Jung-Won Shin

VGKC-complex/LGI1-antibody encephalitis: clinical manifestations and response to immunotherapy.

Leucine-rich glioma inactivated 1 (LGI1) was recently identified as a target protein in autoimmune synaptic encephalitis, a rare condition associated with autoantibodies against structures in the neuronal synapse. Studies dealing with LGI1 are small in number and the various outcomes of different therapeutic regimens are not well studied. Here, we analyzed clinical characteristics of 14 patients with LGI1 antibodies, and outcomes according to therapeutic strategies. Most patients exhibited abnormal brain positron emission tomography and that patients treated with steroids alone were more likely to relapse and had less favorable outcomes than those treated with steroids and intravenous immunoglobulins.

Primary resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in patients with non-small-cell lung cancer harboring TKI-sensitive EGFR mutations: an exploratory study

BACKGROUND The mechanism of primary resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in EGFR-mutant non-small-cell lung cancer (NSCLC) has not been clearly understood. PATIENTS AND METHODS Eleven patients exhibiting primary resistance (disease progression <3 months) were identified among 197 consecutive NSCLC patients with TKI-sensitive EGFR mutations who received EGFR TKIs at Seoul National University Hospital. Treatment-naïve tumors were examined for concurrent genetic alterations using fluorescence in situ hybridization and targeted deep sequencing of cancer-related genes. Deletion polymorphism of Bcl-2-interacting mediator of cell death (BIM) gene was examined to validate its predictive role for TKI outcome. RESULTS The median progression-free survival (PFS) for patients receiving EGFR TKIs was 11.9 months, and the response rate 78.8%. Among the 11 patients exhibiting primary resistance, a de novo T790M mutation was identified in one patient, and two exhibited mesenchymal-epithelial transition amplification and anaplastic lymphoma kinase fusion. Targeted deep sequencing identified no recurrent, coexistent drivers of NSCLC. Survival analysis revealed that patients with recurrent disease after surgery had a longer PFS than those with initial stage IV disease. However, BIM deletion polymorphism, line of treatment, EGFR genotype, and smoking were not predictive of PFS for EGFR TKIs. CONCLUSIONS We identified coexistent genetic alterations of cancer-related genes that could explain primary resistance in a small proportion of patients. Our result suggests that the mechanism of primary resistance might be heterogeneous.

Clinical manifestations and outcomes of the treatment of patients with GABAB encephalitis

Encephalitis associated with anti-γ-aminobutyric acid-B (GABAB) receptor antibodies has been identified recently. However, only a few cases have been reported to date and its clinical manifestations and prognosis have not been investigated systematically. We identified five cases of GABAB encephalitis in Korea. Here we present the clinical features, treatment responses, and brain positron emission tomography findings of the cases. The patients had a clinical triad of memory changes, seizure, and association with small-cell lung cancer. Early diagnosis and comprehensive immune modulation may provide a good outcome.

Efficacy and safety of liposome-encapsulated 4-n-butylresorcinol 0.1% cream for the treatment of melasma: A randomized controlled split-face trial

Melasma is an acquired pigmentary disorder that most commonly occurs in women of child‐bearing age. Melasma is therapeutically challenging, and most commercially available hypopigmenting agents include tyrosinase inhibitors, which regulate the rate‐limiting step of melanogenesis. 4‐n‐Butylresorcinol has received considerable attention as a novel hypopigmenting agent in the last 15 years because it has an inhibitory effect against tyrosinase and tyrosinase‐related protein‐1. However, the hypopigmenting effect of 4‐n‐butylresorcinol in human subjects has only been shown in a few studies. Liposome encapsulation is known to improve stabilization and enhance penetration of the product. Therefore, this study was conducted to evaluate the hypopigmenting efficacy and safety of liposome‐encapsulated 4‐n‐butylresorcinol 0.1% cream in patients with melasma. This was a randomized, double‐blind, vehicle‐controlled and split‐face comparison study. Twenty‐three patients with a clinical diagnosis of melasma were included. 4‐n‐Butylresorcinol 0.1% cream or vehicle was applied to each side of the face twice daily for 8 weeks. Clinical and photographic evaluations, Mexameter measurements and assessment of patient satisfaction and side‐effects were performed at baseline, 4 and 8 weeks. All subjects completed the study. Mexameter measurements demonstrated that the melanin index of the 4‐n‐butylresorcinol‐treated side showed a significant decrease when compared with the vehicle‐treated side after 8 weeks (P = 0.043). No adverse reactions were observed throughout the study. Subjectively, 4‐n‐butylresorcinol was considered to be efficacious in more than 60% of the patients after 8 weeks of treatment. In conclusion, liposome‐encapsulated 4‐n‐butylresorcinol 0.1% cream was well tolerated and showed significant higher efficacy than vehicle alone for the treatment of melasma.

Novel fusion transcripts in human gastric cancer revealed by transcriptome analysis

Gene fusion is involved in the development of various types of malignancies. Recent advances in sequencing technology have facilitated identification of gene fusions and have stimulated the research of this field in cancer. In the present study, we performed next-generation transcriptome sequencing in order to discover novel gene fusions in gastric cancer. A total of 282 fusion transcript candidates were detected from 12 gastric cancer cell lines by bioinformatic filtering. Among the candidates, we have validated 19 fusion transcripts, which are 7 inter-chromosomal and 12 intra-chromosomal fusions. A novel DUS4L–BCAP29 fusion transcript was found in 2 out of 12 cell lines and 10 out of 13 gastric cancer tissues. Knockdown of DUS4L–BCAP29 transcript using siRNA inhibited cell proliferation. Soft agar assay further confirmed that this novel fusion transcript has tumorigenic potential. We also identified that microRNA-coding gene PVT1, which is amplified in double minute chromosomes in SNU-16 cells, is recurrently involved in gene fusion. PVT1 produced six different fusion transcripts involving four different genes as fusion partners. Our findings provide better insight into transcriptional and genetic alterations of gastric cancer: namely, the tumorigenic effects of transcriptional read-through and a candidate region for genetic instability.

Clinical manifestations of patients with CASPR2 antibodies.

Contactin-associated protein-like 2 (CASPR2) is one of the target antigens of voltage-gated potassium channels (VGKC) complex antibodies. There has been relatively little information in the literature regarding CASPR2 autoimmunity, especially in Asian population. We investigated the presence of CASPR2 antibodies in patients with presumed autoimmune neurological disorders and described the clinical features, laboratory findings, and responses to immunotherapy. Five patients were identified to be positive for CASPR2 antibodies. The results obtained here suggested that CASPR2 antibodies might be the possible cause of epilepsy even in the absence of typical features of limbic encephalitis and that immunotherapy could provide a favorable outcome.

Distinct Expression of Long Non-Coding RNAs in an Alzheimer's Disease Model

With the recent advancement in transcriptome-wide profiling approach, numerous non-coding transcripts previously unknown have been identified. Among the non-coding transcripts, long non-coding RNAs (lncRNAs) have received increasing attention for their capacity to modulate transcriptional regulation. Although alterations in the expressions of non-coding RNAs have been studied in Alzheimers disease (AD), most research focused on the involvement of microRNAs, and comprehensive expression profiling of lncRNAs in AD has been lacking. In this study, microarray analysis was performed to procure the expression profile of lncRNAs dysregulated in a triple transgenic model of AD (3xTg-AD). A total of 4,622 lncRNAs were analyzed: 205 lncRNAs were significantly dysregulated in 3xTg-AD compared with control mice, and 230 lncRNAs were significantly dysregulated within 3xTg-AD in an age-dependent manner (≥2.0-fold, p < 0.05). Among these, 27 and 15 lncRNAs, respectively, had adjacent protein-coding genes whose expressions were also significantly dysregulated. A majority of these lncRNAs and their adjacent genes shared the same direction of dysregulation. For these pairs of lncRNAs and adjacent genes, significant Gene Ontology terms were DNA-dependent regulation of transcription, transcription regulator activity, and embryonic organ morphogenesis. One of the most highly upregulated lncRNAs had a 395 bp core sequence that overlapped with multiple chromosomal regions. This is the first study that comprehensively identified dysregulated lncRNAs in 3xTg-AD mice and will likely facilitate the development of therapeutics targeting lncRNAs in AD.

Insulin-like Growth Factor–Binding Protein Contributes to the Proliferation of Less Proliferative Cells in Forming Skin Equivalents

In this study, the effects and the mediating factors of dermal cells on the epidermal regenerative ability were investigated. Human epidermal cells were separated into rapidly adhering (RA) cells and slowly adhering (SA) cells and used for culturing skin equivalents (SEs). For dermal part, normal human fibroblasts, dermal sheath cells (DSCs), and dermal papilla cells were used. SEs produced using SA cells and DSCs showed a thicker epidermis and higher expressions of alpha(6)- and beta1-integrin than SEs using SA cells and normal fibroblasts showed. We hypothesized that DSCs may secrete specific cytokines that can influence the regenerative potential of epidermal cells, and compared cytokine secretion by DSCs and normal human fibroblasts. Using RayBio human cytokine antibody array C (series 1000), 120 cytokines were tested. Results showed that DSCs produced a much greater amount of insulin-like growth factor-binding protein (IGFBP-2), angiogenin, and BMP-6 than normal human fibroblasts produced. On the basis of the cytokine antibody array, we next investigated whether IGFBP-2, angiogenin, or BMP-6 has effects on SEs reconstruction. The addition of IGFBP-2 induced a thicker and more mature epidermis and higher expressions of alpha(6)- and beta1-integrin, whereas BMP-6 exhibited little effect. Thus, the SEs with IGFBP-2 showed almost the same morphology of the SEs using DSCs. Further, p63, a putative keratinocyte stem cell marker, was more frequently observed in the basal layer of SE with IGFBP-2. In conclusion, IGFBP-2 is a major factor from DSCs that affects epidermal regenerative capacity of skin and may play an important role for stemness maintenance in human epidermal keratinocytes.

The HLA-A*2402/Cw*0102 haplotype is associated with lamotrigine-induced maculopapular eruption in the Korean population.

The use of lamotrigine (LTG) can be limited by the occurrence of cutaneous adverse drug reactions (cADRs) that range from maculopapular eruption (MPE) to the more severe Stevens‐Johnson syndrome and toxic epidermal necrolysis. A few human leukocyte antigen (HLA)–related genetic risk factors for carbamazepine‐induced cADR have been identified. However, the HLA‐related genetic risk factors associated with LTG‐induced cADR are not yet well known. We performed HLA genotyping in 50 Korean patients with epilepsy, including 21 patients presenting LTG‐induced MPE and 29 LTG‐tolerant patients. A significant association between the HLA‐A*2402 allele and LTG‐induced MPE was identified, in comparison with the LTG‐tolerant group (odds ratio [OR] 4.09, p = 0.025) and the general Korean population (OR 3.949, p = 0.005). The frequencies of the Cw*0102 or Cw*0702 alleles were significantly higher in the LTG‐MPE group than in the Korean population, whereas the frequency of the A*3303 allele was lower. The coexistence of the A*2402 and Cw*0102 alleles was significantly associated with the LTG‐MPE group when compared to the LTG‐tolerant group (OR 7.88, p = 0.007). In addition, the Cw*0701 allele was more frequent in the LTG‐tolerant group than in the Korean population. These findings suggest the presence of HLA‐related genetic risk factors for LTG‐induced MPE in the Korean population.

Early diagnosis of Alzheimer's disease from elevated olfactory mucosal miR-206 level.

MicroRNA-206, which suppresses the expression of brain-derived neurotrophic factor, is known to be elevated in the brains of Alzheimer’s disease (AD) patients. We performed intranasal biopsy of the olfactory epithelia of early dementia patients (n = 24) and cognitively healthy controls (n = 9). Patients with significant depression (n = 8) were analyzed separately, as their cognitive impairments were thought to be caused by their depression. Real-time PCR was performed on the biopsied tissues. The relative microRNA-206 level exhibited a 7.8-fold increase (P = 0.004) in the mild cognitive impairment group (CDR 0.5; n = 13) and a 41.5-fold increase (P < 0.001) in the CDR 1 group (n = 11). However, this level was not increased in the depression group, even in those with cognitive decline. Using the optimal cutoff value, the sensitivity/specificity for diagnosing CDR 0.5 and CDR 1 dementia were 87.5%/94.1% and 90.9%/93.3%, respectively. In ROC analysis, the AUCs were 0.942 and 0.976 in the CDR 0.5 and CDR 1 groups, respectively. The olfactory mucosal microRNA-206 level and cognitive assessment scores were significantly correlated in the non-depressed subjects with cognitive impairment. In conclusion, the olfactory mucosal microRNA-206 level can be easily measured, and it can be utilized as an excellent biomarker for the diagnosis of early AD, including mild cognitive impairment.