Publications by authors named "Do Hoon Kwon"

91 Publications

Heat-dependent opening of TRPV1 in the presence of capsaicin.

Nat Struct Mol Biol 2021 Jul 8;28(7):554-563. Epub 2021 Jul 8.

Department of Biochemistry, Duke University School of Medicine, Durham, NC, USA.

Transient receptor potential vanilloid member 1 (TRPV1) is a Ca-permeable cation channel that serves as the primary heat and capsaicin sensor in humans. Using cryo-EM, we have determined the structures of apo and capsaicin-bound full-length rat TRPV1 reconstituted into lipid nanodiscs over a range of temperatures. This has allowed us to visualize the noxious heat-induced opening of TRPV1 in the presence of capsaicin. Notably, noxious heat-dependent TRPV1 opening comprises stepwise conformational transitions. Global conformational changes across multiple subdomains of TRPV1 are followed by the rearrangement of the outer pore, leading to gate opening. Solvent-accessible surface area analyses and functional studies suggest that a subset of residues form an interaction network that is directly involved in heat sensing. Our study provides a glimpse of the molecular principles underlying noxious physical and chemical stimuli sensing by TRPV1, which can be extended to other thermal sensing ion channels.
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http://dx.doi.org/10.1038/s41594-021-00616-3DOI Listing
July 2021

Structural basis for the N-degron specificity of ClpS1 from Arabidopsis thaliana.

Protein Sci 2021 03 30;30(3):700-708. Epub 2020 Dec 30.

Department of Life Sciences, Korea University, Seoul, South Korea.

The N-degron pathway determines the half-life of proteins in both prokaryotes and eukaryotes by precisely recognizing the N-terminal residue (N-degron) of substrates. ClpS proteins from bacteria bind to substrates containing hydrophobic N-degrons (Leu, Phe, Tyr, and Trp) and deliver them to the caseinolytic protease system ClpAP. This mechanism is preserved in organelles such as mitochondria and chloroplasts. Bacterial ClpS adaptors bind preferentially to Leu and Phe N-degrons; however, ClpS1 from Arabidopsis thaliana (AtClpS1) shows a difference in that it binds strongly to Phe and Trp N-degrons and only weakly to Leu. This difference in behavior cannot be explained without structural information due to the high sequence homology between bacterial and plant ClpS proteins. Here, we report the structure of AtClpS1 at 2.0 Å resolution in the presence of a bound N-degron. The key determinants for α-amino group recognition are conserved among all ClpS proteins, but the α3-helix of eukaryotic AtClpS1 is significantly shortened, and consequently, a loop forming a pocket for the N-degron is moved slightly outward to enlarge the pocket. In addition, amino acid replacement from Val to Ala causes a reduction in hydrophobic interactions with Leu N-degron. A combination of the fine-tuned hydrophobic residues in the pocket and the basic gatekeeper at the entrance of the pocket controls the N-degron selectivity of the plant ClpS protein.
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http://dx.doi.org/10.1002/pro.4018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7888574PMC
March 2021

Targeted Degradation of Transcription Coactivator SRC-1 through the N-Degron Pathway.

Angew Chem Int Ed Engl 2020 09 12;59(40):17548-17555. Epub 2020 Aug 12.

Department of Chemistry and Division of Advanced Materials Science, Pohang University of Science and Technology (POSTECH), 77 Cheongam-Ro, Nam-Gu, Pohang, 37673, South Korea.

Aberrantly elevated steroid receptor coactivator-1 (SRC-1) expression and activity are strongly correlated with cancer progression and metastasis. Here we report, for the first time, the development of a proteolysis targeting chimera (PROTAC) that is composed of a selective SRC-1 binder linked to a specific ligand for UBR box, a unique class of E3 ligases recognizing N-degrons. We showed that the bifunctional molecule efficiently and selectively induced the degradation of SRC-1 in cells through the N-degron pathway. Importantly, given the ubiquitous expression of the UBR protein in most cells, PROTACs targeting the UBR box could degrade a protein of interest regardless of cell types. We also showed that the SRC-1 degrader significantly suppressed cancer cell invasion and migration in vitro and in vivo. Together, these results demonstrate that the SRC-1 degrader can be an invaluable chemical tool in the studies of SRC-1 functions. Moreover, our findings suggest PROTACs based on the N-degron pathway as a widely useful strategy to degrade disease-relevant proteins.
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http://dx.doi.org/10.1002/anie.202005004DOI Listing
September 2020

Hypofractionated stereotactic radiosurgery for large-sized skull base meningiomas.

J Neurooncol 2020 Aug 1;149(1):87-93. Epub 2020 Jul 1.

Radiosurgery Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

Purpose: Although stereotactic radiosurgery (SRS) has been proven to be effective and safe for treating intracranial meningiomas, concerns have been raised about the use of SRS for large-sized tumors involving the skull base that frequently encroach onto adjacent critical neural structures. The purpose of this study was to investigate the role of hypofractionated SRS as a therapeutic option for large-sized skull base meningiomas.

Methods: Thirty-one consecutive patients (median age: 55 years, 9 men and 22 women) who had been treated with hypofractionated SRS using CyberKnife for large-sized skull base meningiomas (> 10 cm in volume, median of 18.9 cm, range 11.6-58.2 cm) were enrolled. All patients harbored middle or posterior skull base tumors, most frequently of cavernous sinus (n = 7, 22.6%), petroclival (n = 6, 19.4%), or tentorial edge (n = 6, 19.4%) locations. SRS was delivered in five daily fractions (range 3-5 fractions) with a median cumulative dose of 27.8 Gy (range 22.6-27.8 Gy).

Results: With a median follow-up of 57 months (range 9-98 months), tumor control was achieved for 28 (90.3%) of 31 patients. Treatment response on MRI included partial response (volume decrease > 20%) in 17 (54.8%) patients, stable in 11 (35.5%), and progression (volume increase > 20%) in 3 (9.7%). Of 21 patients with cranial neuropathy, 20 (95.2%) showed improved neurological status.

Conclusions: Our current results suggest a promising role of hypofractionated SRS for large-sized skull base megningiomas in terms of tumor control and neurological outcomes. It is a reasonable therapeutic option for select patients.
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http://dx.doi.org/10.1007/s11060-020-03575-9DOI Listing
August 2020

Radiosurgery for Cerebral Arteriovenous Malformation (AVM) : Current Treatment Strategy and Radiosurgical Technique for Large Cerebral AVM.

J Korean Neurosurg Soc 2020 Jul 20;63(4):415-426. Epub 2020 May 20.

Department of Neurological Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

Arteriovenous malformations (AVMs) are congenital anomalies of the cerebrovascular system. AVM harbors 2.2% annual hemorrhage risk in unruptured cases and 4.5% annual hemorrhage risk of previously ruptured cases. Stereotactic radiosurgery (SRS) have been shown excellent treatment outcomes for patients with small- to moderated sized AVM which can be achieved in 80-90% complete obliteration rate with a 2-3 years latency period. The most important factors are associated with obliteration after SRS is the radiation dose to the AVM. In our institutional clinical practice, now 22 Gy (50% isodose line) dose of radiation has been used for treatment of cerebral AVM in single-session radiosurgery. However, dose-volume relationship can be unfavorable for large AVMs when treated in a single-session radiosurgery, resulting high complication rates for effective dose. Thus, various strategies should be considered to treat large AVM. The role of pre-SRS embolization is permanent volume reduction of the nidus and treat high-risk lesion such as AVM-related aneurysm and high-flow arteriovenous shunt. Various staging technique of radiosurgery including volume-staged radiosurgery, hypofractionated radiotherapy and dose-staged radiosurgery are possible option for large AVM. The incidence of post-radiosurgery complication is varied, the incidence rate of radiological post-radiosurgical complication has been reported 30-40% and symptomatic complication rate was reported from 8.1% to 11.8%. In the future, novel therapy which incorporate endovascular treatment using liquid embolic material and new radiosurgical technique such as gene or cytokine-targeted radio-sensitization should be needed.
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http://dx.doi.org/10.3340/jkns.2020.0008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7365281PMC
July 2020

Development and validation of a risk scoring model for postoperative adult moyamoya disease.

J Neurosurg 2020 May 8;134(5):1505-1514. Epub 2020 May 8.

1Department of Neurosurgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul.

Objective: The current grading system for moyamoya disease (MMD) is focused on angiographic studies with limited clinical application. The authors aimed to determine relevant factors that may impact postoperative outcome and establish a scoring system to predict the functional outcome.

Methods: Adult patients with MMD who underwent treatment between 1998 and 2016 were included. Factors such as age, sex, comorbidity, smoking, MMD family history, initial presentation, multimodal imaging modalities, and types of surgical revascularization were thoroughly reviewed. These factors were analyzed to determine possible risk factors related to unfavorable 6-month postoperative outcomes using the modified Rankin Scale (mRS) (unfavorable: mRS score ≥ 3). A scoring system was developed using these independent risk factors to predict the outcome and validated using prospectively collected data from multiple centers between 2017 and 2018.

Results: Of 302 patients for whom applications were submitted, 260 patients (321 hemispheres) met the diagnostic criteria. In multivariate analysis, hyperlipidemia, smoking, cerebral infarction on preoperative CT or MRI, and moderately to severely reduced regional cerebrovascular reserve results from Diamox SPECT were significantly related to unfavorable outcome. The authors developed a scoring system and stratified patients into risk groups according to their scores: low-risk (score 0-3), intermediate-risk (score 4-6), and high-risk (score 7-9) groups. This model demonstrated both good discrimination and calibration using C-statistics and the Hosmer-Lemeshow goodness-of-fit test showing 0.812 (95% CI 0.743-0.881) (p = 0.568) for the development and 0.954 (95% CI 0.896-1) (p = 0.097) for the temporal and external validation cohort.

Conclusions: The authors' scoring system is readily adoptable to predict the postoperative outcome for MMD. Their data revealed the importance of smoking and hyperlipidemia, which were the only modifiable factors included in the scoring system. The authors validated their scoring system both internally and externally and maintained good performance, highlighting the system's generalizability and reliability.
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http://dx.doi.org/10.3171/2020.2.JNS193221DOI Listing
May 2020

Role of gamma knife radiosurgery for recurrent or residual World Health Organization grade II and III intracranial meningiomas.

Br J Neurosurg 2020 Jun 13;34(3):239-245. Epub 2020 Feb 13.

Department of Neurological Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.

To analysis the role of gamma knife radiosurgery (GKRS) in treatment of the recurrent or residual World Health Organization (WHO) grade II and III meningiomas. Between 1995 and 2015, a total of 1163 meningioma patients were treated with GKRS at our single institute; 26 atypical and 6 anaplastic meningiomas were enrolled. The group consisted of 16 men and 16 women with a median age of 59.5 years (range 30-78 years). The median follow-up was 106.5 months (range 40-216 months). All were cases of tumour recurrence except 7 cases of residual lesions. Six patients were given fractionated radiotherapy before the initial course of GKRS (median dose, 56 Gy). The median tumour volume was 3035 mm (range 247-11400 mm). The median prescribed dose to high grade meningioma margin was 14 Gy (range 12-20 Gy,). The median prescribed dose to WHO II and III meningioma were 14 Gy (range 12-18 Gy) and 15 Gy (range 14-20 Gy), respectively. After radiosurgery, local tumour control rate was 50%. Tumour progression was observed in 28 patients; 16 recurrences were local (12 atypical and 4 anaplastic), 8 were marginal (7 atypical and 1 anaplastic), and 4 were distal (3 atypical and 1 anaplastic). Seven patients (21.88%) developed adverse radiation effects after GKRS. WHO grade was strongly associated with survival, with grade II showing a much longer survival ( = 0.01), and a prior history of radiation was associated with decreased survival ( = 0.003). Multivariate analysis showed that WHO grade (hazard ratio, HR: 5.051,  = 0.01) and prior radiation (HR: 5.763,  = 0.004) were independently associated with survival. WHO grade and a prior history of radiation therapy are reliable long-term predictors of overall outcome when treated with GKRS.
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http://dx.doi.org/10.1080/02688697.2020.1726285DOI Listing
June 2020

Use of the LC3B-fusion technique for biochemical and structural studies of proteins involved in the N-degron pathway.

J Biol Chem 2020 02 9;295(9):2590-2600. Epub 2020 Jan 9.

Department of Life Sciences, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, South Korea. Electronic address:

The N-degron pathway, formerly the N-end rule pathway, is a protein degradation process that determines the half-life of proteins based on their N-terminal residues. In contrast to the well-established studies over decades, studies of this pathway, including biochemical characterization and high-resolution structures, are relatively limited. In this study, we have developed a unique fusion technique using microtubule-associated protein 1A/1B light chain 3B, a key marker protein of autophagy, to tag the N terminus of the proteins involved in the N-degron pathway, which enables high yield of homogeneous target proteins with variable N-terminal residues for diverse biochemical studies including enzymatic and binding assays and substrate identification. Intriguingly, crystallization showed a markedly enhanced probability, even for the N-degron complexes. To validate our results, we determined the structures of select proteins in the N-degron pathway and compared them with the Protein Data Bank-deposited proteins. Furthermore, several biochemical applications of this technique were introduced. Therefore, this technique can be used as a general tool for the study of the N-degron pathway.
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http://dx.doi.org/10.1074/jbc.RA119.010912DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7049975PMC
February 2020

Impact of clinicopathologic features on leptomeningeal metastasis from lung adenocarcinoma and treatment efficacy with epidermal growth factor receptor tyrosine kinase inhibitor.

Thorac Cancer 2020 02 7;11(2):436-442. Epub 2020 Jan 7.

Department of Pulmonology and Critical Care Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.

Background: We investigated the risk factors for leptomeningeal carcinomatosis (LMC) and compared clinical efficacies of various treatment modalities including intrathecal (IT) chemotherapy in patients with lung adenocarcinoma harboring epidermal growth factor receptor (EGFR) mutations.

Methods: Using clinical research data from the Asan Medical Center, we retrospectively analyzed data of patients diagnosed with LMC, confirmed via cerebrospinal fluid (CSF) analysis from January 2008 to December 2017.

Results: We identified 1189 patients with lung adenocarcinoma harboring EGFR mutations. Among these, 9.8% had a median duration of 13.5 (interquartile range [IQR] 6.8-23.6) months from the initial lung cancer diagnosis to LMC occurrence. Younger age (hazard ratio [HR] 1.043, P < 0.001), initial metastatic disease (HR 3.768, P < 0.001), and metastasis to the brain (HR 8.682, P < 0.001) or lung (HR 2.317, P = 0.004) were risk factors associated with LMC. Median survival duration from LMC diagnosis was 3.8 (IQR 1.5-8.6) months. Eastern Cooperative Oncology Group performance status score ≤ 2 (HR 0.505, P = 0.007) and insertion of Ommaya reservoir (HR 0.445, P = 0.005) were associated with longer survival. EGFR-tyrosine kinase inhibitor (TKI) conferred survival benefits compared to cytotoxic chemotherapy or best supportive care (HR 2.222, P = 0.018; HR 5.638, P < 0.001, respectively). Although IT chemotherapy showed no survival benefit, it was associated with improved neurologic symptoms and signs and CSF negative conversion.

Conclusions: Younger age, initial diagnosis of metastatic disease, and metastasis to the brain or different lobes were associated with LMC in patients with EGFR-mutant lung adenocarcinoma. Therapeutic interventions including EGFR-TKIs, cytotoxic chemotherapy, or Ommaya reservoir, and good performance status were related to favorable survival outcomes.

Key Points: Age and disease status were associated with LMC in patients with EGFR-mutant adenocarcinoma, and EGFR-TKI, Ommaya reservoir, and good performance status were related to survival benefit.
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http://dx.doi.org/10.1111/1759-7714.13296DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6996974PMC
February 2020

Single-fraction versus hypofractionated stereotactic radiosurgery for medium-sized brain metastases of 2.5 to 3 cm.

J Neurooncol 2019 Oct 16;145(1):49-56. Epub 2019 Aug 16.

Department of Neurosurgery, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Republic of Korea.

Purpose: Given recently suggested utility of hypofractionated stereotactic radiosurgery (SRS) in treating large brain metastases (BMs) > 3 cm, we sought to prospectively control tumor size variable to investigate the efficacy and safety of hypofractionated SRS for medium-sized BMs (2.5 to 3 cm) compared with single-fraction SRS.

Methods: Between 2011 and 2015, a total of 100 patients with newly diagnosed BMs (n = 105) of 2.5 to 3 cm had been treated with either single-fraction (n = 67; median dose 20 Gy) or hypofractionated SRS (n = 38; median cumulative dose 35 Gy in 5 daily fractions). No patients received any prior or upfront whole brain radiotherapy. In each patient, treatment outcome was measured by local tumor control (LTC), overall and progression-free survival (OS and PFS), and the occurrence of radiation necrosis (RN).

Results: With a median follow-up of 14 months, significant differences were observed between the single-fraction versus hypofractionated SRS groups in the incidence of RN (29.9% vs. 5.3%, P < 0.001) and LTC (1-year LTC rates 66.6% vs. 92.4%, P = 0.028). There were no differences in PFS (median 6 months vs. 6 months, P = 0.381) and OS (median 13 months vs. 18 months, P = 0.239). Treatment-related adverse events ( ≥ grade 2 toxicity by CTCAE ver. 4.0) occurred more frequently in single-fraction group, although the difference did not reach statistical significance (56.3% vs. 36.1%, P = 0.084).

Conclusions: Our results suggest a better safety and efficacy profile of hypofractionated SRS for medium-sized BMs compared with single-fraction SRS. Further prospective studies are needed to confirm these results.
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http://dx.doi.org/10.1007/s11060-019-03265-1DOI Listing
October 2019

Endoribonucleolytic Cleavage of mA-Containing RNAs by RNase P/MRP Complex.

Mol Cell 2019 05 28;74(3):494-507.e8. Epub 2019 Mar 28.

Creative Research Initiatives Center for Molecular Biology of Translation, Korea University, Seoul 02841, Republic of Korea; Division of Life Sciences, Korea University, Seoul 02841, Republic of Korea. Electronic address:

N-methyladenosine (mA) is the most abundant internal modification in RNAs and plays regulatory roles in a variety of biological and physiological processes. Despite its important roles, the molecular mechanism underlying mA-mediated gene regulation is poorly understood. Here, we show that mA-containing RNAs are subject to endoribonucleolytic cleavage via YTHDF2 (mA reader protein), HRSP12 (adaptor protein), and RNase P/MRP (endoribonucleases). We demonstrate that HRSP12 functions as an adaptor to bridge YTHDF2 and RNase P/MRP, eliciting rapid degradation of YTHDF2-bound RNAs. Transcriptome-wide analyses show that mA RNAs that are preferentially targeted for endoribonucleolytic cleavage have an HRSP12-binding site and a RNase P/MRP-directed cleavage site upstream and downstream of the YTHDF2-binding site, respectively. We also find that a subset of mA-containing circular RNAs associates with YTHDF2 in an HRSP12-dependent manner and is selectively downregulated by RNase P/MRP. Thus, our data expand the known functions of RNase P/MRP to endoribonucleolytic cleavage of mA RNAs.
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http://dx.doi.org/10.1016/j.molcel.2019.02.034DOI Listing
May 2019

Pediatric Intracranial Aneurysms: Favorable Outcomes Despite Rareness and Complexity.

World Neurosurg 2019 05 19;125:e1203-e1216. Epub 2019 Feb 19.

Department of Neurosurgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea. Electronic address:

Objective: Pediatric intracranial aneurysms (IAs) are rare and differ from their adult counterparts in terms of their aneurysmal characteristics, presentation, treatment, and outcomes. Their treatment is often more difficult and complex compared with that of adults. However, studies outlining the clinical effect of pediatric IAs remain sparse.

Methods: We retrospectively reviewed the data from patients aged ≤18 years admitted to our hospital from 2000 to 2017 with a diagnosis of IAs.

Results: From the sample of 8207 patients with an IA diagnosis, 26 patients with 33 IAs were involved. Our cohort included 17 males and 9 females, with a mean age of 12.5 years. The mean follow-up duration was 4 years and 3 months. Seven patients (26.92%) were assumed to have a traumatic origin for their IAs. Ruptured aneurysms were more common than unruptured ones (61.53% vs. 38.46%). Complex features were observed in 14 aneurysms (42.42%). Initially, microsurgical and endovascular treatment were both performed in 10 patients (38.46%). A good recovery was obtained in 16 patients (61.54%) as determined by the Glasgow outcome scale scores at the 6-month follow-up visits. The complete obliteration of aneurysms was observed in 17 patients (65.38%). Endovascular treatment was the initial treatment in 3 patients with incomplete obliteration.

Conclusions: The treatment of pediatric IAs is challenging and technically demanding owing to their discrete nature compared with adult IAs and the need for greater surgical skills. We found a male predominance, with internal carotid artery bifurcation as the most frequent location of the aneurysms. Despite the greater incidence of ruptured and complex aneurysm cases, many patients had experienced a good recovery at the 6-month follow-up examinations.
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http://dx.doi.org/10.1016/j.wneu.2019.01.280DOI Listing
May 2019

eIF4A3 Phosphorylation by CDKs Affects NMD during the Cell Cycle.

Cell Rep 2019 02;26(8):2126-2139.e9

Creative Research Initiatives Center for Molecular Biology of Translation, Korea University, Seoul 02841, Republic of Korea; Division of Life Sciences, Korea University, Seoul 02841, Republic of Korea. Electronic address:

Exon junction complexes (EJCs) loaded onto spliced mRNAs during splicing serve as molecular markers for various post-transcriptional gene-regulatory processes, including nonsense-mediated mRNA decay (NMD). Although the composition and structure of EJCs are well characterized, the mechanism regulating EJC deposition remains unknown. Here we find that threonine 163 (T163) within the RNA-binding motif of eIF4A3 (a core EJC component) is phosphorylated by cyclin-dependent protein kinases 1 and 2 in a cell cycle-dependent manner. T163 phosphorylation hinders binding of eIF4A3 to spliced mRNAs and other EJC components. Instead, it promotes association of eIF4A3 with CWC22, which guides eIF4A3 to an active spliceosome. These molecular events ensure the fidelity of specific deposition of the EJC ∼20-24 nt upstream of an exon-exon junction. Accordingly, NMD is affected by T163 phosphorylation. Collectively, our data provide evidence that T163 phosphorylation affects EJC formation and, consequently, NMD efficiency in a cell cycle-dependent manner.
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http://dx.doi.org/10.1016/j.celrep.2019.01.101DOI Listing
February 2019

Long-Term Efficacy and Tolerability of Gamma Knife Radiosurgery for Growth Hormone-Secreting Adenoma: A Retrospective Multicenter Study (MERGE-001).

World Neurosurg 2019 Feb 15;122:e1291-e1299. Epub 2018 Nov 15.

Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. Electronic address:

Objective: Little is known about the long-term efficacy, prognostic factors, and tolerability of gamma knife radiosurgery (GKS) for acromegaly. The aim of this study was to investigate long-term hormonal effects, prognostic factors, and tolerability of GKS in patients with growth hormone-secreting adenoma.

Methods: A retrospective multicenter study over 25 years with a median follow-up of 85.2 months was performed. A total of 138 patients from 3 tertiary referral centers in South Korea were included in this study between 1991 and 2017. Main outcome measures were endocrine remission, endocrine control under somatostatin analogues, and hypopituitarism.

Results: With a mean follow-up period of 85.2 months (range, 12-304 months), overall median time to the endocrine remission and control under long-acting somatostatin analogues was 138 months and 96 months, respectively. Female sex, normal age-adjusted insulin growth factor-1 (IGF-1) ≤ 2, and GKS as an adjuvant treatment were significantly favorable factors for remission (P = 0.004, P = 0.001, P = 0.010, respectively). The early response group had a significantly lower proportion of normal age-adjusted IGF-1 levels >2 than did the late response group (22.2% vs. 51.7%, P = 0.035); also, the early response group had lower radiation dose than the late response group (24.3 Gy vs. 27.0 Gy, P = 0.003). The incidence of GKS-induced hypopituitarism (1 or more) was 12 of 138 patients (8.6%) at the last follow-up.

Conclusions: In acromegalic patients, women with normal age-adjusted IGF-1 ≤ 2 and GKS as an adjuvant treatment have a better response to GKS. We should take into account the variability of radiosensitivity of the tumor according to the gender and IGF-1 level.
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http://dx.doi.org/10.1016/j.wneu.2018.11.038DOI Listing
February 2019

Cyberknife Dosimetric Planning Using a Dose-Limiting Shell Method for Brain Metastases.

J Korean Neurosurg Soc 2018 Nov 30;61(6):753-760. Epub 2018 Oct 30.

Department of Neurosurgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

Objective: We investigated the effect of optimization in dose-limiting shell method on the dosimetric quality of CyberKnife (CK) plans in treating brain metastases (BMs).

Methods: We selected 19 BMs previously treated using CK between 2014 and 2015. The original CK plans (CKoriginal) had been produced using 1 to 3 dose-limiting shells : one at the prescription isodose level (PIDL) for dose conformity and the others at lowisodose levels (10-30% of prescription dose) for dose spillage. In each case, a modified CK plan (CKmodified) was generated using 5 dose-limiting shells : one at the PIDL, another at intermediate isodose level (50% of prescription dose) for steeper dose fall-off, and the others at low-isodose levels, with an optimized shell-dilation size based on our experience. A Gamma Knife (GK) plan was also produced using the original contour set. Thus, three data sets of dosimetric parameters were generated and compared.

Results: There were no differences in the conformity indices among the CKoriginal, CKmodified, and GK plans (mean 1.22, 1.18, and 1.24, respectively; p=0.079) and tumor coverage (mean 99.5%, 99.5%, and 99.4%, respectively; p=0.177), whereas the CKmodified plans produced significantly smaller normal tissue volumes receiving 50% of prescription dose than those produced by the CKoriginal plans (p<0.001), with no statistical differences in those volumes compared with GK plans (p=0.345).

Conclusion: These results indicate that significantly steeper dose fall-off is able to be achieved in the CK system by optimizing the shell function while maintaining high conformity of dose to tumor.
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http://dx.doi.org/10.3340/jkns.2018.0075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6280060PMC
November 2018

pH-dependent regulation of SQSTM1/p62 during autophagy.

Autophagy 2019 01 12;15(1):180-181. Epub 2018 Oct 12.

a Department of Life Sciences , Korea University , Seoul , Korea.

During macroautophagy/autophagy, SQSTM1/p62 plays dual roles as a key mediator of cargo selection and as an autophagic substrate. SQSTM1 links N-degrons and/or ubiquitinated cargoes to the autophagosome by forming homo- or hetero-oligomers, although its N-degron recognition and oligomerization mechanisms are not well characterized. We recently found that SQSTM1 is a novel type of N-recognin whose ZZ domain provides a negatively-charged binding pocket for Arg-charged N-degron (Nt-Arg), a prototype type-1 substrate. Although differences in binding affinity exist for each N-degron, SQSTM1 also interacts with type-2 N-degrons, such as Nt-Tyr and Nt-Trp. Intriguingly, interactions between SQSTM1's ZZ domain and various N-degrons are greatly influenced by pH-dependent SQSTM1 oligomerization via its PB1 domain. Because cellular pH conditions vary from neutral to acidic depending on the stage of autophagy, the pH-dependent regulation of SQSTM1's oligomerization must be tightly coupled with the autophagic process.
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http://dx.doi.org/10.1080/15548627.2018.1532264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6287675PMC
January 2019

Gamma Knife Radiosurgery for Metastatic Brain Tumors with Exophytic Hemorrhage.

J Korean Neurosurg Soc 2018 Sep 31;61(5):592-599. Epub 2018 Aug 31.

Department of Neurological Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

Objective: Metastatic brain tumors (MBTs) often present with intracerebral hemorrhage. Although Gamma Knife surgery (GKS) is a valid treatment option for hemorrhagic MBTs, its efficacy is unclear. To achieve oncologic control and reduce radiation toxicity, we used a radiosurgical targeting technique that confines the tumor core within the hematoma when performing GKS in patients with such tumors. We reviewed our experience in this endeavor, focusing on local tumor control and treatment-associated morbidities.

Methods: From 2007 to 2014, 13 patients with hemorrhagic MBTs were treated via GKS using our targeting technique. The median marginal dose prescribed was 23 Gy (range, 20-25). GKS was performed approximately 2 weeks after tumor bleeding to allow the patient's condition to stabilize.

Results: The primary sites of the MBTs included the liver (n=7), lung (n=2), kidney (n=1), and stomach (n=1); in two cases, the primary tumor was a melanoma. The mean tumor volume was 4.00 cm3 (range, 0.74-11.0). The mean overall survival duration after GKS was 12.5 months (range, 3-29), and three patients are still alive at the time of the review. The local tumor control rate was 92% (tumor disappearance 23%, tumor regression 46%, and stable disease 23%). There was one (8%) instance of local recurrence, which occurred 11 months after GKS in the solid portion of the tumor. No GKS-related complications were observed.

Conclusion: Our experience shows that GKS performed in conjunction with our targeting technique safely and effectively treats hemorrhagic MBTs. The success of this technique may reflect the presence of scattered metastatic tumor cells in the hematoma that do not proliferate owing to the inadequate microenvironment of the hematoma. We suggest that GKS can be a useful treatment option for patients with hemorrhagic MBTs that are not amenable to surgery.
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http://dx.doi.org/10.3340/jkns.2017.0303.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6129753PMC
September 2018

Insights into degradation mechanism of N-end rule substrates by p62/SQSTM1 autophagy adapter.

Nat Commun 2018 08 17;9(1):3291. Epub 2018 Aug 17.

Department of Life Sciences, Korea University, Seoul, 02841, Korea.

p62/SQSTM1 is the key autophagy adapter protein and the hub of multi-cellular signaling. It was recently reported that autophagy and N-end rule pathways are linked via p62. However, the exact recognition mode of degrading substrates and regulation of p62 in the autophagic pathway remain unknown. Here, we present the complex structures between the ZZ-domain of p62 and various type-1 and type-2 N-degrons. The binding mode employed in the interaction of the ZZ-domain with N-degrons differs from that employed by classic N-recognins. It was also determined that oligomerization via the PB1 domain can control functional affinity to the R-BiP substrate. Unexpectedly, we found that self-oligomerization and disassembly of p62 are pH-dependent. These findings broaden our understanding of the functional repertoire of the N-end rule pathway and provide an insight into the regulation of p62 during the autophagic pathway.
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http://dx.doi.org/10.1038/s41467-018-05825-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6098011PMC
August 2018

Long-Term Outcome of Gamma Knife Radiosurgery for Brain Cavernoma: Factors Associated with Subsequent De Novo Cavernoma Formation.

World Neurosurg 2018 Dec 17;120:e17-e23. Epub 2018 Jul 17.

Department of Neurological Surgery, Asan Medical Center, University of Ulsan College of Medicine, Songpa-gu, Seoul, Korea. Electronic address:

Background: We aimed to evaluate the factors associated with de novo brain cavernoma formations after patients underwent gamma knife radiosurgery (GKRS) and confirmed whether developmental venous anomaly (DVA) presented with a cavernoma and whether the cavernoma was included in the GKRS target location.

Methods: From January 2003 to December 2008, 95 patients underwent radiosurgery for brain cavernoma at our institution. Of these, 15 with multiple cavernomas related to familial cavernoma or with a history of surgical treatment for cavernoma were excluded. A total of 80 patients (44 men and 36 women; average age, 39.4 years) with sporadic cavernoma were retrospectively analyzed by considering the patient characteristics, including sex, age, target volume, radiation dose, clinical symptoms, cavernoma location, radiosurgery complications, and morphology of DVA.

Results: The average target volume, mean radiation dose, and mean target percentage were 1019.2 mm, 13.7 Gy, and 51.1%, respectively. Nineteen patients showed cavernomas associated with DVA; of these, de novo cavernoma formations were noticed in 4 patients at a median of 49.5 months after undergoing GKRS. All de novo cavernomas were related to the presence of DVA and were located near the brainstem or cerebral peduncle. De novo cavernomas occurred when DVAs were not included in the GKRS-target location.

Conclusions: All de novo cavernomas were located near the brainstem or cerebral peduncle, and they occurred in the presence of DVAs. The presence of DVA in the radiosurgery target location might be potentially an important factor associated with de novo cavernoma formation.
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http://dx.doi.org/10.1016/j.wneu.2018.07.046DOI Listing
December 2018

Structural and Biochemical Study of the Mono-ADP-Ribosyltransferase Domain of SdeA, a Ubiquitylating/Deubiquitylating Enzyme from Legionella pneumophila.

J Mol Biol 2018 08 2;430(17):2843-2856. Epub 2018 Jun 2.

Department of Life Sciences, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Korea. Electronic address:

Conventional ubiquitylation occurs through an ATP-dependent three-enzyme cascade (E1, E2, and E3) that mediates the covalent conjugation of the C-terminus of ubiquitin to a lysine on the substrate. SdeA, which belongs to the SidE effector family of Legionella pneumophila, can transfer ubiquitin to endoplasmic reticulum-associated Rab-family GTPases in a manner independent of E1 and E2 enzymes. The novel ubiquitin-modifying enzyme SdeA utilizes NAD as a cofactor to attach ubiquitin to a serine residue of the substrate. Here, to elucidate the coupled enzymatic reaction of NAD+ hydrolysis and ADP-ribosylation of ubiquitin in SdeA, we characterized the mono-ADP-ribosyltransferase domain of SdeA and show that it consists of two sub-domains termed mART-N and mART-C. The crystal structure of the mART-C domain of SdeA was also determined in free form and in complex with NAD at high resolution. Furthermore, the spatial orientations of the N-terminal deubiquitylase, phosphodiesterase, mono-ADP-ribosyltransferase, and C-terminal coiled-coil domains within the 180-kDa full-length SdeA were determined. These results provide insight into the unusual ubiquitylation mechanism of SdeA and expand our knowledge on the structure-function of mono-ADP-ribosyltransferases.
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http://dx.doi.org/10.1016/j.jmb.2018.05.043DOI Listing
August 2018

Unveiling the pathway to Z-DNA in the protein-induced B-Z transition.

Nucleic Acids Res 2018 05;46(8):4129-4137

Center for Molecular Spectroscopy and Dynamics, Institute for Basic Science, Seoul 02841, South Korea.

Left-handed Z-DNA is an extraordinary conformation of DNA, which can form by special sequences under specific biological, chemical or physical conditions. Human ADAR1, prototypic Z-DNA binding protein (ZBP), binds to Z-DNA with high affinity. Utilizing single-molecule FRET assays for Z-DNA forming sequences embedded in a long inactive DNA, we measure thermodynamic populations of ADAR1-bound DNA conformations in both GC and TG repeat sequences. Based on a statistical physics model, we determined quantitatively the affinities of ADAR1 to both Z-form and B-form of these sequences. We also reported what pathways it takes to induce the B-Z transition in those sequences. Due to the high junction energy, an intermediate B* state has to accumulate prior to the B-Z transition. Our study showing the stable B* state supports the active picture for the protein-induced B-Z transition that occurs under a physiological setting.
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http://dx.doi.org/10.1093/nar/gky200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5934635PMC
May 2018

A Structural View of Xenophagy, a Battle between Host and Microbes.

Mol Cells 2018 Jan 23;41(1):27-34. Epub 2018 Jan 23.

Department of Life Sciences, Korea University, Seoul 02841, Korea.

The cytoplasm in mammalian cells is a battlefield between the host and invading microbes. Both the living organisms have evolved unique strategies for their survival. The host utilizes a specialized autophagy system, xenophagy, for the clearance of invading pathogens, whereas bacteria secrete proteins to defend and escape from the host xenophagy. Several molecules have been identified and their structural investigation has enabled the comprehension of these mechanisms at the molecular level. In this review, we focus on one example of host autophagy and the other of bacterial defense: the autophagy receptor, NDP52, in conjunction with the sugar receptor, galectin-8, plays a critical role in targeting the autophagy machinery against ; and the cysteine protease, RavZ secreted by cleaves the LC3-PE on the phagophore membrane. The structure-function relationships of these two examples and the directions of future research will be discussed.
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http://dx.doi.org/10.14348/molcells.2018.2274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5792709PMC
January 2018

A novel conformation of the LC3-interacting region motif revealed by the structure of a complex between LC3B and RavZ.

Biochem Biophys Res Commun 2017 08 29;490(3):1093-1099. Epub 2017 Jun 29.

Department of Life Sciences, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Republic of Korea. Electronic address:

LC3-family member proteins play a critical role in autophagy, a cellular process responsible for the degradation of massive cellular components including intracellular pathogens. A variety of molecules involved in the autophagic pathway engage in specific interactions with a unique sequence motif referred to as the LIR (LC3-interacting region) motif. Although identification of conserved structural features of LIR motifs in complex with LC3-family members has established a canonical LIR motif, atypical conformations of LIR motifs have recently been revealed. Here, we determined the three-dimensional crystal structures of LC3B in complex with three different LIR motifs of RavZ from Legionella pneumophila, an intracellular pathogen that can manipulate the host autophagy system. The tandem LIR motifs located in the N-terminal region of RavZ adopt a novel β-sheet conformation and thus provide specific ionic interactions with LC3B in addition to canonical hydrophobic plugged-in interactions. Consequently, these motifs possess higher binding affinity to LC3-family members than canonical LIR motifs, although the tandem repeats can only bind to one LC3 molecule. These findings broaden our understanding of the functional repertoire of LIR motifs in autophagy.
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http://dx.doi.org/10.1016/j.bbrc.2017.06.173DOI Listing
August 2017

ACCORD: an assessment tool to determine the orientation of homodimeric coiled-coils.

Sci Rep 2017 03 7;7:43318. Epub 2017 Mar 7.

Division of Life Sciences, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Korea.

The coiled-coil (CC) domain is a very important structural unit of proteins that plays critical roles in various biological functions. The major oligomeric state of CCs is a dimer, which can be either parallel or antiparallel. The orientation of each α-helix in a CC domain is critical for the molecular function of CC-containing proteins, but cannot be determined easily by sequence-based prediction. We developed a biochemical method for assessing differences between parallel and antiparallel CC homodimers and named it ACCORD (Assessment tool for homodimeric Coiled-Coil ORientation Decision). To validate this technique, we applied it to 15 different CC proteins with known structures, and the ACCORD results identified these proteins well, especially with long CCs. Furthermore, ACCORD was able to accurately determine the orientation of a CC domain of unknown directionality that was subsequently confirmed by X-ray crystallography and small angle X-ray scattering. Thus, ACCORD can be used as a tool to determine CC directionality to supplement the results of in silico prediction.
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http://dx.doi.org/10.1038/srep43318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5339707PMC
March 2017

Analysis the causes of radiosurgical failure in intracranial meningiomas treated with radiosurgery.

Clin Neurol Neurosurg 2017 Mar 20;154:51-58. Epub 2017 Jan 20.

Department of Neurological Surgery, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, 05505, Republic of Korea. Electronic address:

Objectives: Surgical resection is a primary indication for intracranial meningioma. Radiosurgery is also an excellent treatment modality for postoperative residual tumors, or tumors in high-risk locations, such as the skull base. Despite multimodality treatments, there are some cases in which radiosurgery fails and surgical resection or re-radiosurgery is required. However, there has not been a comprehensive study focusing on the causes of secondary treatment for local recurrence or a new mass that develops outside the target area after radiosurgery. Hence, we analyzed the causes of radiosurgical failure in patients with meningioma.

Methods: From 2000 to 2015, we retrospectively reviewed 1086 patients who underwent gamma knife radiosurgery (GKRS) for intracranial meningioma at the Asan Medical Center. Multiple meningiomas or tumors with a volume greater than 7000mm were excluded. All patients had a minimum follow-up of 12 months. Finally, 771 patients were enrolled in this study. Clinical symptoms and brain MRI findings were assessed by neurosurgeons. When the tumor size increased and was accompanied by newly developed neurological symptoms, further management was considered (e.g. microsurgical resection and stereotactic radiosurgery). Histological analyses of the resected tumors were performed by neuropathologists.

Results: Among the 771 patients, tumor growth was observed in 60 patients (7.78%). Seven patients showed transient tumor growth after GKRS. These patients have been under close observation without any further treatment. Thirty patients (3.89%) underwent re-radiosurgery for tumor control. Another 23 patients underwent procedures other than re-radiosurgery; 8 underwent microsurgical resection, 3 underwent cyber knife radiosurgery (CKRS), 1 underwent radiation therapy, and 8 were closely followed-up. Three patients visited other clinics or were lost to follow-up. Of the remaining 30 patients, 22 (group 1) underwent microsurgical resection prior to their initial course of GKRS and the other 8 (group 2) were treated only with re-radiosurgery. In group 1, recurrence rates after radiosurgery were 2.47% (n=19) and 0.39% (n=3) for local and distant recurrence, respectively. In group 2, recurrence rates after radiosurgery were 0.52% (n=4) and 0.52% (n=4) for local and distant recurrence, respectively. An analysis was performed to determine the factors that may result in differences between the two groups. Of the many variables, local recurrence (p=0.0331, Fisher's exact test) was the only significant factor.

Conclusion: We analyzed the causes of radiosurgical failure in meningioma patients and observed that microsurgery before radiosurgery was significantly associated with a high local recurrence rate compared with primary radiosurgery. Furthermore, the percentage of local recurrence cases that required secondary radiosurgery was as low as 2.98%. This result is comparable with that of microsurgical resection, which is the mainstay of treatment for meningioma.
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http://dx.doi.org/10.1016/j.clineuro.2017.01.013DOI Listing
March 2017

Analysis of the results of recurrent intracranial meningiomas treated with re-radiosurgery.

Clin Neurol Neurosurg 2017 Feb 29;153:93-101. Epub 2016 Dec 29.

Department of Neurological Surgery, Asan Medical Center, College of Medicine, University of Ulsan, Seoul 05505, Republic of Korea. Electronic address:

Objects: Meningioma is the most common intracranial neoplasm, comprising approximately 30% of all primary intracranial tumors (Claus et al., 2005) [1]. Treatment options include observation, microsurgical resection, stereotactic radiosurgery (SRS), and whole brain radiation therapy (WBRT). Gamma knife radiosurgery (GKRS) is a very effective treatment for intracranial meningiomas; previous studies showed the tumor control rate at 5-10 years of follow-up as 84.3%-100% in all cases (Feigl et al., 2005; Linskey et al., 2005; Malik et al., 2005; Aichholzer et al., 2000; Hakim et al., 1998; Chang and Adler 1997; Lunsford, 1994; Ganz et al., 1993) [2-9]. Many studies have discussed issues like optimal dose, conformal configurations, and adverse effects to improve the treatment result with GKRS (Malik et al., 2005; Kenai et al., 2005; Rowe et al., 2004; Shrieve et al., 2004) [4,10-12]. There are some cases in which the radiosurgery result is unfavorable and perhaps further treatment is needed. In these cases, re-radiosurgery can be an option. However, there have not been comprehensive studies discussing the issues of re-radiosurgery. Therefore, we analyzed the result of re-radiosurgery for recurrent meningiomas and their impact on clinical outcomes.

Methods: From 1995 to 2015, we retrospectively reviewed 1163 patients who underwent GKRS for intracranial meningioma at the Asan Medical Center. Patients with multiple meningiomas or a follow-up with a period of less than a year were excluded from this study. Finally, 865 patients were enrolled in this study. Clinical symptoms and brain magnetic resonance imaging (MRI) scans were assessed by neurosurgeons. When tumor size increased together with newly developed neurologic symptoms, further management, such as microsurgical resection or SRS, was considered. Histologic analysis of the resected tumors was performed by neuropathologists. Clinical data, including patient's sex, age, and tumor locations were recorded. Treatment data included tumor volume, tumor grade, radiation dose, and presence of edema. Final outcome data including follow-up period, time to progression, interval between first and second radiosurgery courses and interval between microsurgery and radiosurgery were obtained.

Results: Among 865 patients, tumor recurrence was found in 63 patients (7.28%). Seven patients showed transient tumor growth after GKRS. These patients have been under close observation without any further treatments. Fifty-six patients (6.47%) showed permanent tumor growth on follow-up MRI. Thirty-three patients from this group underwent repeated radiosurgery owing to tumor growth, resulting in a re-irradiation rate of 3.82% at our radiosurgery center. The other 23 patients were treated using methods other than re-radiosurgery. Among the 33 patients, 25 underwent microsurgical resection prior to their initial course of GKRS, and the other 8 were treated with re-radiosurgery only. An analysis was performed to determine factors that may have a role in treatment results. Of the many variables, tumor grade (p=0.004, Fisher's exact test) was the only significant factor for progression-free survival (PFS). Thirteen patients with unbiopsied or benign meningioma showed stable tumor size, while there was tumor growth in 8 patients. Among high-grade meningioma patients, 3 and 9 showed stable disease and tumor growth, respectively. As a result of re-radiosurgery, 11 out of 17 patients showed tumor growth and needed further treatments; this involved a third GKRS for 4 patients, microsurgical resection for 6 patients, and cyber knife radiosurgery (CKRS) for 1 patient. Four patients from this group were also treated with WBRT.

Conclusion: We analyzed the results of re-radiosurgery for recurrent meningiomas and observed that World Health Organization (WHO) grade II and III was significantly associated with a lower PFS rate compared with low-grade meningiomas (p=0.004). Conversely, patients with benign meningioma or unbiopsied tumors had much better results. Hence, re-radiosurgery is recommended for patients with unknown or benign meningiomas if their first GKRS result is unsatisfactory. However, re-radiosurgery should be considered carefully for recurrent high-grade tumors. Owing to the small number of recurrent meningioma patients treated with re-radiosurgery, further studies are required to delineate the role of this treatment.
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http://dx.doi.org/10.1016/j.clineuro.2016.12.014DOI Listing
February 2017

Hypofractionated stereotactic radiosurgery for pituitary metastases.

J Neurooncol 2017 03 9;132(1):127-133. Epub 2017 Jan 9.

Department of Neurosurgery, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Republic of Korea.

Pituitary metastases (PMs) are uncommon, representing only 1% of pituitary lesions. The diagnosis of PMs can be challenging and an optimal management remains to be determined. Here, we present a pilot clinical study on the efficacy and safety of hypofractionated stereotactic radiosurgery (SRS) with an optimized dosimetric plan in treating PMs. Between June 2013 and December 2014, seven consecutive patients (4 men and 3 women; median age 62 years) had been diagnosed with PMs based on their characteristic clinical and radiological features and subsequently treated using hypofractionated SRS. Primary cancers originated from the lung (n = 5) or the breast (n = 2). All patients presented with diabetes insipidus (DI). Anterior pituitary and visual dysfunction were combined in 4 and 3 patients, respectively. On magnetic resonance imaging (MRI), PMs involved the pituitary stalk and/or the posterior lobe in all patients. SRS of a cumulative marginal dose 31 Gy with dose-volume constraints for the optic apparatus was delivered in 5 daily fractions. As results, tumor was locally controlled in all patients with substantial responses on MRI (including complete remission in 4 patients). The median survival time was 14 months (range, 6-24 months) after SRS. DI and visual dysfunction improved in all patients, although anterior pituitary dysfunction did not recover. No patients experienced any deterioration in visual, pituitary, or other cranial nerve functions. These results suggest a promising role of hypofractionated SRS in treating PMs in terms of both tumor control and functional outcomes.
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http://dx.doi.org/10.1007/s11060-016-2346-zDOI Listing
March 2017

Fusion 3-Dimensional Angiography of Both Internal Carotid Arteries in the Evaluation of Anterior Communicating Artery Aneurysms.

World Neurosurg 2017 Feb 19;98:484-491. Epub 2016 Nov 19.

Department of Radiology, Research Institute of Radiology, University of Ulsan College of Medicine, Seoul, Korea. Electronic address:

Background: To determine whether fusion 3-dimensional (3D) angiography of both internal carotid arteries can better disclose vascular details in patients diagnosed with anterior communicating artery (ACoA) aneurysms by computed tomography angiography (CTA) or magnetic resonance angiography (MRA).

Methods: Thirty-eight patients diagnosed with ACoA aneurysms by CTA or MRA were evaluated by the new postprocessing feature, fusion 3D angiography, with results individually interpreted by 4 experts. Those experts compared fusion 3D angiography with dominant A1 side single 3D angiography to define advantages and disadvantages for ACoA aneurysms. Patients with unilateral A1 aplasia or rudimentary A1 were excluded. Patients who showed any disadvantages with this additional feature were classified as group 1, those with no advantages were classified as group 2, those with 1 or 2 advantages were classified as group 3, and those with 3 or more advantages were classified as group 4. Radiologic and clinical results were also evaluated.

Results: Of the 38 patients, 33 (87%) benefited from fusion 3D angiography, including 17 in group 3 and 16 in group 4; of the remaining patients, 1 was classified as group 1 and 4 were classified as group 2. Representative 5 categories of advantage to fusion angiography were found and summarized by the 4 experts. All 33 patients showed defining the exact anatomy of the ACoA, and 22 (67%) showed full angiographic features of A2 or A3, including branches.

Conclusions: Fusion 3D angiography can significantly contribute to a better understanding of the complex anatomy of the anterior cerebral artery-ACoA complex, which is essential for successful treatment planning for ACoA aneurysms.
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http://dx.doi.org/10.1016/j.wneu.2016.11.047DOI Listing
February 2017

Self-reverse-biased solar panel optical receiver for simultaneous visible light communication and energy harvesting.

Opt Express 2016 Oct;24(22):A1300-A1305

We propose a self-reverse-biased solar panel optical receiver for energy harvesting and visible light communication. Since the solar panel converts an optical component into an electrical component, it provides both energy harvesting and communication. The signal component can be separated from the direct current component, and these components are used for communication and energy harvesting. We employed a self-reverse-biased receiver circuit to improve the communication and energy harvesting performance. The reverse bias on the solar panel improves the responsivity and response time. The proposed system achieved 17.05 mbps discrete multitone transmission with a bit error rate of 1.1 x 10-3 and enhanced solar energy conversion efficiency.
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http://dx.doi.org/10.1364/OE.24.0A1300DOI Listing
October 2016

The structure of the pleiotropic transcription regulator CodY provides insight into its GTP-sensing mechanism.

Nucleic Acids Res 2016 Nov 4;44(19):9483-9493. Epub 2016 Sep 4.

Department of Biosystems & Biotechnology, Korea University, Anam-dong, Seoungbuk-gu, Seoul 136-713, South Korea

GTP and branched-chain amino acids (BCAAs) are metabolic sensors that are indispensable for the determination of the metabolic status of cells. However, their molecular sensing mechanism remains unclear. CodY is a unique global transcription regulator that recognizes GTP and BCAAs as specific signals and affects expression of more than 100 genes associated with metabolism. Herein, we report the first crystal structures of the full-length CodY complex with sensing molecules and describe their functional states. We observed two different oligomeric states of CodY: a dimeric complex of CodY from Staphylococcus aureus with the two metabolites GTP and isoleucine, and a tetrameric form (apo) of CodY from Bacillus cereus Notably, the tetrameric state shows in an auto-inhibitory manner by blocking the GTP-binding site, whereas the binding sites of GTP and isoleucine are clearly visible in the dimeric state. The GTP is located at a hinge site between the long helical region and the metabolite-binding site. Together, data from structural and electrophoretic mobility shift assay analyses improve understanding of how CodY senses GTP and operates as a DNA-binding protein and a pleiotropic transcription regulator.
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http://dx.doi.org/10.1093/nar/gkw775DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5100569PMC
November 2016
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