Soon Tae Lee

Stretchable silicon nanoribbon electronics for skin prosthesis

Sensory receptors in human skin transmit a wealth of tactile and thermal signals from external environments to the brain. Despite advances in our understanding of mechano- and thermosensation, replication of these unique sensory characteristics in artificial skin and prosthetics remains challenging. Recent efforts to develop smart prosthetics, which exploit rigid and/or semi-flexible pressure, strain and temperature sensors, provide promising routes for sensor-laden bionic systems, but with limited stretchability, detection range and spatio-temporal resolution. Here we demonstrate smart prosthetic skin instrumented with ultrathin, single crystalline silicon nanoribbon strain, pressure and temperature sensor arrays as well as associated humidity sensors, electroresistive heaters and stretchable multi-electrode arrays for nerve stimulation. This collection of stretchable sensors and actuators facilitate highly localized mechanical and thermal skin-like perception in response to external stimuli, thus providing unique opportunities for emerging classes of prostheses and peripheral nervous system interface technologies.

IRE1 plays an essential role in ER stress-mediated aggregation of mutant huntingtin via the inhibition of autophagy flux

Huntingtons disease (HD), an inherited neurodegenerative disorder, is caused by an expansion of cytosine-adenine-guanine repeats in the huntingtin gene. The aggregation of mutant huntingtin (mtHTT) and striatal cell loss are representative features to cause uncontrolled movement and cognitive defect in HD. However, underlying mechanism of mtHTT aggregation and cell toxicity remains still elusive. Here, to find new genes modulating mtHTT aggregation, we performed cell-based functional screening using the cDNA expression library and isolated IRE1 gene, one of endoplasmic reticulum (ER) stress sensors. Ectopic expression of IRE1 led to its self-activation and accumulated detergent-resistant mtHTT aggregates. Treatment of neuronal cells with ER stress insults, tunicamycin and thapsigargin, increased mtHTT aggregation via IRE1 activation. The kinase activity of IRE1, but not the endoribonuclease activity, was necessary to stimulate mtHTT aggregation and increased death of neuronal cells, including SH-SY5Y and STHdhQ111/111 huntingtin knock-in striatal cells. Interestingly, ER stress impaired autophagy flux via IRE1-TRAF2 pathway, thus enhancing cellular accumulation of mtHTT. Atg5 deficiency in M5-7 cells increased mtHTT aggregation but blocked ER stress-induced mtHTT aggregation. Further, ER stress markers including p-IRE1 and autophagy markers such as p62 were up-regulated exclusively in the striatal tissues of HD mouse models and in HD patients. Moreover, down-regulation of IRE1 expression rescues the rough-eye phenotype by mtHTT in a HD fly model. These results suggest that IRE1 plays an essential role in ER stress-mediated aggregation of mtHTT via the inhibition of autophagy flux and thus neuronal toxicity of mtHTT aggregates in HD.

Modification of ASC1 by UFM1 Is Crucial for ERα Transactivation and Breast Cancer Development

Biological roles for UFM1, a ubiquitin-like protein, are largely unknown, and therefore we screened for targets of ufmylation. Here we show that ufmylation of the nuclear receptor coactivator ASC1 is a key step for ERα transactivation in response to 17β-estradiol (E2). In the absence of E2, the UFM1-specific protease UfSP2 was bound to ASC1, which maintains ASC1 in a nonufmylated state. In the presence of E2, ERα bound ASC1 and displaced UfSP2, leading to ASC1 ufmylation. Polyufmylation of ASC1 enhanced association of p300, SRC1, and ASC1 at promoters of ERα target genes. ASC1 overexpression or UfSP2 knockdown promoted ERα-mediated tumor formation in vivo, which could be abrogated by treatment with the anti-breast cancer drug tamoxifen. In contrast, expression of ufmylation-deficient ASC1 mutant or knockdown of the UFM1-activating E1 enzyme UBA5 prevented tumor growth. These findings establish a role for ASC1 ufmylation in breast cancer development by promoting ERα transactivation.

Altered Functional Connectivity in Idiopathic Rapid Eye Movement Sleep Behavior Disorder: A Resting-State EEG Study

Study ObjectivesnIdiopathic rapid eye movement sleep behavior disorder (iRBD) is considered as a prodromal stage of synucleinopathy. Although loss of functional connectivity is implicated in neurodegenerative diseases, network characteristics of electroencephalography (EEG) in iRBD are unknown. Therefore, we evaluated resting-state EEG functional connectivity to identify the brain network changes in patients with iRBD.nnnMethodsnWe prospectively enrolled 20 patients with polysomnography-confirmed iRBD and 16 controls. Four patients with mild cognitive impairment were excluded from the analysis after cognitive function tests. EEG was recorded during relaxed wakefulness. We computed the weighted phase lag index as a measure of functional connectivity from EEG recordings.nnnResultsnAll patients with iRBD (mean age 64.3 years; men, 68.8%) had no overt manifestations of neurodegenerative diseases such as Parkinsonism or dementia. The mean duration from symptom onset was 4.8 years. Overall connectivity strength did not differ between the two groups in all frequency bands. However, comparisons of each functional connection with the nonparametric permutation test demonstrated iRBD had decreased delta-band functional connectivity in the frontal regions. There were no significantly increased functional connections in all frequencies. The altered connections had a significant correlation with RBD questionnaire scores. Notably, delta-band weighted phase lag index between left frontal and central regions was correlated with verbal fluency performance (r = 0.486, p = .007).nnnConclusionsnResting-state brain network of iRBD was characterized by a loss of delta-band functional connectivity. Therefore, functional networks in iRBD are altered at the early phase of disease.

Prognostic Value of Initial Standard EEG and MRI in Patients with Herpes Simplex Encephalitis

Background and Purpose Herpes simplex encephalitis (HSE) is the most common type of sporadic encephalitis worldwide, and it remains fatal even when optimal antiviral therapy is applied. There is only a weak consensus on the clinical outcomes and prognostic factors in patients with HSE. This study examined whether the radiological and electrophysiological findings have a prognostic value in patients with HSE. Methods We retrospectively analyzed patients who were diagnosed with HSE by applying the polymerase chain reaction to cerebrospinal fluid and who received intravenous acyclovir at our hospital from 2000 to 2014. We evaluated the clinical outcomes at 6 months after onset and their correlations with initial and clinical findings, including the volume of lesions on MRI, the severity of EEG findings, and the presence of epileptic seizures at the initial presentation. Results Twenty-nine patients were enrolled (18 men and 11 women). Univariate analysis revealed that the presence of severe EEG abnormality and epileptic seizures at the initial presentation were significant correlated with a poor clinical outcome at 6 months (p=0.005 and p=0.009, respectively). In multivariate analysis, the presence of severe EEG abnormality was the only independent predictor of a poor outcome at 6 months (p=0.006). Conclusions In cases of HSE, the initial EEG severity and seizure presentation may be useful predictive factors for the outcome at 6 months after acyclovir treatment.

Underexpression of HOXA11 is Associated with Treatment Resistance and Poor Prognosis in Glioblastoma

Purpose Homeobox (HOX) genes are essential developmental regulators that should normally be in the silenced state in an adult brain. The aberrant expression of HOX genes has been associated with the prognosis of many cancer types, including glioblastoma (GBM). This study examined the identity and role of HOX genes affecting GBM prognosis and treatment resistance. Materials and Methods The full series of HOX genes of five pairs of initial and recurrent human GBM samples were screened by microarray analysis to determine the most plausible candidate responsible for GBM prognosis. Another 20 newly diagnosed GBM samples were used for prognostic validation. In vitro experiments were performed to confirm the role of HOX in treatment resistance. Mediators involved in HOX gene regulation were searched using differentially expressed gene analysis, gene set enrichment tests, and network analysis. Results The underexpression of HOXA11 was identified as a consistent signature for a poor prognosis among the HOX genes. The overall survival of the GBM patients indicated a significantly favorable prognosis in patients with high HOXA11 expression (31±15.3 months) compared to the prognoses in thosewith low HOXA11 expression (18±7.3 months, p=0.03). When HOXA11 was suppressed in the GBM cell lines, the anticancer effect of radiotherapy and/or temozolomide declined. In addition, five candidate mediators (TGFBR2, CRIM1, TXNIP, DPYSL2, and CRMP1) that may confer an oncologic effect after HOXA11 suppression were identified. Conclusion The treatment resistance induced by the underexpression of HOXA11 can contribute to a poor prognosis in GBM. Further investigation will be needed to confirm the value of HOXA11 as a potential target for overcoming the treatment resistance by developing chemo- or radiosensitizers.

Anti-LGI1 Limbic Encephalitis Presented with Atypical Manifestations

Anti-leucine-rich glioma inactivated-1 (LGI1) limbic encephalitis (LE) is a rare neurological disorder that has a subacute course of progressive encephalopathy and fasciobrachial dystonic seizures. We report a patient with anti-LGI1 LE that presented with atypical manifestations that complicated the diagnosis. A 62-year-old woman presented with a chronic course of memory disturbance and a subsequent relapse with an altered mental status after 10 months. The patient reported frequent chest pain of squeezing and dull nature, typically lasting 10-30 seconds. The chest pain was related to partial seizures, which were confirmed by video-EEG monitoring. Anti-LGI1 antibody was identified in serum and CSF. The patients symptoms improved by immune modulation treatment. Patients with anti-LGI1 LE can experience atypical partial seizures, and a chronic relapsing course. Clinical suspicions and video-EEG monitoring are helpful for the early diagnosis and effective immune modulation.

Novel recursive partitioning analysis classification for newly diagnosed glioblastoma: A multi-institutional study highlighting the MGMT promoter methylation and IDH1 gene mutation status

BACKGROUND AND PURPOSEnTo refine the recursive partitioning analysis (RPA) classification for glioblastoma incorporating the MGMT methylation and IDH1 mutation status.nnnMETHODS AND MATERIALSnThree-hundred forty patients were treated with radiotherapy plus concurrent and adjuvant temozolomide in three tertiary-referral hospitals. MGMT methylation and IDH1 mutation status were available in all patients. Methylation of the MGMT (MGMTmeth) and mutation of IDH1 (IDH1mut) were observed in 42.4% and 6.2% of the patients, respectively.nnnRESULTSnThe median follow-up for survivors and all patients was 33.2 and 20.5months, respectively. The median survival (MS) was 23.6months. RPA was performed on behalf of the results of the Cox proportional hazards model. MGMT methylation generated the initial partition (MGMTmeth vs. MGMTunmeth) in the RPA. Three final RPA classes were identified; class I=MGMTmeth/IDH1mut or MGMTmeth/IDH1wt/GTR/KPS≥90 (MS, 67.2months); class II=MGMTmeth/IDH1wt/GTR/KPS<90, MGMTmeth/IDH1wt/residual disease, MGMTunmeth/age<50, or MGMTunmeth/age≥50/GTR (MS, 24.0months); class III=MGMTunmeth/age≥50/residual disease (MS, 15.2months).nnnCONCLUSIONSnA novel RPA classification for glioblastoma was formulated highlighting the impact of MGMTmeth and IDH1mut in the temozolomide era. This model integrating pertinent molecular information can be used effectively for the patient stratification in future clinical trials. An external validation is ongoing.

Dynamic contrast-enhanced MR imaging in predicting progression of enhancing lesions persisting after standard treatment in glioblastoma patients: a prospective study

ObjectivesTo prospectively explore the value of dynamic contrast-enhanced magnetic resonance imaging (DCE–MRI) in predicting the progression of enhancing lesions persisting after standard treatment in patients with surgically resected glioblastoma (GBM).MethodsForty-seven GBM patients, who underwent near-total tumorectomy followed by concurrent chemoradiation therapy (CCRT) with temozolomide (TMZ) between May 2014 and February 2016, were enrolled. Twenty-four patients were finally analyzed for measurable enhancing lesions persisting after standard treatment. DCE-MRI parameters were calculated at enhancing lesions. Mann–Whitney U tests and multivariable stepwise logistic regression were used to compare parameters between progression (nu2009=u200916) and non-progression (nu2009=u20098) groups.ResultsMean Ktrans and ve were significantly lower in progression than in non-progression (Pu2009=u20090.037 and Pu2009=u20090.037, respectively). The 5th percentile of the cumulative Ktrans histogram was also significantly lower in the progression than in non-progression group (Pu2009=u20090.017). Mean ve was the only independent predictor of progression (Pu2009=u20090.007), with a sensitivity of 100%, specificity of 63%, and an overall accuracy of 88% at a cut-off value of 0.873.ConclusionsDCE-MRI may help predict the progression of enhancing lesions persisting after the completion of standard treatment in patients with surgically resected GBM, with mean ve serving as an independent predictor of progression.Key points• Enhancing lesions may persist after standard treatment in GBM patients.• DCE-MRI may help predict the progression of the enhancing lesions.• Mean Ktransand vewere lower in progression than in non-progression group.• DCE-MRI may help identify patients requiring close follow-up after standard treatment.• DCE-MRI may help plan treatment strategies for GBM patients.

Rituximab Treatment for Idiopathic Hypertrophic Pachymeningitis

Background and Purpose Hypertrophic pachymeningitis (HP) is a rare disease caused by autoimmunity in the meninx that causes various neurologic symptoms, including headache, seizures, weakness, paresthesia, and cranial nerve palsies. Although the first-line therapy for HP is steroids, many HP cases are refractory to steroids or recur when the steroids are tapered. Here we report three HP cases that were successfully treated with rituximab (RTX). Methods From an institutional cohort recruited from April 2012 to July 2016, three HP cases that were identified to be steroid-refractory were treated with RTX (four weekly doses of 375 mg/m2). Clinical improvement was assessed by the number of relapses of any neurologic symptom and the largest dural thickness in MRI. Results All three patients were recurrence-free of neurologic symptoms and exhibited prominent decreases in the dural thickness after RTX treatment. No adverse events were observed in the patients. Conclusions We suggest RTX as a second-line therapy for steroid-refractory HP. Further studies are warranted to confirm this observation in a larger population and to consider RTX as a first-line therapy.