Search

Genetically engineered fusion polypeptides have been investigated to introduce unique bio-functionality and improve some therapeutic activity for anti-angiogenesis. We report herein that stimuli-responsive, vascular endothelial growth factor receptor 1 (VEGFR1) targeting fusion polypeptides composed of a VEGFR1 (fms-like tyrosine kinase-1 (Flt1)) antagonist, an anti-Flt1 peptide, and a thermally responsive elastin-based polypeptide (EBP) were rationally designed at the genetic level, biosynthesized, and purified by inverse transition cycling to develop potential anti-angiogenic fusion polypeptides to treat neovascular diseases. A series of hydrophilic EBPs with different block lengths were fused with an anti-Flt1 peptide, forming anti-Flt1-EBPs, and the effect of EBP block length on their physicochemical properties was examined. While the anti-Flt1 peptide decreased phase-transition temperatures of anti-Flt1-EBPs, compared with EBP blocks, anti-Flt1-EBPs were soluble under physiological conditions. The anti-Flt1-EBPs dose dependently inhibited the binding of VEGFR1 against vascular endothelial growth factor (VEGF) as well as tube-like network formation of human umbilical vein endothelial cells under VEGF-triggered angiogenesis in vitro because of the specific binding between anti-Flt1-EBPs and VEGFR1. Furthermore, the anti-Flt1-EBPs suppressed laser-induced choroidal neovascularization in a wet age-related macular degeneration mouse model in vivo. Our results indicate that anti-Flt1-EBPs as VEGFR1-targeting fusion polypeptides have great potential for efficacious anti-angiogenesis to treat retinal-, corneal-, and choroidal neovascularization.

Emergency department has been shown to be suitable for conducting screening and interventions for at-risk drinking groups. Simple screening test is needed for crowded environments such as the emergency department. This study explores the validity of screening test for at-risk drinking, which was a newly developed abbreviated version of the alcohol use disorder identification test, among patients in the emergency department. A survey was conducted at the emergency department of an academic tertiary hospital in South Korea during 4?months. All patients, who visited the emergency department and were between 19 and 65?years of age, answered the alcohol use disorder identification test questionnaire. In this study, at-risk drinking was identified using alcohol use disorder identification test. The screening test was completed by 178 patients in this study. At-risk drinking group comprises 78 patients (43.8%). The cut-off values of screening test for at-risk drinking were 3 for males and 2 for females. As a result, the sensitivity/specificity was 98.0/93.5 and 96.4/79.6 for men and women, respectively. Area under the receiver operating characteristics of screening test for at-risk drinking was 0.9 and 0.9 in men and women, respectively. screening test for at-risk drinking is a useful test that easily identifies at-risk drinking. It is expected that this test can facilitate screening for at-risk drinking in emergency department setting.

Background: Emergency department has been shown to be suitable for conducting screening and interventions for at-risk drinking groups. Simple screening test is needed for crowded environments such as the emergency department.Objective: This study explores the validity of screening test for at-risk drinking, which was a newly developed abbreviated version of the alcohol use disorder identification test, among patients in the emergency department.Method: A survey was conducted at the emergency department of an academic tertiary hospital in South Korea during 4 months. All patients, who visited the emergency department and were between 19 and 65 years of age, answered the alcohol use disorder identification test questionnaire. In this study, at-risk drinking was identified using alcohol use disorder identification test.Results: The screening test was completed by 178 patients in this study. At-risk drinking group comprises 78 patients (43.8%). The cut-off values of screening test for at-risk drinking were 3 for males and 2 for females. As a result, the sensitivity/specificity was 98.0/93.5 and 96.4/79.6 for men and women, respectively. Area under the receiver operating characteristics of screening test for at-risk drinking was 0.9 and 0.9 in men and women, respectively.Conclusion: screening test for at-risk drinking is a useful test that easily identifies at-risk drinking. It is expected that this test can facilitate screening for at-risk drinking in emergency department setting.

Nuclear power plants (NPPs) have technical specifications (Tech Specs) to ensure that the equipment and key operating parameters necessary for the safe operation of the power plant are maintained within limiting conditions for operation (LCO) determined by a safety analysis. The LCO of Tech Specs that identify the lowest functional capability of equipment required for safe operation for a facility must be complied for the safe operation of NPP.

Background: To investigate the clinical treatment status, such as treatment regimen, bleeding events, and drug dose, in patients with hemophilia B in South Korea. Methods: In this retrospective chart review, data of patients with hemophilia B from eight university hospitals were collected. Demographic and clinical data, treatment data, such as regimen and number of injections, dose of factor IX concentrate, and bleeding data were reviewed. Descriptive analyses were performed with annual data for 2019, 2020, and 2021, as well as the three years consecutively. Results: The medical records of 150 patients with hemophilia B between January 1, 2019, and December 31, 2021, were collected. Among these, 72 (48.0%) were severe, 47 (31.3%) were moderate, and 28 (18.7%) were mild. The results showed approximately two times more patients receiving prophylaxis as those receiving on-demand therapy, with 66.1% of patients receiving prophylaxis in 2019, 64.9% in 2020, and 72.1% in 2021. Annualized bleeding rates were 2.2% (± 3.1) in 2019, 1.8% (± 3.0) in 2020, and 1.8% (± 2.9) in 2021 among patients receiving prophylaxis. For the doses of factor IX concentrate, patients receiving prophylaxis received an average of 41.6 (± 11.9) IU/Kg/Injection in 2019, 45.7 (± 12.9) IU/Kg/Injection in 2020, and 60.1 (± 24.0) IU/Kg/Injection in 2021. Conclusions: Clinically, prophylaxis is more prevalent than reported. Based on insights gained from current clinical evidence, it is expected that the unmet medical needs of patients can be identified, and physicians can evaluate the status of patients and actively manage hemophilia B using more effective treatment strategies.

Aim: Injury causes numerous socioeconomic losses. We aimed to discover the pattern of alcohol-associated injury in South Korea. Subject and methods: This study retrospectively analysed patients who visited emergency departments (EDs) between January 2011 and December 2016, using the emergency department-based injury In-depth surveillance data of the Korea Disease Control and Prevention Agency. Demographic and injury characteristics, clinical outcome, and injury severity [admission rate, ICU care, mortality, excess mortality ratio-adjusted injury severity score (EMR-ISS)] were analysed. Results: In total, 1,383,740 patients were analysed (alcohol-use group 143,506, non-alcohol-use group 1,240,234). The mean age of the alcohol-use group (40.90 ± 15.02) was 10 years older than the non-alcohol-use group (30.19 ± 24.47). The proportion of males (74.4%) and night-time emergency department visits (59.8%) in the alcohol-use group was higher. Injury mechanism rates for assault (22.6%) and self-harm/suicides (9.9%) were significantly higher in the alcohol-use group. The odds ratios of the alcohol-use group for admission, intensive care, mortality, and EMR-ISS ≥ 25 were 1.305 (1.287–1.324), 2.403 (2.340–2.468), 1.134 (1.066–1.206), and 2.855 (2.810–2.900) respectively. Conclusion: Alcohol-related injuries in South Korea have a higher incidence in males, and night-time ED visits and intentional injury mechanisms are significantly higher than in the group who do not use alcohol. Alcohol-related injuries are associated with a higher trauma severity and death rate.

A variety of block copolypeptides with stimuli responsiveness have been of growing interest for dynamic self-assembly. Here, multistimuli-responsive triblock copolypeptides composed of thermosensitive elastin-based polypeptides (EBP) and ligand-responsive calmodulin (CalM) were genetically engineered, over-expressed, and nonchromatographically purified by inverse transition cycling. Diluted EBP-CalM-EBP (ECE) triblock copolypeptides under physiological conditions self-assembled into vesicles at the nanoscale by temperature-triggered aggregation of the EBP block with lower critical solution temperature behaviors. Furthermore, concentrated ECE triblock copolypeptides under identical conditions exhibited thermally induced gelation, resulting in physically crosslinked hydrogels. They showed controlled rheological and mechanical properties depending on the conformational change of the CalM middle block induced by binding either Ca2+or Ca2+and trifluoperazines (TFPs) as ligands. In addition, both Ca2+-free and Ca2+-bound ECE triblock copolypeptide hydrogels exhibited biocompatibility, while those bound to both Ca2+and TFPs showed severe cytotoxicity because of controlled TFP release of the CalM blocks. The ECE triblock hydrogels with stimuli responsiveness would be useful as injectable drug delivery depots for biomedical applications.

Self-assembly of thermally responsive polypeptides into unique nanostructures offers intriguing attributes including dynamic physical dimensions, biocompatibility, and biodegradability for the smart bio-nanomaterials. As elastin-based polypeptide (EBP) fusion proteins with lower critical solution temperature (LCST) are studied as drug delivery systems, EBP block copolypeptides with the resilin-based polypeptide (RBP) displaying an upper critical solution temperature (UCST) have been of great interest. In this study, we report thermally triggered, dynamic self-assembly of EBP- and RBP-based diblock copolypeptides into switched nanostructures with reversibility under physiological conditions. Molecular DNA clones encoding for the EBP–RBP diblocks at different block length ratios were biosynthesized via recursive directional ligation and overexpressed, followed by nonchromatographic purification by inverse transition cycling. Genetically engineered diblock copolypeptides composed of the EBP with an LCST and the RBP with a UCST showed converse phase transition behaviors with both a distinct LCST and a distinct UCST (LCST < UCST). As temperature increased, three phases of these EBP–RBP diblocks were observed: (1) self-assembled micelles or vesicles below both LCST and UCST, (2) whole aggregates above LCST and below UCST, and (3) reversed micelles above both LCST and UCST. In conclusion, these stimuli-triggered, dynamic protein-based nanostructures are promising for advanced drug delivery systems, regenerative medicine, and biomedical nanotechnology.

Background: The os subfibulare is usually asymptomatic and found incidentally on radiographs. However, sometimes it may cause subfibular pain and may be associated with chronic lateral ankle instability (CLAI). We hypothesized that os subfibulare could interrupt the talofibular space causing impingement, resulting in chronic pain and functional instability around the lateral malleolus. The purposes of this study were to analyze morphologic characteristics of os subfibulare, and to evaluate the clinical significance of the os subfibulare in patients with CLAI.Methods: Between November 2011 and April 2015, 70 patients who had both computed tomography (CT) and magnetic resonance imaging (MRI) among 252 patients who visited our hospital with the symptom of lateral ankle instability were included in this study. The location of the ossicle was classified into 3 zones in reference to the attachment site of the lateral ankle ligaments. The impingement was classified into 2 groups according to the presence of talofibular encroachment. Digital radiographs were used to measure the ossicle width and shape determined by the length and width on an magnetic resonance (MR) image.Results: The most common shape of ossicles was oval, and the most common location of ossicles was at the anterior talofibular ligament (ATFL) attachment site. Sixty-one percent of patients showed talofibular impingement on coronal MR images. In 48 cases, the dimension of fibula plus os subfibulare was larger than that of the contralateral normal fibula. The larger size and talofibular impingement of the ossicle were associated with greater need for operative treatment in patients with ankle instability.Conclusion: The morphologic analysis of the os subfibulare revealed that there might be impingement of the talofibular space by the ossicle in some patients. We suggest that morphologic characteristics of the os subfibulare should be considered when selecting treatment options in patients with CLAI and os subfibulare.Level of Evidence: Level III, retrospective comparative series.

We analyze data acquired by the Kaguya satellite on 14 October 2008 when the Moon was in the terrestrial magnetotail lobe to gain new insight into the energization of ions originating from the Moon. The Moon‐originating ions were detected over a broad range of latitudes from −80° to 50° above the Moon's dayside at ∼100 km altitude. The fluxes of the Moon‐originating ions were observed at energies from ∼50 to ∼1,000 eV. Additionally, these ions exhibited a wide distribution pitch angle spanning from ∼45 to 90°. The energy levels of ions originating from the Moon show rapid changes, either increasing or decreasing by a factor of ∼10 within 8 min without the solar zenith angle dependence. Such rapid energy changes were observed over the highland regions. These observations are discussed in light of possible acceleration mechanisms of Moon‐originating ions, including temporal and spatial effects. The Moon‐originating ions are distributed over a broad range of latitudes from −80° to 50°The median peak energy of Moon‐originating ions does not show a significant dependence on the solar zenith angle between 0° and 60°The energy of the Moon‐originating ions shows a sudden rise or drop by a factor of ∼10 in 8 min over the highland regions The Moon‐originating ions are distributed over a broad range of latitudes from −80° to 50° The median peak energy of Moon‐originating ions does not show a significant dependence on the solar zenith angle between 0° and 60° The energy of the Moon‐originating ions shows a sudden rise or drop by a factor of ∼10 in 8 min over the highland regions

The critical issues that hinder the practical applications of lithium–sulfur batteries, such as dissolution and migration of lithium polysulfides, poor electronic conductivity of sulfur and its discharge products, and low loading of sulfur, have been addressed by designing a functional separator modified using hydroxyl-functionalized carbon nanotubes (CNTOH). Density functional theory calculations and experimental results demonstrate that the hydroxyl groups in the CNTOH provoked strong interaction with lithium polysulfides and resulted in effective trapping of lithium polysulfides within the sulfur cathode side. The reduction in migration of lithium polysulfides to the lithium anode resulted in enhanced stability of the lithium electrode. The conductive nature of CNTOH also aided to efficiently reutilize the adsorbed reaction intermediates for subsequent cycling. As a result, the lithium–sulfur cell assembled with a functional separator exhibited a high initial discharge capacity of 1056 mAh g–1(corresponding to an areal capacity of 3.2 mAh cm–2) with a capacity fading rate of 0.11% per cycle over 400 cycles at 0.5 C rate.

Wearable displays are considered as a bilateral communication tool in the hyperconnected era. Although several electronic clothing display was demonstrated, high power consumption issue still remained. Here, we present wireless powered wearable μLEDs (WμLEDs) with excellent stability. A custom-designed wireless power supply system operated a 30 × 30 WμLED array on a fabric. The WμLED stability was intensively investigated under bending, stretching, 85 °C/85% relative humidity and artificial sunlight conditions, showing the suitability of WμLED outdoor usage. Finally, a passive-matrix WμLED display successfully emitted a brilliant red glow on a fabric.

To reduce problems caused by alcohol drinking, it is necessary to identify those with ‘at-risk drinking’ behavior to maximize therapeutic access or intervention. To this end, we sought to determine the cut-off point for screening of at-risk drinking by the Korean version of the AUDIT-C (Alcohol Use Disorder Identification Test-Consumption).

Highlights:

Flash-induced porous graphene (FPG) was synthesized via a broad-spectrum flash lamp that induced synergistic photo-effects between ultraviolet and visible-near-infrared wavelengths, resulting in large-area synthesis in just a few milliseconds.

A hollow pillar graphene with low sheet resistance of 18 Ω sq−1was produced, exhibiting low density (0.0354 g cm−3) and outstanding absolute electromagnetic interference shielding effectiveness of 1.12 × 105dB cm2g−1.

A lightweight, flexible, and high-throughput FPG is applied for electromagnetic interference shielding of a drone radar system and the human body. Abstract: Porous 2D materials with high conductivity and large surface area have been proposed for potential electromagnetic interference (EMI) shielding materials in future mobility and wearable applications to prevent signal noise, transmission inaccuracy, system malfunction, and health hazards. Here, we report on the synthesis of lightweight and flexible flash-induced porous graphene (FPG) with excellent EMI shielding performance. The broad spectrum of pulsed flashlight induces photo-chemical and photo-thermal reactions in polyimide films, forming 5 × 10 cm2-size porous graphene with a hollow pillar structure in a few milliseconds. The resulting material demonstrated low density (0.0354 g cm−3) and outstanding absolute EMI shielding effectiveness of 1.12 × 105dB cm2g−1. The FPG was characterized via thorough material analyses, and its mechanical durability and flexibility were confirmed by a bending cycle test. Finally, the FPG was utilized in drone and wearable applications, showing effective EMI shielding performance for internal/external EMI in a drone radar system and reducing the specific absorption rate in the human body.

ABSTRACTIntroduction: Although many caspase inhibitors have been patented, caspase inhibitors have not entered the market due to their toxicity and poor pharmacokinetic profile.Areas covered: In this article, we review patents (2013–2015) for peptide and non-peptide caspase inhibitors and their compositions.Expert opinion: Noteworthy patents include a peptidic caspase-2 inhibitor for nasal administration and a peptidomimetic caspase-6 inhibitor that can be administered via several routes for the treatment of neurodegenerative diseases. Furthermore, caspase-1 inhibitors for contact dermatitis and inflammation, cardiovascular diseases, and liver diseases and a caspase-3 inhibitor for cerebral stroke have been patented. Of particular interest is the novel use of tyrosine kinase inhibitors (sunitinib and its derivatives) for the prevention and treatment of age-related ocular diseases via inhibition of the caspase-3, dual-leucine zipper kinase (DLK) and leucine zipper-bearing kinase (LZK) pathways. However, for effective clinical application of caspase inhibitors, novel peptidic and nonpeptidic caspase inhibitors with lower toxicity and improved efficacy should be developed via structural modifications, and further animal studies and preclinical and clinical trials are needed. In addition, the poor pharmacokinetic properties of classic caspase inhibitors may be improved by using advanced drug delivery systems that employ liposomes, polymers, and nanoparticles through effective administration routes.

A number of mitochondrial diseases arise from single-nucleotide variant (SNV) accumulation in multiple mitochondria. Here, we present a method for identification of variants present at the single-mitochondrion level in individual mouse and human neuronal cells, allowing for extremely high-resolution study of mitochondrial mutation dynamics. We identified extensive heteroplasmy between individual mitochondrion, along with three high-confidence variants in mouse and one in human that were present in multiple mitochondria across cells. The pattern of variation revealed by single-mitochondrion data shows surprisingly pervasive levels of heteroplasmy in inbred mice. Distribution of SNV loci suggests inheritance of variants across generations, resulting in Poisson jackpot lines with large SNV load. Comparison of human and mouse variants suggests that the two species might employ distinct modes of somatic segregation. Single-mitochondrion resolution revealed mitochondria mutational dynamics that we hypothesize to affect risk probabilities for mutations reaching disease thresholds.

In our search for novel small molecules targeting histone deacetylases, we have designed and synthesized a series of novel hydroxamic acids incorporating indole moiety as a cap group (3a–l). Biological evaluation showed that these hydroxamic acids potently inhibited HDAC2 with IC50values in submicromolar range and up to tenfold (compound 3j) better than that of SAHA (also known as suberoylanilide hydroxamic acid). In four human cancer cell lines [SW620 (colon), PC-3 (prostate), AsPC-1 (pancreatic), NCI-H23 (lung)], the synthesized compounds that exhibited potent cytotoxicity with several compounds (3k, 3l) were found to be 12- to 77-fold more cytotoxic than SAHA. Docking experiments indicated that the compounds tightly bound to HDAC2 at the active binding site with binding affinities much higher than that of SAHA. Our present results demonstrate that these novel hydroxamic acids are potential for further development as anticancer agents.

AbstractDisseminated intravascular coagulation is a rare complication of Kawasaki disease and appears in <0.1% of Kawasaki disease patients. We report a case of refractory Kawasaki disease complicated with disseminated intravascular coagulation and giant coronary aneurysm. A 5-month-old boy presented with Kawasaki disease with coagulopathy. Although the coagulopathy improved after fresh-frozen plasma and antithrombin-III administration, the fever persisted despite two rounds of intravenous immunoglobulin, along with intravenous methylprednisolone pulse therapy and infliximab administration. Despite all efforts to treatment, the patient had giant coronary aneurysms and died suddenly.

Neurofibromatosis 1 is an autosomal dominant disorder characterized by cafe-au-lait spots, cutaneous neurofibroma, and bony deformities. Vascular abnormality such as stenosis, aneurysm, or rupture associated with neurofibromatosis 1 is rare. Rupture of vertebral artery aneurysm into the thoracic cavity is extremely rare. The outcomes of patients with aneurysmal ruptures are very poor when spontaneous hemothorax occur. A 31-year-old woman presented to the emergency department with left shoulder pain and with both lower chest wall pain and left supraclavicular area swelling. The chest computed tomography scan revealed about 4-cm pseudo-aneurysm probable arising from the left vertebral artery with large hematoma at left supraclavicular area. Neurofibromatosis 1 is generally being regarded as a benign disease but has the potential for serious vascular complications. When aneurysms were ruptured, cervical hematoma, hemothorax, or hypotension was developed. It is potentially a life-threatening condition, so it must require emergent management. Emergency physicians must remember the relation of neurofibromatosis 1 and serious vascular complications and ensure rapid access to rule out vascular lesions, so as to prevent the life-threatening condition.

Neurofibromatosis 1 is an autosomal dominant disorder characterized by cafe-au-lait spots, cutaneous neurofibroma, and bony deformities. Vascular abnormality such as stenosis, aneurysm, or rupture associated with neurofibromatosis 1 is rare. Rupture of vertebral artery aneurysm into the thoracic cavity is extremely rare. The outcomes of patients with aneurysmal ruptures are very poor when spontaneous hemothorax occur. A 31-year-old woman presented to the emergency department with left shoulder pain and with both lower chest wall pain and left supraclavicular area swelling. The chest computed tomography scan revealed about 4-cm pseudo-aneurysm probable arising from the left vertebral artery with large hematoma at left supraclavicular area. Neurofibromatosis 1 is generally being regarded as a benign disease but has the potential for serious vascular complications. When aneurysms were ruptured, cervical hematoma, hemothorax, or hypotension was developed. It is potentially a life-threatening condition, so it must require emergent management. Emergency physicians must remember the relation of neurofibromatosis 1 and serious vascular complications and ensure rapid access to rule out vascular lesions, so as to prevent the life-threatening condition.

Wearable light‐emitting diode (LED)‐based phototherapeutic devices have recently attracted attention as skin care tools for wrinkles, acne, and hyperpigmentation. However, the therapeutic effectiveness and safety of LED stimulators are still controversial due to their inefficient light transfer, high heat generation, and non‐uniform spot irradiation. Here, a wearable surface‐lighting micro‐LED (SµLED) photostimulator is reported for skin care and cosmetic applications. The SµLEDs, consisting of a light diffusion layer (LDL), 900 thin film µLEDs, and polydimethylsiloxane (PDMS), achieve uniform surface‐lighting in 2 × 2 cm2‐sized area with 100% emission yields. The SµLEDs maximize photostimulation effectiveness on the skin surface by uniform irradiation, high flexibility, and thermal stability. The SµLED's effect on melanogenesis inhibition is evaluated via in vitro and in vivo experiments to human skin equivalents (HSEs) and mouse dorsal skin, respectively. The anti‐melanogenic effect of SµLEDs is confirmed by significantly reduced levels of melanin contents, melan‐A, tyrosinase, and microphthalmia‐associated transcription factor (MITF), compared to a conventional LED (CLED) stimulator. A wearable surface‐lighting micro‐LED (SµLED) photostimulator is reported for skin‐bleaching applications. The SµLEDs, consisting of a light diffusion layer (LDL), 900 thin film µLEDs, and polydimethylsiloxane (PDMS), achieve uniform surface‐lighting in 2 × 2 cm2‐sized area with 100% emission yields. The SµLEDs maximize melanogenesis inhibition effect on the skin surface by uniform irradiation, high flexibility, and thermal stability.

Flexible piezoelectric acoustic sensors (f-PAS) have attracted significant attention as a promising component for voice user interfaces (VUI) in the era of artificial intelligence of things (AIoT). The signal distortion issue of highly sensitive biomimetic f-PAS is one of the most challenging obstacle for real-life application, due to the fundamental difference compared with the conventional microphones. Here, a noise-robust flexible piezoelectric acoustic sensor (NPAS) is demonstrated by designing the multi-resonant bands outside the noise dominant frequency range. Broad voice coverage up to 8 kHz is achieved by adopting an advanced piezoelectric membrane (Nb-doped PZT; PNZT) with the optimized polymer ratio. Deep learning-based speech processing of multi-channel NPAS is demonstrated to show the outstanding improvement in speaker recognition and speech enhancement compared to a commercial microphone. Finally, the NPAS filtered the crowd condition noises, showing independent speaker’s speeches can be identified and digitalized simultaneously.

The loss of unilateral vestibular function causes vestibulogastrointestinal symptoms that include nausea and vomiting. However, the temporal changes occurring on vestibular compensation are unclear. Thus, the temporal changes and the role of the cerebellum in the recovery of vestibulogastrointestinal symptoms after unilateral labyrinthectomy (UL) were investigated in this study.

The authors assessed the effect of noise on the detectability of rib fractures by residents.

Infantile hemangioendothelioma (IHE) is a rare benign vascular tumor with potentially life-threatening complications. Various therapeutic options have been recommended according to the site, extent, and behavior of the IHE. Because of the slow and unpredictable response to treatment with using a single drug in critically ill patients, there is a tendency to administer drugs in combination to treat this disease. Here, we report on a 1-month-old female infant who had a retroperitoneal IHE with Kasabach-Merritt syndrome and she was successfully treated with a combination of steroid, interferon-α, and vincristine.

Optogenetic neuromodulation is a promising technology for continuously caring various neurological diseases. Optogenetic modulating systems were demonstrated by several researchers, but still have critical issues of short lifetime of conventional or biocompatible batteries. Here, we present an optogenetic stimulating system by scavenging wasted magnetic field of home appliance. A flash-enhanced magneto-mechano-triboelectric nanogenerator (MMTENG) was fabricated to demonstrate optogenetic neuromodulation by operating a flexible micro-light-emitting diode (f-μLED). The output performance of MMTENG was enhanced by the flash-induced nano/microscale surface structure of the triboelectric Nylon film. The flash-stamped MMTENG effectively generated an open-circuit peak-to-peak voltage (Vpp) of 870 V and a short-circuit current of 145 μA under a gentle alternating current (AC) magnetic field of 7 Oe. A maximum peak power of 8.1 mW was observed from the flash-induced harvester, which was 2.6 times higher than the non-treated device. A high-performance f-μLED with low-resistive ohmic contacts had the improvement of thermal/mechanical stability as well as power efficiency. The MMTENG generated a rectified output voltage of 134 V by a 60 Hz stray magnetic field of home appliance, enabling to operate the f-μLED continuously. An optogenetic stimulator composed of MMTENG and f-μLED was implanted under a living mouse skull without mechanical damage.

ABSTRACTCD226 is an activating receptor expressed on natural killer (NK) cells, CD8+T cells, and other immune cells. Upon binding to its ligands expressed on target cells, CD226 activates intracellular signaling that triggers cytokine production and degranulation in NK cells. However, the role of CD226 in contact dynamics between NK and cancer cells has remained unclear. Our time-lapse images showed that individual wild-type CD226+NK cells contacted B16F10 melanoma cells for 23.7 min, but Cd226−/−NK cells only for 12.8 min, although both NK cell subsets showed equal contact frequency over 4 h. On the surface of B16F10 cells, CD226+cells stayed at the same site with oscillating movement (named stable contact), while Cd226−/−NK cells moved around at a velocity of 4 μm/min (named unstable contact). Consequently, Cd226−/−NK cells did not kill B16F10 cells in vitroand did not inhibit their metastasis into the lung in vivo. Taken together, our data demonstrate that CD226 enables prolonged stable interaction between NK and cancer cells, which is needed for efficient killing of cancer cells.

No relevant conflicts of interest to declare.

We previously showed that preantral follicle could be a source of developmentally-competent oocyte, which confirmed by establishing autologous embryonic stem (ES) cell through follicle culture and oocyte parthenogenesis. In this study, we further examined how many number of follicles could be retrieved from the ovaries. The ovaries were retrieved from 7- to 14-day-old neonatal mice of B6CBAF1 strain and primary, early secondary and late secondary follicles of 75–99 μm, 100–124 μm and >124 μm in diameter, respectively, were collected from ovarian tissue by mechanical isolation. The number of primary follicles retrieved was the largest in the 11-day-old ovaries (35.7±5.5 follicles/ovary), while gradual increase in the number of early and late secondary follicles was detected up to the 13-day-old (2±2.0 to 54.3±21.7 and 0 to 14.3±9.6 follicles/ovary, respectively). Preantral follicles were re-classified as single, single+multi (partially surrounded by multi layer) or multi layer by the status of surrounded granulosa cell layer, regardless of their diameter. The number of the single (7.7 to 0%) and single+multi follicles (65.4 to 17.7%) was gradually decreased, while prominent increase in the number of multi layer follicles was noticed as the age was increased (26.9 to 82.3%). Finally, primary follicles retrieved from 9-, 10- or 11-day-old ovaries (optimal ages of preantral follicle retrieval) were singly cultured in 10 μl drops for 4 days in a primary culture medium, ribonucleosides- and deoxyribonucleosides-free alpha-minimum essential medium (MEM) supplemented with 1% (v/v) fetal bovine serum (FBS). Growing follicles were transferred to a secondary culture medium, ribonucleosides- and deoxyribonucleosides-containing alpha-MEM supplemented with 5% FBS and further cultured for 7 days. More (p<0.05) follicles retrieved from the 11-day-old ovaries were grown to the follicles of 100–124 μm in diameter (38.6% vs. 12.8–28.7%) than the follicles retrieved from the other ages, while the follicles retrieved from the 10-day-old yielded the best growth to the follicles of more than 125 μm (5.1% vs. 0–2.5%). There were no significant differences in the number of follicles reached to the pseudoantral stage (20.1–26.3%), cumulus-oocyte-complexes released from diffused or pseudoantral follicles (31.7–39%), and the rates of maturation (29.5–43.5%) and cleavage (53.8–66.7%) after parthenogenetic activation. However, the follicles retrieved from the 11-day-old ovaries tended to yield the best culture outcome compared with the follicles retrieved from the other ages. The results of these experiments show that more than 50 preantral follicles per ovary can be retrieved from the neonatal ovaries aged more than 9-day-old and that even primary follicles retrieved can yield developmentally-competent oocytes after in vitro-culture. (platform)

Background: Hereditary spherocytosis (HS) is the most common cause of hereditary hemolytic anemia. Current tests used to diagnose HS focus on the detection of hemolysis or indirectly assess protein defects. Direct methods to detect protein defects are complicated and difficult to implement. Recent next-generation sequencing (NGS) methods enable large-scale gene mutation analyses to be used for such diagnoses. In this study, we investigated the patterns of genetic variation associated with HS among the patients diagnosed with HS clinically. Specifically, we analyzed mutations in red blood cell membrane protein-encoding genes (17 genes) in context with 5 genes for the differential diagnosis (thalassemia, congenital dyserythropoietic anemia, paroxysmal nocturnal hemoglobinuria) in Korean HS.

Since the acquired somatic mutation, JAK2 V617F, was discovered as a first molecular marker of myeloproliferative neoplasms (MPN), and it has been detected variably in each MPN subtypes. However, JAK2 V617F does not found in all of MPN cases and not necessarily specific to a particular clinicpathologic entity. Recently, mutation of the putative tumor suppressor gene, Ten-Eleven-Translocation-2(TET2), has been identified in MPN patients. However, the frequency of TET2 mutation or its relationship with JAK2 V617F mutation or pathologic function in MPN has not been concluded, yet. The aim of our study was to evaluate the frequency of TET2 in MPN patients, and whether there is any correlation of TET2 mutation with JAK2V617F mutation or the clinicohematologic parameters.Total 99 adult MPN patients (18 PV, 62 ET, 11 PMF and 8 MPN unclassified) whose bone marrow cells had been stored from 2007 to 2010 at point of first diagnosis were included in this study. Hematological diagnoses and subtyping were reconfirmed according to the 2008 WHO classification and clinicohematologic datas were collected from patient records. Direct sequencing for TET2(exon3–11) and JAK2 (exons 12 and 14) were performed using an ABI 3730XL DNA analyzer. The JAK2V617F allele burdens were determined by pyrosequencing for samples available and MPL was analyzed by allele-specific PCR.The overall TET2 mutational frequency was 12.1%, and disease-specific mutational frequencies were 22.2% in PV, 9.7% in ET and 18.2% in PMF. The found mutations included 11 mutations, 7 frame-shift (p.Lys95AsnfsX18, p.Gln967AsnfsX40, p.Lys1022GlufsX4, p.Asp1314MetfsX49, p.Gln1534AlafsX43, p.Tyr1618LeufsX4, p.Leu1609GlufsX45), 1 nonsense (p.Gly1735X), 1 missense (Q599R) and 2 splicing mutations (c.3409+1G>T, c.4044+2insT). Those mutations most frequently involved exon 3(four mutations) and exon 11(four mutaions), and rarely intron 3, intron 8 and exon 7. None of the mutations were associated with a karyotypically apparent 4q24 rearrangement. All patients were also screened for JAK2 V617F, and the overall JAK2 V617F positive rate was 68%(94.4% in PV, 69.4% in ET, 45.5% in PMF and 37.5% in MPN, unclassified). All TET2 mutations occurred in JAK2 V617F positive cases. JAK2 exon12 mutation was not found in all patients. MPL W515L was found in one ET patient who also carried JAK2V617F, but not TET2 mutation. Information on JAK2 V617F allele burden was available in 78 patients.Considering all 99 patients, the patient age, hematologic indexes (leukocyte count, neutrophil fraction, lymphocyte fraction, monocyte fraction, Hb, Hct and platelet count), the frequency of organomegaly, marrow fibrosis or thrombotic/hemorrhagic complications were not different according to carrying TET2 mutation. However, TET2 mutation was more frequently found in JAK2 V617F carriers than non-carriers (P=0.008), but JAK2 V617F allele burden did not correlated with the presence of mutant TET2.When analysis was performed for each PV, ET, and PMF (no TET2 mutation in MPN-unclassifiable patients), correlation between TET2 and JAK2 V617F mutational status was not found in each subtypes (P=0.078 in PV, P=0.099 in ET and P=0.182 in PMF). However, the JAK2 V617F allele burden was significantly higher in PMF harboring TET2 mutation than PMF patients did not (88.0 ± 4.3% vs 19.1 ± 28.7%, P=0.034). In statistical analysis for the correlations of clinicohematologic parameters with TET2 mutation in each PV, ET and PMF patients, only a few statistically significant results were identified. The presence of TET2 mutation was correlated with high Hct in PMF (47.4 ± 5.4 vs 25.5 ± 6.2, P=0.037), and TET2 positive ET patients showed relatively higher frequency of organomegaly compared to ET patients without TET2 mutation (50% vs 19.6%, P=0.018).The overall and disease-specific frequencies of TET2 mutation in our study are similar with previous studies, and frame-shift mutation is the most frequent mutation type. There is no specific relationship between JAK2 V617F and TET2 mutation occurrence, but TET2 mutant PMF has higher JAK2 V617F allele burden than non-mutant. TET2 mutation is also associated with a higher Hct in PMF and higher frequency of organomegaly in ET. Larger scale studies involving more MPN patients are needed.No relevant conflicts of interest to declare.

Abstract 1455

Abstract 5138

Antiphospholipid syndrome (APS) is a immune, thrombotic disorder of unknown etiology, characterized by the association of arterial or venous thrombosis and/or pregnancy morbidity, with the presence of antiphospholipid antibodies (aPL): anticardiolipin antibodies (aCL) and/or lupus anticoagulant (LA) and/or anti-b2-glycoprotein 1 antibodies (anti-b2GP1). In recent years, epigenetic modification has been studied in many autoimmune, immune disorders to elucidate its pathophysiologic correlation, along with genomic, epigenomic profiling. Among them, aberrant DNA methylation (hypo-, or hypermethylation) and its impact on gene expression have been implicated in diverse spectrum of diseases, including immune disease or cancer. The objective of this study is to investigate a global DNA methylation status of antiphospholipid syndrome patients with CpG microarray, and compared it with healthy controls.Human peripheral whole blood samples were obtained from 6 APS (2 primary APS and 4 secondary APS, which were 3 systemic lupus erythematosus and 1 Behçet's disease) and from 6 age, sex-matched healthy controls. Total genomic DNA extracted using the QIAamp DNA mini and blood kit protocol (Qiagen, Hilden, Germany). To discover aberrantly methylated genes in APS by genome-wide search, we introduce Illumina Infinium Human Methylation 450K BeadChip (Illumina Inc, San Diego, USA) for directly identifying differentially methylated regions of the genomes in each pooled whole blood between APS patients and healthy controls. Immunologic profiles of the patient group including aPL, aCL, LA, anti-b2GP1 were obtained. This study was reviewed by the institutional ethical board and written informed consent was completed.All patients and the control groups were female and there was no statistical difference in age distribution (age of patients=35. 26 ±10. 34 year). The fluorescent signal intensities were extracted using GenomeStudio Methylation module (1. 8. 5) software. One-hundred and thirty two CpG sites were filtered by criteria of delta mean (difference of average b value from patients and controls)>0. 2, and p value<0. 05 after the quantile normalization to reliably compare data from multiple samples by minimize non-biologic differences. Seventy nine CpG sites (KNDC1, ABHD8, CDK2AP1, MX1, IL16, ROCK2, SNTG2, SORCS2, mi518, mi662, NLRC5, PARP9, etc) were hypermethylated and 53 sites (CYP2E1, BTNL2, DTX2, GCC2, SLC9A3, PLOD1, PXDN, PROZ, ATP4B, etc) were hypomethylated. All differentially methylated CpG sites were located in 5'UTR, TSS1500, TSS200, Exon, intergenic body, 3'UTR. Hierachical clustering (figure 1) and the functional classification analysis using DAVID was done.Hundreds of candidate genes were screened by BeadChip microarray of peripheral blood in APS patients. High-throuput, next generation sequencing of the individual patients for validation will be underwent and the correlation with immunologic profile and thrombotic features will be investigated.Kim: National Research Foundation of Korea(NRF) funded by the Ministry of Education, Science and Technology: Research Funding.

Hematopoietic stem cell transplantation (HSCT) is a curative therapeutic modality for severe aplastic anemia, but optimal conditioning regimen for the HSCT with an unrelated donor has not been defined yet. As the thymoglobulin had been found to be more effective among many kinds of anti-thymocyte globulins, and fludarabine based conditioning regimens without total body irradiation have been reported to be promising for transplantation from unrelated donors in SAA, combination of fludarabine, cyclophosphamide and thymoglobulin conditioning regimens had been tried to reduce GVHD and to allow good engraftment. Our previous phase II study (study 1) of fludarabine, cyclophosphamide plus thymoglobulin conditioning regimen resulted in successful engraftment (100%), but treatment-related mortality (TRM) occurred in 9 (32.1%) patients (NCT00737685, Biol Blood Marrow Transplant. 2010.16;1582). As cyclophosphamide is more toxic than fludarabine with similar effect, then we performed a new phase II study (study 2) with reduced toxicity fludarabine, cyclophosphamide plus thymoglobulin conditioning regimen by reducing dosage of cyclophosphamide and increasing dosage of fludarabine (NCT00882323).Twenty-eight and 31 patients were enrolled in study 1 and 2, respectively. In study 1, cyclophosphamide (50 mg/kg once daily i.v. on days −9, −8, −7 & −6), fludarabine (30 mg/m2̂ once daily i.v. on days −5, −4, −3 & −2) and thymoglobulin (2.5 mg/kg once daily i.v. on days −3, −2 & −1) were used for the conditioning regimen. For study 2, cyclophosphamide was reduced to 60 mg/kg once daily i.v. on days −8 & −7, and fludarabine was increased to 40 mg/m2̂ once daily i.v. on days −6, −5, −4, −3 & −2. Thymoglobulin (2.5 mg/kg once daily i.v. on days −4, −3 & −2) was also used.Donor type hematologic recovery was achieved in all patients of study 1 (100%) and study 2 (100%). Events were occurred in 10 patients of study 1. Nine patients developed TRM, which included thrombotic microangiopathy (N=2), pneumonia (N=1), myocardiac infarction (N=1), post-transplantation lymphoprolifarative disease (N=3), and chronic GVHD-associated complications (N=2). Delayed graft failure occurred in 1 patient at 37 months after HSCT. In study 2, 2 patients had events. One patient developed TRM (pneumonia) and delayed graft failure occurred in 1 patient at 4 months after HSCT. Overall survival rate of study 2 (96.7%) was significantly higher than that of study 1 (67.9%) (P=0.005). Event free survival of patients was significantly better in study 2 (93.3%) compared to that of study 1 (64.3%) (P=0.014).Reduced toxicity fludarabine, cyclophosphamide plus thymoglobulin conditioning regimen showed promising results with same successful engraftment and less TRM compared to the previous combination and was optimal for the unrelated donor transplantation in severe aplastic anemia.No relevant conflicts of interest to declare.

Abstract 220

Infertility rates in humans have increased to approximately 10-15% in recent years. A major cause of infertility is implantation failure. Decidualization, mediated by the ovarian steroids estrogen and progesterone, is required to sustain the post-implantation phase. Mitogen inducible gene 6 (Mig-6) is an essential mediator of progesterone receptor (PR) function in the uterus. Signal transducer and activator of transcription-3 (Stat3) has been identified as a MIG-6-associated molecule, and interaction of STAT3 with PR has been detected in decidual lysates. To identify the interaction of STAT3 with PR and MIG-6 and its effect on uterine function, we performed immunoprecipitation using transient co-transfection and mouse uteri treated with estrogen and progesterone. STAT3 interacted with PR-A and MIG-6 but not with PR-B. The interaction of STAT3 with MIG-6 was also identified by co-immunoprecipitation in uterine lysate of control mice but not in PRcre/+Mig-6f/fmice. These results indicate that STAT3, MIG-6 and PR-A form a complex and may regulate each other's function. Stat3activation during the implantation period has been shown to be important for uterine receptivity and decidualization. However, research on the role of Stat3has been restricted to transient Stat3knockdown because Stat3-deficient mice are embryo lethal. Therefore, a Stat3conditional knockout mouse model is critical for understanding the role of Stat3 in vivo. In order to investigate the role of Stat3in uterine function, we have conditionally ablated Stat3in the PR-positive cells (PRcre/+Stat3f/f; Stat3d/d). Female Stat3d/dmice developed normal uterine and ovarian morphology and structure. Ovulation and fertilization rate of Stat3d/dmice did not differ from control Stat3f/fmice. Stat3d/dmice have fertility defects. Analysis of the uterus on day 5.5 of pregnancy showed disrupted blastocyst implantation in Stat3d/dmice. Stat3d/dmice also showed a defect of the uterus to respond to the artificial induction of the decidual response. In conclusion, our study suggests that Stat3regulates decidualization and implantation which is a requisite for fertility, through interaction of PRand Mig-6in the mouse uterus. This work was supported by National Institutes of Health Grant R01HD057873.

Familial hemophagocytic lymphohistiocytosis (FHL) is a rare and genetically heterogeneous disorder characterized by immune dysregulation with a defect in apoptosis triggering and in natural killer and cytotoxic T lymphocyte cellular cytotoxicity. It occurs mostly in infancy and early childhood, and without treatment, is invariably fatal with a median survival of less than 2 months after diagnosis. Only early hematopoietic stem cell transplantation (HSCT) has been shown to cure the disease. The molecular genetic defect causing FHL has been intensively investigated for recent years and classification of FHL according to the genetic abnormality has been tried. It has been noted that some mutations appear to be more frequent in patients from a certain geographical region, but there is no data available for the genetic background of Korean FHL patients. The aim of this study was to identify causative gene(s) and mutation(s) by mutation analyses of three known HLH causative genes, namely PRF1, UNC13D, and STX11 in Korean FHL patients. We also analyzed whether there were genotype-phenotype correlations among these genetic subtypes, and intended to provide critical information for the decision making for timely and most appropriate treatment of FHL patients. Fifteen patients with suspected FHL were recruited from the Korean National Registry of HLH between January 2007 and March 2008. By using genomic DNA samples extracted from peripheral blood leukocytes, direct sequencing was performed in all the exons and their flanking intronic sequences of the PRF1 gene, UNC13D gene, and STX11 gene by genetic analyzer. The correlation between clinical features and genetic subtypes was investigated. Of the 15 HLH patients, 8 mutations of UNC13D gene were found in 5 patients, and 5 of the 8 mutations were novel (Q98X, IVS24+1G>A, IVS21-2A>G, IVS30+5G>A, c.1693delG). Neither PRF1 nor STX11 mutation was identified. IVS9-1G>C, one of the previously reported UNC13D mutations, was found in 3 patients. The clinical features of the patients with UNC13D mutation were associated with earlier age of disease onset (median: 2 months, versus 21 months), more frequent involvement of central nervous system (60% versus 20%), and poorer treatment response (complete response rate 20% versus 70%) than those of FHL patients without UNC13D mutation. This study is the first report to indicate UNC13D mutations as a molecular genetic cause in Korean patients with FHL by direct gene sequencing. The novel UNC13D mutations found in Korean FHL patients implicate the possible presence of an ethnical difference in the genetic background of FHL development. Further study with a larger number of FHL patients would be needed to identify other potential causative genes and mutations and to clarify the genotype-phenotype correlation for each mutation. Moreover, earlier detection of UNC13D mutation on the basis of this study in a suspected FHL patient would provide important information for the decision making for timely HSCT.

Familial hemophagocytic lymphohistiocytosis (FHL) is a rare and genetically heterogeneous disorder characterized by immune dysregulation with a defect in apoptosis triggering and in natural killer and cytotoxic T lymphocyte cellular cytotoxicity. It occurs mostly in infancy and early childhood, and without treatment, is invariably fatal with a median survival of less than 2 months after diagnosis. Only early hematopoietic stem cell transplantation (HSCT) has been shown to cure the disease. The molecular genetic defect causing FHL has been intensively investigated for recent years and classification of FHL according to the genetic abnormality has been tried. It has been noted that some mutations appear to be more frequent in patients from a certain geographical region, but there is no data available for the genetic background of Korean FHL patients. The aim of this study was to identify causative gene(s) and mutation(s) by mutation analyses of three known HLH causative genes, namely PRF1, UNC13D, and STX11in Korean FHL patients. We also analyzed whether there were genotype-phenotype correlations among these genetic subtypes, and intended to provide critical information for the decision making for timely and most appropriate treatment of FHL patients. Fifteen patients with suspected FHL were recruited from the Korean National Registry of HLH between January 2007 and March 2008. By using genomic DNA samples extracted from peripheral blood leukocytes, direct sequencing was performed in all the exons and their flanking intronic sequences of the PRF1gene, UNC13Dgene, and STX11gene by genetic analyzer. The correlation between clinical features and genetic subtypes was investigated. Of the 15 HLH patients, 8 mutations of UNC13Dgene were found in 5 patients, and 5 of the 8 mutations were novel (Q98X, IVS24+1G>A, IVS21-2A>G, IVS30+5G>A, c.1693delG). Neither PRF1nor STX11mutation was identified. IVS9-1G>C, one of the previously reported UNC13Dmutations, was found in 3 patients. The clinical features of the patients with UNC13Dmutation were associated with earlier age of disease onset (median: 2 months, versus21 months), more frequent involvement of central nervous system (60% versus20%), and poorer treatment response (complete response rate 20% versus70%) than those of FHL patients without UNC13Dmutation. This study is the first report to indicate UNC13Dmutations as a molecular genetic cause in Korean patients with FHL by direct gene sequencing. The novel UNC13Dmutations found in Korean FHL patients implicate the possible presence of an ethnical difference in the genetic background of FHL development. Further study with a larger number of FHL patients would be needed to identify other potential causative genes and mutations and to clarify the genotype-phenotype correlation for each mutation. Moreover, earlier detection of UNC13Dmutation on the basis of this study in a suspected FHL patient would provide important information for the decision making for timely HSCT.

Objective: Chemoimmunotherapy based treatments improved the survival of patients with hemophagocytic lymphohistiocytosis (HLH), but the outcome is still unsatisfactory. We analyzed the outcome of pediatric patients with HLH after hematopoietic stem cell transplantation (HSCT) in a nation-wide HLH registry. Methods: Retrospective nation-wide data recruitment for HLH pediatric patients diagnosed between 1996 and 2005 was carried out by Histiocytosis Working Party of the KSH and KSPHO. Sixteen patients who received HSCT among enrolled 129 pediatric patients with HLH were analyzed for transplant related variables and events. Results: The probability of 3-year survival after HSCT was 81.2% with median follow-up of 27.5 months compared to the 35.2% for patients who were treated with chemoimmunotherapy only (P=0.03). The reasons for HSCT were active disease at 2 months after treatment (n=8), relapsed disease (n=5), and familial HLH (n=3). Eight patients received transplants from matched unrelated donors, 5 from matched siblings and 3 using unrelated cord blood units. Stem cell sources were bone marrow for all the 13 allogeneic transplants other than 3 cord blood transplants. Conditioning regimens were busulphan, cytoxan, and VP-16 with (5) or without (7) antithymocyte globulin (ATG) in 12 patients, fludarabin and melphalan in 3, and other regimen in 1. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine (CSA) + MTX in 11 patients, CSA +MMF in 2, and others in 2. Twelve patients are alive in complete remission state, 3 patients died of infection and graft failure at early post-transplant period, and 1 patient relapsed at post-transplant 30 days. The relapsed patient developed tuberculous encephalitis after retreatment with chemoimmunotherapy, and alive with supportive care. After HSCT, acute GVHD developed in 5 patients, infection in 5, veno-occlusive disease (VOD) in 2, graft failure in 2, and post-transplant lymphoproliferative disease (PTLD) in 1. Acute lymphoblastic leukemia developed in 1 patient about 2 years after HSCT. Variables such as age at diagnosis, etiology of HLH (familial or secondary), central nervous system (CNS) involvement, disease state after 8 weeks of initial treatment, conditioning regimens, and stem cell sources were not associated with significant difference with regard to 3-year overall survival after HSCT. Conclusion: HSCT revealed excellent outcome for patients with familial, relapsed, or severe and persistent secondary HLH in Korean nation-wide HLH registry.