor and chain mechanism of interaction wherein titrating poly(propylene oxide) block end group hydrophobicity directly dictates membrane interaction and stabilization. These findings, obtained in cells and animals in vivo, together with molecular dynamics simulations, provide new insights into copolymer-membrane interactions and establish the diblock copolymer molecular architecture as a valuable platform to inform copolymer-biological membrane interactions. These results have implications for membrane stabilizers in muscular dystrophy and for other biological applications involving damaged cell membranes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.molpharmaceut.7b00197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5648059PMC
July 2017

PEO-PPO Diblock Copolymers Protect Myoblasts from Hypo-Osmotic Stress In Vitro Dependent on Copolymer Size, Composition, and Architecture.

Biomacromolecules 2017 Jul 14;18(7):2090-2101. Epub 2017 Jun 14.

Department of Chemical Engineering and Materials Science, ‡Department of Integrative Biology and Physiology, and §Department of Medicine, Cardiovascular Division, University of Minnesota , Minneapolis, Minnesota 55455, United States.

Poloxamer 188, a triblock copolymer of poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO), protects cellular membranes from various stresses. Though numerous block copolymer variants exist, evaluation of alternative architecture, composition, and size has been minimal. Herein, cultured murine myoblasts are exposed to the stresses of hypotonic shock and isotonic recovery, and membrane integrity was evaluated by quantifying release of lactate dehydrogenase. Comparative evaluation of a systematic set of PEO-PPO diblock and PEO-PPO-PEO triblock copolymers demonstrates that the diblock architecture can be protective in vitro. Short PPO blocks hinder protection with >9 PPO units needed for protection at 150 μM and >16 units needed at 14 μM. Addition of a tert-butyl end group enhances protection at reduced concentration. When the end group and PPO length are fixed, increasing the PEO length improves protection. This systematic evaluation establishes a new in vitro screening tool for evaluating membrane-sealing amphiphiles and provides mechanistic insight to guide future copolymer design for membrane stabilization in vivo.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.biomac.7b00419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5640256PMC
July 2017

Facebook's Spiral of Silence and Participation: The Role of Political Expression on Facebook and Partisan Strength in Political Participation.

Authors:
Mihee Kim

Cyberpsychol Behav Soc Netw 2016 Dec 16;19(12):696-702. Epub 2016 Nov 16.

Department of Journalism and Mass Communication, Sungkyunkwan University , Seoul, South Korea .

This study investigated how Facebook's spiral of silence influences political participation. For doing so, this study focused on the roles of politically expressive activities on Facebook and individuals' levels of partisan strength. An online survey (N = 277) was conducted with Facebook users. Results showed that a perceived hostile opinion climate on Facebook was negatively associated with political expression on Facebook, which, in turn, was positively related with political participation. This indirect relationship was conditioned by the degree of Facebook users' partisan strength. Those with weak or moderate levels of partisan strength were less likely to express their minority views, which led to decrease their political participation in the real world. Such indirect relationship was not the case for those with high levels of partisan strength. Theoretical and political implications of these findings were discussed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/cyber.2016.0137DOI Listing
December 2016

ERN1 and ALPK1 inhibit differentiation of bi-potential tumor-initiating cells in human breast cancer.

Oncotarget 2016 Dec;7(50):83278-83293

Institute of Pathology, University Medical Center Freiburg, Freiburg, Germany.

Cancers are heterogeneous by nature. While traditional oncology screens commonly use a single endpoint of cell viability, altering the phenotype of tumor-initiating cells may reveal alternative targets that regulate cellular growth by processes other than apoptosis or cell division. We evaluated the impact of knocking down expression of 420 kinases in bi-lineage triple-negative breast cancer (TNBC) cells that express characteristics of both myoepithelial and luminal cells. Knockdown of ERN1 or ALPK1 induces bi-lineage MDA-MB-468 cells to lose the myoepithelial marker keratin 5 but not the luminal markers keratin 8 and GATA3. In addition, these cells exhibit increased β-casein production. These changes are associated with decreased proliferation and clonogenicity in spheroid cultures and anchorage-independent growth assays. Confirmation of these assays was completed in vivo, where ERN1- or ALPK1-deficient TNBC cells are less tumorigenic. Finally, treatment with K252a, a kinase inhibitor active on ERN1, similarly impairs anchorage-independent growth of multiple breast cancer cell lines. This study supports the strategy to identify new molecular targets for types of cancer driven by cells that retain some capacity for normal differentiation to a non-tumorigenic phenotype. ERN1 and ALPK1 are potential targets for therapeutic development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.13086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5347769PMC
December 2016

A Case of Severe Pseudomembranous Tracheobronchitis Complicated by Co-infection of Influenza A (H1N1) and Staphylococcus aureus in an Immunocompetent Patient.

Tuberc Respir Dis (Seoul) 2015 Oct 1;78(4):366-70. Epub 2015 Oct 1.

Division of Pulmonology, Department of Internal Medicine, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Suwon, Korea.

Although influenza A (H1N1) virus leads to self-limiting illness, co-infection with bacteria may result in cases of severe respiratory failure due to inflammation and necrosis of intra-airway, as pseudomembranous tracheobronchitis. Pseudomembranous tracheobronchitis is usually developed in immunocompromised patients, but it can also occur in immunocompetent patients on a very rare basis. We report a case of pseudomembranous tracheobronchitis complicated by co-infection of inflenaza A and Staphylococcus aureus, causing acute respiratory failure in immunocompetent patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4046/trd.2015.78.4.366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4620332PMC
October 2015

Intrapleural corticosteroid injection in eosinophilic pleural effusion associated with undifferentiated connective tissue disease.

Tuberc Respir Dis (Seoul) 2013 Oct 29;75(4):161-4. Epub 2013 Oct 29.

Department of Internal Medicine, Hallym University Kangdong Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Korea.

Eosinophilic pleural effusion (EPE) is defined as a pleural effusion that contains at least 10% eosinophils. EPE occurs due to a variety of causes such as blood or air in the pleural space, infection, malignancy, or an autoimmune disease. Undifferentiated connective tissue disease (UCTD) associated with eosinophilic pleural effusion is a rare condition generally characterized by the presence of the signs and symptoms but not fulfilling the existing classification criteria. We report a case involving a 67-year-old man with UCTD and EPE, who has been successfully treated with a single intrapleural corticosteroid injection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4046/trd.2013.75.4.161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3833937PMC
October 2013

Translational control of TOP2A influences doxorubicin efficacy.

Mol Cell Biol 2011 Sep 18;31(18):3790-801. Epub 2011 Jul 18.

Laboratory of Molecular Biology and Immunology, NIA-IRP, NIH, Baltimore, Maryland 21224, USA.

The cellular abundance of topoisomerase IIα (TOP2A) critically maintains DNA topology after replication and determines the efficacy of TOP2 inhibitors in chemotherapy. Here, we report that the RNA-binding protein HuR, commonly overexpressed in cancers, binds to the TOP2A 3'-untranslated region (3'UTR) and increases TOP2A translation. Reducing HuR levels triggered the recruitment of TOP2A transcripts to RNA-induced silencing complex (RISC) components and to cytoplasmic processing bodies. Using a novel MS2-tagged RNA precipitation method, we identified microRNA miR-548c-3p as a mediator of these effects and further uncovered that the interaction of miR-548c-3p with the TOP2A 3'UTR repressed TOP2A translation by antagonizing the action of HuR. Lowering TOP2A by silencing HuR or by overexpressing miR-548c-3p selectively decreased DNA damage after treatment with the chemotherapeutic agent doxorubicin. In sum, HuR enhances TOP2A translation by competing with miR-548c-3p; their combined actions control TOP2A expression levels and determine the effectiveness of doxorubicin.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/MCB.05639-11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3165726PMC
September 2011

Enhanced translation by Nucleolin via G-rich elements in coding and non-coding regions of target mRNAs.

Nucleic Acids Res 2011 Oct 6;39(19):8513-30. Epub 2011 Jul 6.

Laboratory of Molecular Biology and Immunology, National Institute on Aging - Intramural Research Program, NIH, Baltimore, MD 21224, USA.

RNA-binding proteins (RBPs) regulate gene expression at many post-transcriptional levels, including mRNA stability and translation. The RBP nucleolin, with four RNA-recognition motifs, has been implicated in cell proliferation, carcinogenesis and viral infection. However, the subset of nucleolin target mRNAs and the influence of nucleolin on their expression had not been studied at a transcriptome-wide level. Here, we globally identified nucleolin target transcripts, many of which encoded cell growth- and cancer-related proteins, and used them to find a signature motif on nucleolin target mRNAs. Surprisingly, this motif was very rich in G residues and was not only found in the 3'-untranslated region (UTR), but also in the coding region (CR) and 5'-UTR. Nucleolin enhanced the translation of mRNAs bearing the G-rich motif, since silencing nucleolin did not change target mRNA stability, but decreased the size of polysomes forming on target transcripts and lowered the abundance of the encoded proteins. In summary, nucleolin binds G-rich sequences in the CR and UTRs of target mRNAs, many of which encode cancer proteins, and enhances their translation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/nar/gkr488DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3201861PMC
October 2011

Molecular layer-by-layer self-assembly and mercury sensing characteristics of novel brush polymers bearing thymine moieties.

ACS Appl Mater Interfaces 2011 Jul 22;3(7):2655-64. Epub 2011 Jun 22.

Department of Chemistry, Division of Advanced Materials Science, Center for Electro-Photo Behaviors in Advanced Molecular Systems, Polymer Research Institute, Pohang 790-784, Republic of Korea.

Two new brush polyoxyethylenes bearing thymine moieties at the bristle ends have been synthesized as model polymers in which the chemical loading of the thymine functional group into the polymer is maximized: poly(oxy(11-thyminoacetyloxyundecylthiomethyl)ethylene) (PECH(S)-T) and poly(oxy(11-thyminoacetyloxyundecylsulfonylmethyl)ethylene) (PECH(SO(2))-T). These brush polymers are thermally stable up to around 225 °C, and their glass transitions occur in the range 23-27 °C, but they have significantly different properties despite the similarity of their chemical structures. In particular, PECH(SO(2))-T films exhibit better performance in sensing mercury ions than PECH(S)-T films. These differences were found to originate in the differences between their morphological structures. The PECH(SO(2))-T film has a multi-bilayer structure without interdigitation, in which the layers stack along the out-of-plane of the film and provide a thymine-rich surface. In contrast, the PECH(S)-T film is amorphous with a relatively low population of thymine moieties at the surface. This study demonstrated that a thymine-rich surface is required for recyclable thymine-based polymers to provide highly improved sensitivity and selectivity as well as full reversibility in the sensing of mercury ions. A thymine-rich surface can be achieved with a brush polymer bearing thymine moieties that can self-assemble into a multi-bilayer structure. Because of the thymine-rich surface, the PECH(SO(2))-T thin films even in only 6 nm thickness demonstrate the detection of mercury ions in aqueous solutions with a detection limit of 10(-6) M.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/am200454xDOI Listing
July 2011

Well-defined DNA-mimic brush polymers bearing adenine moieties: synthesis, layer-by-layer self-assembly, and biocompatibility.

Biomacromolecules 2011 Jul 27;12(7):2822-33. Epub 2011 May 27.

Department of Chemistry, Polymer Research Institute, and BK School of Molecular Science, Pohang University of Science and Technology, Pohang 790-784, Republic of Korea.

Two new DNA-mimicking brush polymers were synthesized: poly[oxy(11-(3-(9-adeninyl)propionato)-undecanyl-1-thiomethyl)ethylene] (PECH-AP) and poly[oxy(11-(5-(9-adenylethyloxy)-4-oxopentanoato)undecanyl-1-thiomethyl)ethylene] (PECH-AS). These polymers were found to be thermally stable up to 220 °C and could be applied easily by conventional coating processes to produce good quality films. Interestingly, both brush polymers formed molecular multibilayer structures to provide an adenine-rich surface. Despite the structural similarities, PECH-AS surprisingly exhibited higher hydrophilicity and better water sorption properties than PECH-AP. These differences were attributed to the chemical structures in the bristles of the polymers. The adenine-rich surfaces of the polymer films demonstrated selective protein adsorption, suppressed bacterial adherence, facilitated HEp-2 cell adhesion, and exhibited good biocompatibility in mice. However, the high hydrophilicity and good water sorption characteristics of the PECH-AS film suggest that this brush polymer is better suited to applications requiring good biocompatibility and reduced chance of bacterial infection compared with the PECH-AP film.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/bm200572tDOI Listing
July 2011

pH-dependent structures of ferritin and apoferritin in solution: disassembly and reassembly.

Biomacromolecules 2011 May 8;12(5):1629-40. Epub 2011 Apr 8.

Department of Chemistry, Division of Advanced Material Science, BK School of Molecular Science, Pohang University of Science and Technology, Pohang, Republic of Korea.

The pH-dependent structures of the ferritin shell (apoferritin, 24-mer) and the ferrihydrite core, under physiological conditions that permit enzymatic activity, were investigated by synchrotron small-angle X-ray scattering (SAXS). The solution structure of apoferritin was found to be nearly identical to the crystal structure. The shell thickness and hollow core volumes were estimated. The intact hollow spherical apoferritin was stable over a wide pH range, 3.40-10.0, and the ferrihydrite core was stable over the pH range 2.10-10.0. The apoferritin subunits underwent aggregation below pH 0.80, whereas the ferrihydrite cores aggregated below pH 2.10 as a result of the disassembly of the ferritin shell under the strongly acidic conditions. As the pH decreased from 3.40 to 0.80, apoferritin underwent stepwise disassembly by first forming a hollow sphere with two holes, then a headset-shaped structure, and, finally, rodlike oligomers. As the pH was increased from pH 1.96, the disassembled rodlike oligomers recovered only to the headset-shaped structure, and the disassembled headset-shaped intermediates recovered only to the hollow spherical structure with two hole defects. The apoferritin hole defects that formed during the disassembly process did not heal as the pH was increased to neutral or slightly basic conditions. The pH-induced apoferritin disassembly and reassembly processes were not fully reversible, although they were pseudoreversible over a limited pH range, between 10.0 and 2.66.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/bm200026vDOI Listing
May 2011

Possible role of phosphoinositide-3-kinase in Mx1 protein translation and antiviral activity of interferon-omega-stimulated HeLa cells.

Pharmacology 2011 25;87(3-4):224-31. Epub 2011 Mar 25.

Advanced Therapy Products Research Division, National Institute of Food and Drug Safety Evaluation, Korea Food and Drug Administration, Chungcheongbuk-do, Republic of Korea.

Interferon ω (IFN-ω), a cytokine released during innate immune activation, is well known for promoting direct antiviral responses; however, the possible signal pathways that are initiated by IFN-ω binding to the type I IFN receptors have not been fully studied. Here, we provide evidence that activation of phosphoinositide-3-kinase/protein kinase B (PI3K/Akt) signaling plays a pivotal role in the generation of IFN-ω-mediated biological responses. We found that LY294002 (PI3K inhibitor)-attenuated antiviral activities are induced by IFN-ω treatment. Although such effects of LY294002 are unrelated to regulatory activities on IFN-ω-dependent Mx1 (myxovirus resistance 1) or Mx2 gene transcriptional regulation, translation of Mx1 protein, which was known as a key mediator of cell-autonomous antiviral resistance, was significantly reduced by PI3K inhibition. Further studies showed that PI3K inhibition using LY294002 leads to a decrease in PI3K substrate Akt and mitogen-activated protein kinase extracellular signal-regulated kinase and p38 phosphorylation/activation. In addition, although LY294002 was not able to reduce STAT1 activation, we found that the mammalian target of rapamycin (mTOR)/p70 S6 kinase pathway was significantly attenuated by inhibition of the PI3K/Akt signaling pathway. These results indicate that the PI3K/Akt pathway is a common and central integrator for antiviral responses in IFN-ω signaling via its regulatory effects on mTOR that are required for initiation of mRNA translation of Mx genes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000324536DOI Listing
August 2011

Global dissociation of HuR-mRNA complexes promotes cell survival after ionizing radiation.

EMBO J 2011 Mar 11;30(6):1040-53. Epub 2011 Feb 11.

Laboratory of Molecular Biology and Immunology, Baltimore, MD, USA.

Ionizing radiation (IR) triggers adaptive changes in gene expression. Here, we show that survival after IR strongly depends on the checkpoint kinase Chk2 acting upon its substrate HuR, an RNA-binding protein that stabilizes and/or modulates the translation of target mRNAs. Microarray analysis showed that in human HCT116 colorectal carcinoma cells (WT), IR-activated Chk2 triggered the dissociation of virtually all of HuR-bound mRNAs, since IR did not dissociate HuR target mRNAs in Chk2-null (CHK2-/-) HCT116 cells. Accordingly, several HuR-interacting mRNAs encoding apoptosis- and proliferation-related proteins (TJP1, Mdm2, TP53BP2, Bax, K-Ras) dissociated from HuR in WT cells, but remained bound and showed altered post-transcriptional regulation in CHK2-/- cells. Use of HuR mutants that were not phosphorylatable by Chk2 (HuR(3A)) and HuR mutants mimicking constitutive phosphorylation by Chk2 (HuR(3D)) revealed that dissociation of HuR target transcripts enhanced cell survival. We propose that the release of HuR-bound mRNAs via an IR-Chk2-HuR regulatory axis improves cell outcome following IR.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/emboj.2011.24DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3061031PMC
March 2011

miR-130 suppresses adipogenesis by inhibiting peroxisome proliferator-activated receptor gamma expression.

Mol Cell Biol 2011 Feb 6;31(4):626-38. Epub 2010 Dec 6.

Laboratory of Molecular Biology and Immunology, NIA-IRP, NIH, Baltimore, Maryland 21224, USA.

Adipose tissue development is tightly regulated by altering gene expression. MicroRNAs are strong posttranscriptional regulators of mammalian differentiation. We hypothesized that microRNAs might influence human adipogenesis by targeting specific adipogenic factors. We identified microRNAs that showed varying abundance during the differentiation of human preadipocytes into adipocytes. Among them, miR-130 strongly affected adipocyte differentiation, as overexpressing miR-130 impaired adipogenesis and reducing miR-130 enhanced adipogenesis. A key effector of miR-130 actions was the protein peroxisome proliferator-activated receptor γ (PPARγ), a major regulator of adipogenesis. Interestingly, miR-130 potently repressed PPARγ expression by targeting both the PPARγ mRNA coding and 3' untranslated regions. Adipose tissue from obese women contained significantly lower miR-130 and higher PPARγ mRNA levels than that from nonobese women. Our findings reveal that miR-130 reduces adipogenesis by repressing PPARγ biosynthesis and suggest that perturbations in this regulation is linked to human obesity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/MCB.00894-10DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3028659PMC
February 2011

MicroRNA profiling in human diploid fibroblasts uncovers miR-519 role in replicative senescence.

Aging (Albany NY) 2010 Jun;2(6):333-43

Laboratory of Cellular and Molecular Biology, NIA-IRP, NIH, Baltimore, MD 21224, USA.

MicroRNAs (miRNAs) are short non-coding RNAs that regulate diverse biological processes by controlling the pattern of expressed proteins. In mammalian cells, miRNAs partially complement their target sequences leading to mRNA degradation and/or decreased mRNA translation. Here, we have analyzed transcriptome-wide changes in miRNAs in senescent relative to early-passage WI-38 human diploid fibroblasts (HDFs). Among the miRNAs downregulated with senescence were members of the let-7 family, while upregulated miRNAs included miR-1204, miR-663 and miR-519. miR-519 was recently found to reduce tumor growth at least in part by lowering the abundance of the RNA-binding protein HuR. Overexpression of miR-519a in either WI-38 or human cervical carcinoma HeLa cells triggered senescence, as measured by monitoring beta-galactosidase activity and other senescence markers. These data suggest that miR-519 can suppress tumor growth by triggering senescence and that miR-519 elicits these actions by repressing HuR expression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2919253PMC
http://dx.doi.org/10.18632/aging.100159DOI Listing
June 2010

miR-375 inhibits differentiation of neurites by lowering HuD levels.

Mol Cell Biol 2010 Sep 28;30(17):4197-210. Epub 2010 Jun 28.

Laboratory of Cellular and Molecular Biology, National Institute on Aging-Intramural Research Program, NIH, Baltimore, MD 21224, USA.

Neuronal development and plasticity are maintained by tightly regulated gene expression programs. Here, we report that the developmentally regulated microRNA miR-375 affects dendrite formation and maintenance. miR-375 overexpression in mouse hippocampus potently reduced dendrite density. We identified the predominantly neuronal RNA-binding protein HuD as a key effector of miR-375 influence on dendrite maintenance. Heterologous reporter analysis verified that miR-375 repressed HuD expression through a specific, evolutionarily conserved site on the HuD 3' untranslated region. miR-375 overexpression lowered both HuD mRNA stability and translation and recapitulated the effects of HuD silencing, which reduced the levels of target proteins with key functions in neuronal signaling and cytoskeleton organization (N-cadherin, PSD-95, RhoA, NCAM1, and integrin alpha1). Moreover, the increase in neurite outgrowth after brain-derived neurotrophic factor (BDNF) treatment was diminished by miR-375 overexpression; this effect was rescued by reexpression of miR-375-refractory HuD. Our findings indicate that miR-375 modulates neuronal HuD expression and function, in turn affecting dendrite abundance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/MCB.00316-10DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2937556PMC
September 2010

miR-519 suppresses tumor growth by reducing HuR levels.

Cell Cycle 2010 Apr 1;9(7):1354-9. Epub 2010 Apr 1.

Laboratory of Cellular and Molecular Biology, NIA-IRP, National Institutes of Health Bethesda, MD, USA.

The RNA-binding protein HuR is highly abundant in many cancers. HuR expression was recently found to be repressed by microRNA miR-519, which potently lowered HuR translation without influencing HuR mRNA abundance. Here, we examined the levels of HuR and miR-519 in pairs of cancer and adjacent healthy tissues from ovary, lung, and kidney. In the three sample collections, the cancer specimens showed dramatically higher HuR levels, unchanged HuR mRNA concentrations, and markedly reduced miR-519 levels, when compared with healthy tissues. As tested using human cervical carcinoma cells, miR-519 reduced tumorigenesis in athymic mice. Compared with the tumors arising from control cells, cells overexpressing miR-519 formed significantly smaller tumors, while cells expressing reduced miR-519 levels gave rise to substantially larger tumors. Evidence that the miR-519-elicited reduction of HuR was critical for its tumor suppressor influence was obtained by reducing HuR, as HuR-silenced cells formed markedly smaller tumors and were unable to form large tumors even after lowering miR-519 abundance. Together, our data reveal that miR-519 inhibits tumorigenesis in large part by repressing HuR expression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3057889PMC
http://dx.doi.org/10.4161/cc.9.7.11164DOI Listing
April 2010

The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1.

Nat Cell Biol 2010 Mar 21;12(3):213-23. Epub 2010 Feb 21.

Laboratory of Frontier Science, Tokyo Metropolitan Institute of Medical Science, Bunkyo-ku, Tokyo 113-8613, Japan.

Impaired selective turnover of p62 by autophagy causes severe liver injury accompanied by the formation of p62-positive inclusions and upregulation of detoxifying enzymes. These phenotypes correspond closely to the pathological conditions seen in human liver diseases, including alcoholic hepatitis and hepatocellular carcinoma. However, the molecular mechanisms and pathophysiological processes in these events are still unknown. Here we report the identification of a novel regulatory mechanism by p62 of the transcription factor Nrf2, whose target genes include antioxidant proteins and detoxification enzymes. p62 interacts with the Nrf2-binding site on Keap1, a component of Cullin-3-type ubiquitin ligase for Nrf2. Thus, an overproduction of p62 or a deficiency in autophagy competes with the interaction between Nrf2 and Keap1, resulting in stabilization of Nrf2 and transcriptional activation of Nrf2 target genes. Our findings indicate that the pathological process associated with p62 accumulation results in hyperactivation of Nrf2 and delineates unexpected roles of selective autophagy in controlling the transcription of cellular defence enzyme genes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ncb2021DOI Listing
March 2010

Induction of cytoplasmic accumulation of p53: a mechanism for low levels of arsenic exposure to predispose cells for malignant transformation.

Cancer Res 2008 Nov;68(22):9131-6

Department of Genetics and Complex Disease, Harvard School of Public Health, Boston, Massachusetts, USA.

Although epidemiologic studies have linked arsenic exposure to the development of human cancer, the mechanisms underlying the tumorigenic role of arsenic remain largely undefined. We report here that treatment of cells with sodium arsenite at the concentrations close to environmental exposure is associated with the up-regulation of Hdm2 and the accumulation of p53 in the cytoplasm. Through the mitogen-activated protein kinase pathway, arsenite stimulates the P2 promoter-mediated expression of Hdm2, which then promotes p53 nuclear export. As a consequence, the p53 response to genotoxic stress is compromised, as evidenced by the impaired p53 activation and apoptosis in response to UV irradiation or 5FU treatment. The ability of arsenite to impede p53 activation is further demonstrated by a significantly blunted p53-dependent tissue response to 5FU treatment when mice were fed with arsenite-containing water. Together, our data suggests that arsenic compounds predispose cells to malignant transformation by up-regulation of Hdm2 and subsequent p53 inactivation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/0008-5472.CAN-08-3025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2717853PMC
November 2008