Chondrogenesis is a highly coordinated event in embryo development, adult homeostasis, and repair of the vertebrate cartilage. Fate decisions and differentiation of chondrocytes accompany ...differential expression of genes critical for each step of chondrogenesis. SOX9 is a master transcription factor that participates in sequential events in chondrogenesis by regulating a series of downstream factors in a stage-specific manner. SOX9 either works alone or in combination with downstream SOX transcription factors, SOX5 and SOX6 as chondrogenic SOX Trio. SOX9 is reduced in the articular cartilage of patients with osteoarthritis while highly maintained during tumorigenesis of cartilage and bone. Gene therapy using viral and non-viral vectors accompanied by tissue engineering (scaffolds) is a promising tool to regenerate impaired cartilage. Delivery of SOX9 or chondrogenic SOX Trio into cells produces efficient therapeutic effects on chondrogenesis and this event is facilitated by scaffolds. Non-viral vector-guided delivery systems encapsulated or loaded in mechanically stable solid scaffolds are useful for the regeneration of articular cartilage. Here we review major milestones and most recent studies focusing on regulation and function of chondrogenic SOX Trio, during chondrogenesis and cartilage regeneration, and on the development of advanced technologies in gene delivery with tissue engineering to improve efficiency of cartilage repair process.
This study develops multimodal magnetic nanoclusters (M‐MNCs) for gene transfer, directed migration, and tracking of human mesenchymal stem cells (hMSCs). The M‐MNCs are designed with 5 nm iron oxide ...nanoparticles and a fluorescent dye (i.e., Rhodamine B) in the matrix of the Food and Drug Administration approved polymer poly(lactide‐co‐glycolide) using a nanoemulsion method. The synthesized M‐MNCs have a hydrodynamic diameter of ≈150 nm, are internalized by stem cells via endocytosis, and deliver genes with high efficiency. The cellular internalization and gene expression efficiency of the clustered nanoparticles are significantly higher than that of single nanoparticles. The M‐MNC‐labeled hMSCs migrate upon application of a magnetic force and can be visualized by both optical and magnetic resonance (MR) imaging. In animal models, the M‐MNC‐labeled hMSCs are also successfully tracked using optical and MR imaging. Thus, the M‐MNCs not only allow the efficient delivery of genes to stem cells but also the tracking of cells in animal models. Taken together, the results show that this new type of nanocomposite can be of great help in future stem cell research and in the development of cell‐based therapeutic agents.
Multimodal magnetic nanoclusters (M‐MNCs) for gene delivery, directed migration, and tracking of stem cells are developed through an easy nanoemulsion method. The M‐MNCs show high transfection efficacy and allow directed migration of the stem cells under magnetic fields and provide multimodal imaging modality to enable tracking of the stem cells.
Objective
Heritability of stroke is assumed not to be low, especially in the young stroke population. However, most genetic studies have been performed in highly selected patients with typical ...clinical or neuroimaging characteristics. We investigated the prevalence of 15 Mendelian stroke genes and explored the relationships between variants and the clinical and neuroimaging characteristics in a large, unselected, young stroke population.
Methods
We enrolled patients aged ≤55 years with stroke or transient ischemic attack from a prospective, nationwide, multicenter stroke registry. We identified clinically relevant genetic variants (CRGVs) in 15 Mendelian stroke genes (GLA, NOTCH3, HTRA1, RNF213, ACVRL1, ENG, CBS, TREX1, ABCC6, COL4A1, FBN1, NF1, COL3A1, MT‐TL1, and APP) using a customized, targeted next generation sequencing panel.
Results
Among 1,033 patients, 131 (12.7%) had 28 CRGVs, most frequently in RNF213 (n = 59), followed by ABCC6 (n = 53) and NOTCH3 (n = 15). The frequency of CRGVs differed by ischemic stroke subtypes (p < 0.01): the highest in other determined etiology (20.1%), followed by large artery atherosclerosis (13.6%). It also differed between patients aged ≤35 years and those aged 51 to 55 years (17.1% vs 9.3%, p = 0.02). Only 27.1% and 26.7% of patients with RNF213 and NOTCH3 variants had typical neuroimaging features of the corresponding disorders, respectively. Variants of uncertain significance (VUSs) were found in 15.4% patients.
Interpretation
CRGVs in 15 Mendelian stroke genes may not be uncommon in the young stroke population. The majority of patients with CRGVs did not have typical features of the corresponding monogenic disorders. Clinical implications of having CRGVs or VUSs should be explored. ANN NEUROL 2023;93:768–782
A facile in situ supramolecular assembly and modular modification of biocompatible hydrogels were demonstrated using cucurbit6uril-conjugated hyaluronic acid (CB6-HA), diaminohexane-conjugated HA ...(DAH-HA), and tags-CB6 for cellular engineering applications. The strong and selective host–guest interaction between CB6 and DAH made possible the supramolecular assembly of CB6/DAH-HA hydrogels in the presence of cells. Then, the 3D environment of CB6/DAH-HA hydrogels was modularly modified by the simple treatment with various multifunctional tags-CB6. Furthermore, we could confirm in situ formation of CB6/DAH-HA hydrogels under the skin of nude mice by sequential subcutaneous injections of CB6-HA and DAH-HA solutions. The fluorescence of modularly modified fluorescein isothiocyanate (FITC)-CB6 in the hydrogels was maintained for up to 11 days, reflecting the feasibility to deliver the proper cues for cellular proliferation and differentiation in the body. Taken together, CB6/DAH-HA hydrogels might be successfully exploited as a 3D artificial extracellular matrix for various tissue engineering applications.
The mitochondrial HSP70 chaperone mortalin (HSPA9/GRP75) is often upregulated and mislocalized in MEK/ERK-deregulated tumors. Here, we show that mortalin depletion can selectively induce death of ...immortalized normal fibroblasts IMR90E1A when combined with K-Ras
expression, but not with wild-type K-Ras expression, and that K-Ras
-driven MEK/ERK activity is necessary for this lethality. This cell death was attenuated by knockdown or inhibition of adenine nucleotide translocase (ANT), cyclophilin D (CypD), or mitochondrial Ca
uniporter (MCU), which implicates a mitochondria-originated death mechanism. Indeed, mortalin depletion increased mitochondrial membrane permeability and induced cell death in KRAS-mutated human pancreatic ductal adenocarcinoma (PDAC) and colon cancer lines, which were attenuated by knockdown or inhibition of ANT, CypD, or MCU, and occurred independently of TP53 and p21
. Intriguingly, JG-98, an advanced MKT-077 derivative, phenocopied the lethal effects of mortalin depletion in K-Ras
-expressing IMR90E1A and KRAS-mutated tumor cell lines in vitro. Moreover, JG-231, a JG-98 analog with improved microsomal stability effectively suppressed the xenograft of MIA PaCa-2, a K-Ras
-expressing human PDAC line, in athymic nude mice. These data demonstrate that oncogenic KRAS activity sensitizes cells to the effects of mortalin depletion, suggesting that mortalin has potential as a selective therapeutic target for KRAS-mutated tumors.
Despite the great socioeconomic burden of stroke, there have been few reports of stroke statistics in Korea. In this scenario, the Epidemiologic Research Council of the Korean Stroke Society launched ...the "Stroke Statistics in Korea" project, aimed at writing a contemporary, comprehensive, and representative report on stroke epidemiology in Korea. This report contains general statistics of stroke, prevalence of behavioral and vascular risk factors, stroke characteristics, pre-hospital system of care, hospital management, quality of stroke care, and outcomes. In this report, we analyzed the most up-to-date and nationally representative databases, rather than performing a systematic review of existing evidence. In summary, one in 40 adults are patients with stroke and 232 subjects per 100,000 experience a stroke event every year. Among the 100 patients with stroke in 2014, 76 had ischemic stroke, 15 had intracerebral hemorrhage, and nine had subarachnoid hemorrhage. Stroke mortality is gradually declining, but it remains as high as 30 deaths per 100,000 individuals, with regional disparities. As for stroke risk factors, the prevalence of smoking is decreasing in men but not in women, and the prevalence of alcohol drinking is increasing in women but not in men. Population-attributable risk factors vary with age. Smoking plays a role in young-aged individuals, hypertension and diabetes in middle-aged individuals, and atrial fibrillation in the elderly. About four out of 10 hospitalized patients with stroke are visiting an emergency room within 3 hours of symptom onset, and only half use an ambulance. Regarding acute management, the proportion of patients with ischemic stroke receiving intravenous thrombolysis and endovascular treatment was 10.7% and 3.6%, respectively. Decompressive surgery was performed in 1.4% of patients with ischemic stroke and in 28.1% of those with intracerebral hemorrhage. The cumulative incidence of bleeding and fracture at 1 year after stroke was 8.9% and 4.7%, respectively. The direct costs of stroke were about ₩1.68 trillion (KRW), of which ₩1.11 trillion were for ischemic stroke and ₩540 billion for hemorrhagic stroke. The great burden of stroke in Korea can be reduced through more concentrated efforts to control major attributable risk factors for age and sex, reorganize emergency medical service systems to give patients with stroke more opportunities for reperfusion therapy, disseminate stroke unit care, and reduce regional disparities. We hope that this report can contribute to achieving these tasks.
Abstract
We introduce a 0.7 m telescope system at the Miryang Arirang Astronomical Observatory (MAAO), a public observatory in Miryang, Korea. System integration and a scheduling program enable the ...0.7 m telescope system to operate completely robotically during nighttime, eliminating the need for human intervention. Using the 0.7 m telescope system, we obtain atmospheric extinction coefficients and the zero-point magnitudes by observing standard stars. As a result, we find that atmospheric extinctions are moderate but they can sometimes increase depending on the weather conditions. The measured 5
σ
limiting magnitudes reach down to
BVRI
= 19.4–19.6 AB mag for a point source with a total integrated time of 10 minutes under clear weather conditions, demonstrating comparable performance with other observational facilities operating under similar specifications and sky conditions. We expect that the newly established MAAO 0.7 m telescope system will contribute significantly to the observational studies of astronomy. Particularly, with its capability for robotic observations, this system, although its primary duty is for public viewing, can be extensively used for the time-series observation of transients.
Objective
We investigated (1) the associations of pre‐stroke aspirin use with thrombus burden, infarct volume, hemorrhagic transformation, early neurological deterioration (END), and functional ...outcome, and (2) whether stroke subtypes modify these associations in first‐ever ischemic stroke.
Methods
This multicenter magnetic resonance imaging (MRI)‐based study included 5,700 consecutive patients with acute first‐ever ischemic stroke, who did not undergo intravenous thrombolysis or endovascular thrombectomy, from May 2011 through February 2014. Propensity score‐based augmented inverse probability weighting was performed to estimate adjusted effects of pre‐stroke aspirin use.
Results
The mean age was 67 years (41% women), and 15.9% (n = 907) were taking aspirin before stroke. Pre‐stroke aspirin use (vs nonuse) was significantly related to a reduced infarct volume (by 30%), particularly in large artery atherosclerosis stroke (by 45%). In cardioembolic stroke, pre‐stroke aspirin use was associated with a ~50% lower incidence of END (adjusted difference = −5.4%, 95% confidence interval CI = −8.9 to −1.9). Thus, pre‐stroke aspirin use was associated with ~30% higher likelihood of favorable outcome (3‐month modified Rankin Scale score < 3), particularly in large artery atherosclerosis stroke and cardioembolic stroke (adjusted difference = 7.2%, 95% CI = 1.8 to 12.5 and adjusted difference = 6.4%, 95% CI = 1.7 to 11.1, respectively). Pre‐stroke aspirin use (vs nonuse) was associated with 85% less frequent cerebral thrombus‐related susceptibility vessel sign (SVS) in large artery atherosclerosis stroke (adjusted difference = −1.4%, 95% CI = −2.1 to −0.8, p < 0.001) and was associated with ~40% lower SVS volumes, particularly in cardioembolic stroke (adjusted difference = −0.16 cm3, 95% CI = −0.29 to −0.02, p = 0.03). Moreover, pre‐stroke aspirin use was not significantly associated with hemorrhagic transformation (adjusted difference = −1.1%, p = 0.09).
Interpretation
Pre‐stroke aspirin use associates with improved functional independence in patients with first‐ever ischemic large arterial stroke by reducing infarct volume and/or END, likely by decreasing thrombus burden, without increased risk of hemorrhagic transformation. ANN NEUROL 2021;90:763–776
Objective
We evaluated the efficacy of endovascular thrombectomy (EVT) on the functional outcome of patients with acute basilar artery occlusion and low posterior circulation acute stroke prognosis ...early computed tomography score (PC‐ASPECTS).
Methods
We identified patients with acute ischemic stroke due to basilar artery occlusion and PC‐ASPECTS of 6 or less, presenting within 24 h between August 2008 and April 2022. The primary outcome was a favorable functional outcome, defined as a modified Rankin Scale (mRS) score of 0–3 at 90 days. The secondary outcomes included an mRS score of 0–2, a favorable shift in the ordinal mRS scale, the occurrence of symptomatic intracranial hemorrhage (sICH), and mortality at 90 days. We compared the outcome of patients treated with EVT and those without EVT, using the inverse probability of treatment weighting methods.
Results
Out of 566 patients, 55.5% received EVT. In the EVT group, 106 (33.8%) achieved favorable outcomes, compared to 56 patients (22.2%) in the conservative group. EVT significantly increased the likelihood of achieving a favorable outcome compared to conservative treatment (relative risk RR 1.39, 95% confidence interval CI, 1.11–1.74, p = 0.004). EVT was associated with a favorable shift in the mRS (RR 1.85, 95% CI, 1.49–2.29, p < 0.001) and reduced mortality without an increase in the risk of sICH. It did not have an impact on achieving an mRS score of 0–2.
Interpretation
Patients with acute basilar artery occlusion and a PC‐ASPECTS of 6 or less might benefit from EVT without an increasing sICH. ANN NEUROL 2024;95:788–799
Spinal fusion has become a common surgical technique to join two or more vertebrae to stabilize a damaged spine; however, the rate of pseudarthrosis (failure of fusion) is still high. To minimize ...pseudarthrosis, bone morphogenetic protein-2 (BMP2) has been approved for use in humans. In this study, we developed a poly(lactide-co-glycolide) (PLGA) composite incorporated with magnesium hydroxide (MH) nanoparticles for the delivery of BMP2. This study aimed to evaluate the effects of released BMP2 from BMP2-immobilized PLGA/MH composite scaffold in an in vitro test and an in vivo mice spinal fusion model. The PLGA/MH composite films were fabricated via solvent casting technique. The surface of the PLGA/MH composite scaffold was modified with polydopamine (PDA) to effectively immobilize BMP2 on the PLGA/MH composite scaffold. Analyzes of the scaffold revealed that using PLGA/MH-PDA improved hydrophilicity, degradation performance, neutralization effects, and increased BMP2 loading efficiency. In addition, releasing BMP2 from the PLGA/MH scaffold significantly promoted the proliferation and osteogenic differentiation of MC3T3-E1 cells. Furthermore, the pH neutralization effect significantly increased in MC3T3-E1 cells cultured on the BMP2-immobilized PLGA/MH scaffold. In our animal study, the PLGA/MH scaffold as a BMP2 carrier attenuates inflammatory responses and promotes BMP2-induced bone formation in posterolateral spinal fusion model. These results collectively demonstrate that the BMP2-immobilized PLGA/MH scaffold offers great potential in effectively inducing bone formation in spinal fusion surgery.
PDF
