CYB5R3 functions as a tumor suppressor by inducing ER stress-mediated apoptosis in lung cancer cells via the PERK-ATF4 and IRE1α-JNK pathways.

Cytochrome b5 reductase 3 (CYB5R3) is involved in various cellular metabolic processes, including fatty acid synthesis and drug metabolism. However, the role of CYB5R3 in cancer development remains poorly understood. Here, we show that CYB5R3 expression is downregulated in human lung cancer cell lines and tissues. Adenoviral overexpression of CYB5R3 suppresses lung cancer cell growth in vitro and in vivo. However, CYB5R3 deficiency promotes tumorigenesis and metastasis in mouse models. Transcriptome analysis revealed that apoptosis- and endoplasmic reticulum (ER) stress-related genes are upregulated in CYB5R3-overexpressing lung cancer cells. Metabolomic analysis revealed that CYB5R3 overexpression increased the production of nicotinamide adenine dinucleotide (NAD+) and oxidized glutathione (GSSG). Ectopic CYB5R3 is mainly localized in the ER, where CYB5R3-dependent ER stress signaling is induced via activation of protein kinase RNA-like ER kinase (PERK) and inositol-requiring enzyme 1 alpha (IRE1α). Moreover, NAD+ activates poly (ADP-ribose) polymerase16 (PARP16), an ER-resident protein, to promote ADP-ribosylation of PERK and IRE1α and induce ER stress. In addition, CYB5R3 induces the generation of reactive oxygen species and caspase-9-dependent intrinsic cell death. Our findings highlight the importance of CYB5R3 as a tumor suppressor for the development of CYB5R3-based therapeutics for lung cancer.

A Novel Mutation in the MBTPS2 Gene Resulting in Ichthyosis Follicularis, Atrichia, and Photophobia Syndrome.

Ichthyosis follicularis, atrichia, and photophobia (IFAP) syndrome is a rare genetic disorder caused by mutations in the MBTPS2 gene. It is characterized by ichthyosis and alopecia from birth. Photophobia may be present in infancy or early childhood. Its mode of inheritance is X-linked recessive; thus, it mostly affects male. The disease severity varies, ranging from mild cases limited to the skin to the severe variant involving multiple extracutaneous features. A 7-year-old boy presented with scanty hair on scalp and eyebrows at birth. On physical examination, scaly patches were observed on the whole body and spiky follicular hyperkeratotic papules were observed on the face and trunk. He also suffered from severe photophobia. Histopathological examination of the scalp showed miniaturized hair follicles without perifollicular fibrosis. Genetic analysis revealed a novel mutation in the MBTPS2 gene which was a homozygous missense mutation of c.245T>C leading to an amino-acid substitution from phenylalanine to serine (p.Phe82Ser). We diagnosed this patient with IFAP syndrome. To date, 25 pathogenic MBTPS2 gene mutations have been identified. To our knowledge, c.245T>C is a novel homozygous missense mutation in the MBTPS2 gene, which has not been reported in Human Gene Mutation Database, ClinVar Database, and Leiden Open Variation Database. Previous reports suggested genotype-phenotype correlations in the MBTPS2 gene mutations. Supported by a previous notion that genotype correlates with phenotype, this novel mutation can be a predictive factor for the mild form of IFAP syndrome, restricted to the classic symptom triad.

The efficacy and safety of topical 10% potassium hydroxide for molluscum contagiosum: a systematic review and meta-analysis.

BACKGROUND: Molluscum contagiosum (MC) is a self-limited cutaneous viral infection. Topical 10% potassium hydroxide (KOH) has been used for treating MC. However, it remains unclear whether it is beneficial or not to apply topical 10% KOH for treating MC. METHODS: To confirm the efficacy and safety of topical 10% KOH compared with placebo as well as other treatments for MC, meta-analysis was used. Up to September 2020, we performed a comprehensive search of literature based on three databases with following keywords including 'molluscum contagiosum' and 'potassium hydroxide'. RESULTS: Our meta-analyses demonstrated a significant difference between topical 10% KOH and placebo for complete clearance of MC (RR: 2.96, 95% CI: 1.69 - 5.17, p = .0001), while there were no statistical differences between them in the number of patients with adverse events (RR: 1.73, 95% CI: 0.67 - 4.45, p = .2562). Also, topical 10% KOH was as effective as mechanical treatments for MC (RR: 0.95, 95% CI: 0.84 - 1.07, p = .3833). CONCLUSION: We demonstrate that application of topical 10% KOH may be one of effective and appropriate methods for the treatment of MC compared with awaiting spontaneous resolution due to its safety and effectiveness.

Cryosurgery as a Minimally Invasive Alternative Treatment for a Patient with Erosive Adenomatosis of the Nipple.

Erosive adenomatosis of the nipple (EAN), also known as nipple adenoma, florid papillomatosis, or papillary adenoma of the nipple, is a benign neoplasm originating from a lactiferous duct of the breast. Although the potential for malignant change is invariably negligible, the nature of the disease is quite intractable despite several treatment methods. Surgical excision is known as the treatment of choice, but this invasive approach is generally not acceptable to the vast majority of patients due to the cosmetic outcomes. Cryosurgery could be an alternative choice to preserve the structure of the nipple-areola complex, though its application has not been studied due to the paucity of cases. A 22-year-old female presented with a unilateral, crater-like erosion of the left nipple with serosanguineous discharge. The skin biopsy revealed proliferation of tubular structures, which corresponded to EAN. She was treated with 4 sessions of cryosurgery (open cryospray with liquid nitrogen) over 6 months, and the skin lesion resolved completely without any recurrence for 12 months. Although further study is required to determine the optimal treatment regimen for EAN, cryosurgery should be considered as an effective option to surgical excision.

Upregulation of DJ-1 expression in melanoma regulates PTEN/AKT pathway for cell survival and migration.

Cutaneous melanoma is known to be one of the most dangerous skin cancers because of its metastatic functions. Today, it is essential to investigate specific biomarkers for the target treatment in many diseases including cancers. DJ-1 protein, also known as Parkinson disease 7, has various functions associated with cancer progression including cell survival and migration. Phosphatase and tensin homolog (PTEN) is a tumor suppressor that regulates the PI3K/AKT signaling pathway and its mutations have been reported to frequently occur in many cancers such as thyroid, breast and skin. Recently, DJ-1 has been identified as a negative regulator of PTEN in many human cancer cells. However, the impacts and relationship of DJ-1 and PTEN have not been studied yet in melanoma. To confirm the expression of DJ-1 and PTEN in melanoma compared to normal skin tissues and find out functions of DJ-1 in melanoma cells, Western blot analysis and immunohistochemical staining were used. Transfection of G361 cells with DJ-1-specific small interfering RNA was performed to figure out the roles of DJ-1 and the relationship between DJ-1 and PTEN in melanoma cells. In our study, the DJ-1 protein was significantly increased with loss of PTEN protein in melanoma compared to that in normal skin. Inhibition of DJ-1 in G361 cells induced apoptosis, and suppressed cell survival and migration. Furthermore, suppression of DJ-1 in G361 cells increased the expression of cleaved caspase-3, cleaved PARP, Bax, p53, and Daxx as well as PTEN, while it decreased expression of survivin, caspase-3, and PARP. Also, downregulated DJ-1 inhibited phosphorylation of AKT in G361 cells. Collectively, DJ-1 overexpression could affect the proliferative and invasive capabilities of melanoma cells via regulating the PTEN/AKT pathway and apoptosis-related proteins. This study suggests that DJ-1 may be a potential target for the treatment of melanoma.

The efficacy of fractional carbon dioxide laser combined with narrow-band ultraviolet B phototherapy for non-segmental vitiligo: a systematic review and meta-analysis.

Fractional carbon dioxide (CO2) laser has been used with conventional treatments for vitiligo, demonstrating more effectiveness compared with conventional treatments alone. Especially, fractional CO2 laser combined with narrow-band ultraviolet B (NB-UVB) was shown to induce more improvement compared with NB-UVB monotherapy for treating stable non-segmental vitiligo. However, the effectiveness of fractional CO2 laser plus NB-UVB for the treatment of non-segmental vitiligo remains controversial. Therefore, this study aimed to confirm the safety and efficacy of fractional CO2 laser combined with NB-UVB compared with NB-UVB monotherapy in stable non-segmental vitiligo. We searched the data from different databases, including Cochrane, Embase, and PubMed up to January 2020. Four randomized controlled trials (RCTs) for comparison between fractional CO2 laser plus NB-UVB and NB-UVB monotherapy in patients with stable non-segmental vitiligo were included. We performed meta-analyses for repigmentation improvement and patient satisfaction as well as subgroup analyses based on acral or non-acral vitiligo, according to the PRISMA guidelines. The combination treatment showed more superior results than NB-UVB monotherapy (≥ 75% repigmentation, RR 4.60, 95% CI 1.19-17.74; ≥ 50% repigmentation, RR 2.24, 95% CI 0.45-11.17; < 25% repigmentation, RR 0.81, 95% CI 0.60-1.08). Also, fractional CO2 laser plus NB-UVB significantly improved acral and non-acral vitiligo compared with NB-UVB monotherapy (standard mean difference (SMD) 1.24, 95% CI 0.66-1.82; SMD 1.14, 95% CI 0.67-1.60, respectively), while it increased markedly patient satisfaction compared with NB-UVB monotherapy (SMD 1.12, 95% CI 0.66-1.58). Collectively, this meta-analysis suggested that fractional CO2 laser combined with NB-UVB might be more effective for treating non-segmental vitiligo than NB-UVB monotherapy.

Public Interest in Acne on the Internet: Comparison of Search Information From Google Trends and Naver.

BACKGROUND: Acne vulgaris is a common skin disease primarily affecting young adults. Given that the internet has become a major source of health information, especially among the young, the internet is a powerful tool of communication and has a significant influence on patients. OBJECTIVE: This study aimed to clarify the features of patients' interest in and evaluate the quality of information about acne vulgaris on the internet. METHODS: We compared the search volumes on acne vulgaris with those of other dermatological diseases using Google Trends from January 2004 to August 2019. We also determined the search volumes for relevant keywords of acne vulgaris on Google and Naver and evaluated the quality of answers to the queries in KnowledgeiN. RESULTS: The regression analysis of Google Trends data demonstrated that the patients' interest in acne vulgaris was higher than that for other dermatological diseases, such as atopic dermatitis (ß=-20.33, 95% CI -22.27 to -18.39, P<.001) and urticaria (ß=-27.09, 95% CI -29.03 to -25.15, P<.001) and has increased yearly (ß=2.38, 95% CI 2.05 to 2.71, P<.001). The search volume for acne vulgaris was significantly higher in the summer than in the spring (ß=-5.04, 95% CI -9.21 to -0.88, P=.018) and on weekends than on weekdays (ß=-6.68, 95% CI -13.18 to -0.18, P=.044). The most frequently searched relevant keywords with "acne vulgaris" and "cause" were "stress," "food," and "cosmetics." Among food, the 2 highest acne vulgaris-related keywords were milk and wheat in Naver and coffee and ramen in Google. The queries in Naver KnowledgeiN were mostly answered by a Korean traditional medicine doctor (53.4%) or the public (33.6%), but only 12.0% by dermatologists. CONCLUSIONS: Physicians should be aware of patients' interest in and beliefs about acne vulgaris to provide the best patient education and care, both online and in the clinic.

The First Case of an Infant with Familial A20 Haploinsufficiency in Korea.

Haploinsufficiency of A20 (HA20) is a newly described autoinflammatory disease caused by loss-of-function mutations in the TNFAIP3 gene. Clinical phenotypes are heterogenous and resemble Behçet's disease, juvenile idiopathic arthritis, inflammatory bowel disease, or periodic fever syndrome, with symptoms developing at an early age. Here, we report the first case of infantile familial HA20 in Korea, which mimics neonatal lupus erythematosus (NLE). A 2-month-old infant exhibited symptoms including recurrent fever, erythematous rashes, and oral ulcers, with elevated liver enzymes, and tested positive for several autoantibodies, similar to systemic lupus erythematosus (SLE); therefore, she was suspected to have NLE. However, six months after birth, symptoms and autoantibodies persisted. Then, we considered the possibility of other diseases that could cause early onset rashes and abnormal autoantibodies, including autoinflammatory syndrome, monogenic SLE, or complement deficiency, all of which are rare. The detailed family history revealed that her father had recurrent symptoms, including oral and genital ulcers, knee arthralgia, abdominal pain, and diarrhea. These Behcet-like symptoms last for many years since he was a teenager, and he takes medications irregularly only when those are severe, but doesn't want the full-scale treatment. Whole-exome sequencing was conducted to identify a possible genetic disorder, which manifested as pathogenic variant nonsense mutation in the TNFAIP3 gene, leading to HA20. In conclusion, HA20 should be considered in the differential diagnosis of an infant with an early-onset dominantly inherited inflammatory disease that presents with recurrent oral and genital ulcerations and fluctuating autoantibodies. Additionally, it also should be considered in an infant with suspected NLE, whose symptoms and abnormal autoantibodies persist.

The efficacy of bleomycin for treating keloid and hypertrophic scar: A systematic review and meta-analysis.

BACKGROUND: Pathologic scars can lead to itching, erythema, and psychological stress due to cosmetic problems. Bleomycin, one of anticancer agents, has been used for treating keloid or hypertrophic scar. Some studies have shown that bleomycin can induce markedly scar improvement. AIMS: To evaluate the efficacy of bleomycin compared to corticosteroid as well as other treatments for keloid or hypertrophic scar using meta-analysis methods. METHODS: A computerized search was performed in different databases including Cochrane, Embase, and PubMed. Three randomized controlled trials (RCTs) and two controlled clinical trials (CCTs) were included. Then, statistical analyses of extracted outcome data from the studies were calculated using Rex (version 3.0.1; RexSoft Inc). RESULTS: Scar improvement was significantly increased in the bleomycin group compared to the triamcinolone acetonide (TAC) group (SMD: 0.59, 95% CI: 0.30-0.88, P < .0001). In addition, there was also statistically significant difference between the bleomycin group and the 5-FU group (SMD: 1.37, 95% CI: 0.88-1.85, P < .0001). Bleomycin increased relatively scar improvement compared to TAC combined with 5-FU, although there was no statistical difference (SMD: 0.63, 95% CI: -0.59-1.84, P = .3108). Furthermore, bleomycin demonstrated significantly increased improvement of scar compared to TAC combined with cryotherapy (SMD: 1.11, 95% CI: 0.48-1.74, P = .0006). CONCLUSIONS: This meta-analysis found that bleomycin was more effective for treating keloid or hypertrophic scar than other treatments including TAC, 5-FU, TAC combined with 5-FU, and TAC combined with cryotherapy. However, further comprehensive studies, including randomized controlled trials, are needed to perform objective analysis.

Overexpression of Nrf2 promotes colon cancer progression via ERK and AKT signaling pathways.

PURPOSE: We investigated the expression of Nrf2 in colorectal cancer and its correlation with clinicopathological characteristics as well as mechanisms and roles of Nrf2 expression including cell signaling pathway, survival, proliferation, and migration. METHODS: Nrf2 expression was measured in 12 and 30 different colorectal cancer (CRC) tissues by western blot (WB) and immunohistochemistry (IHC), respectively. SW480 cells were used for cell proliferation and cell migration tests. The correlation between the expression of Nrf2 and clinicopathologic parameters were evaluated using the chi-square or Fisher exact test. Data are expressed as the mean ± standard deviation for 3 independent experiments. P < 0.05 was considered statistically significant. RESULTS: Analysis of WB demonstrated that Nrf2 proteins were increased in CRC tissues, and decreased in normal tissues. IHC staining showed that the Nrf2 expression was elevated in CRC tissues, compared to matched normal tissues. When SW480 cells were suppressed with small interfering RNA of Nrf2, cell viability was inhibited, and cell apoptosis was increased. These results were found along with suppression of the phosphorylated form of extracellular signal-regulated kinase 1/2 and AKT. CONCLUSION: This study suggests that overexpression of Nrf2 may be related to carcinogenesis and progression of CRC.

Global Analysis of Intercellular Homeodomain Protein Transfer.

The homeodomain is found in hundreds of transcription factors that play roles in fate determination via cell-autonomous regulation of gene expression. However, some homeodomain-containing proteins (HPs) are thought to be secreted and penetrate neighboring cells to affect the recipient cell fate. To determine whether this is a general characteristic of HPs, we carried out a large-scale validation for intercellular transfer of HPs. Our screening reveals that intercellular transfer is a general feature of HPs, but it occurs in a cell-context-sensitive manner. We also found the secretion is not solely a function of the homeodomain, but it is supported by external motifs containing hydrophobic residues. Thus, mutations of hydrophobic residues of HPs abrogate secretion and consequently interfere with HP function in recipient cells. Collectively, our study proposes that HP transfer is an intercellular communication method that couples the functions of interacting cells.

Clinical differences between segmental nevus depigmentosus and segmental vitiligo.

Segmental nevus depigmentosus and segmental vitiligo can be difficult to differentiate from each other. Differential diagnosis of these two diseases is important because they have significantly different prognoses and psychological effects. The purpose of this study is to identify clinical clues that may be helpful in differentiating these two diseases. We enrolled 63 patients with segmental nevus depigmentosus and 149 patients with segmental vitiligo. Sex, age of onset, sites involved, dermatomal distribution, margin of lesion and presence of poliosis were evaluated in both groups. The age of onset was less than 10 years in 96.8% of segmental nevus depigmentosus and 28.9% of segmental vitiligo cases. Trunk (36.5%) and cervical (38.1%) dermatomes were the most commonly involved in segmental nevus depigmentosus and face (67.1%) and trigeminal (64.4%) dermatomes in segmental vitiligo. The average number of dermatomes involved in truncal lesions was different in segmental nevus depigmentosus and segmental vitiligo (2.71 vs 1.62, P = 0.001). Segmental vitiligo on the face, neck and trunk appeared closer to the axis than segmental nevus depigmentosus (P < 0.001). Segmental nevus depigmentosus and segmental vitiligo showed significantly different margins (90.5% and 41.6% serrated, respectively; P < 0.001). We observed clinical differences between patients with segmental nevus depigmentosus and those with segmental vitiligo. Distribution (site, distance to axis, dermatome), vertical width, margin of lesion and presence of poliosis can be helpful in differentiating segmental nevus depigmentosus and segmental vitiligo.

Flavonoid morin inhibits proliferation and induces apoptosis of melanoma cells by regulating reactive oxygen species, Sp1 and Mcl-1.

Reactive oxygen species (ROS) is associated with cancer progression in different cancers, including melanoma. It also affects specificity protein (Sp1), a transcription factor. Flavonoid morin is known to inhibit growth of cancer cells, including lung cancer and breast cancer. Herein, we hypothesized that morin can inhibit cancer activities in melanoma by altering ROS generation. The aim of this study is to determine the effects of morin and its underlying mechanisms in melanoma cells. Effects of morin on cell proliferation and apoptosis were determined using standardized assays. Changes in pro-apoptotic and anti-apoptotic proteins were analyzed by western blot analysis. Cellular ROS levels and mitochondrial function were evaluated by measuring DCF-DA fluorescence and rhodamine-123 fluorescence intensities, respectively. Morin induced ROS production and apoptosis, as presented by increased proportion of cells with Annexin V-PE(+) staining and sub-G0/G1 peak in cell cycle analysis. It also downregulated Sp1, Mcl-1, Bcl-2, and caspase-3 but upregulated cleaved caspase-3, Bax, and PUMA. In immunohistochemical staining, Sp1 was overexpressed in melanoma tissues compared to normal skin tissues. Collectively, our data suggest that morin can induce apoptosis of melanoma cells by regulating pro-apoptotic and anti-apoptotic proteins through ROS, and may be a potential substance for treatment of melanoma.

Evaluation of long-term efficacy of finasteride in Korean men with androgenetic alopecia using the basic and specific classification system.

Finasteride 1 mg is considered to be the standard treatment method for male androgenetic alopecia (AGA). However, there have only been a few studies investigating its long-term efficacy. Moreover, its effect on various types of AGA remains unknown. In this study, the authors investigated the 5-year efficacy of finasteride 1 mg in Korean men with AGA and analyzed the changes in hair growth according to the distribution of hair loss. The medical records of male AGA patients who were treated with oral finasteride for a period of at least 5 years at two university hospitals were retrospectively reviewed. Patients' photographs were evaluated using the basic and specific (BASP) classification and investigator's global assessment. Of the total 126 patients, 108 (85.7%) showed improvement after 5 years of treatment. According to the BASP classification, hair loss of the anterior hair line (basic type), vertex (V type), and frontal area (F type) was improved in 44.4%, 89.7% and 61.2% of patients, respectively. The V type showed a more rapid and steady improvement compared with the other types. Progression of alopecia after peak improvement was seen in 10.3% of cases of the V type, 16.2% of the F type and 0% of the basic type. In conclusion, finasteride 1 mg showed a sustainable effect for at least 5 years in Korean male AGA patients. The exact time points showing signs of first clinical improvement and sustainability were different depending on the type of alopecia.