Immunotherapy for Glioblastoma: Current State, Challenges, and Future Perspectives.

Glioblastoma is the most lethal intracranial primary malignancy by no optimal treatment option. Cancer immunotherapy has achieved remarkable survival benefits against various advanced tumors, such as melanoma and non-small-cell lung cancer, thus triggering great interest as a new therapeutic strategy for glioblastoma. Moreover, the central nervous system has been rediscovered recently as a region for active immunosurveillance. There are vibrant investigations for successful glioblastoma immunotherapy despite the fact that initial clinical trial results are somewhat disappointing with unique challenges including T-cell dysfunction in the patients. This review will explore the potential of current immunotherapy modalities for glioblastoma treatment, especially focusing on major immune checkpoint inhibitors and the future strategies with novel targets and combo therapies. Immune-related adverse events and clinical challenges in glioblastoma immunotherapy are also summarized. Glioblastoma provides persistent difficulties for immunotherapy with a complex state of patients' immune dysfunction and a variety of constraints in drug delivery to the central nervous system. However, rational design of combinational regimens and new focuses on myeloid cells and novel targets to circumvent current limitations hold promise to advent truly viable immunotherapy for glioblastoma.

Therapeutic Effects of Mesenchymal Stem Cells on a Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis Model.

Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are the most severe cutaneous drug hypersensitivity reactions, which are unpredictable adverse drug reactions. SJS/TEN is associated with significant mortality and morbidity; however, effective treatment is difficult. Mesenchymal stem cells (MSCs) are well-known for their anti-inflammatory and tissue regeneration properties. The purpose of the present study was to verify whether MSCs could be applied for the treatment of SJS/TEN. We developed an SJS/TEN mouse model using peripheral blood mononuclear cells from a lamotrigine-induced SJS patient. MSCs were injected into the model to verify the treatment effect. In SJS model mice treated with MSCs, ocular damage rarely occurred, and apoptosis rate was significantly lower. We demonstrated a therapeutic effect of MSCs on SJS/TEN, with these cells presenting a potential novel therapy for the management of this disorder.

3-Hydroxy-2-(trialkylsilyl)phenyl Triflate: A Benzyne Precursor Triggered via 1,3-C-sp2-to-O Silyl Migration.

3-Hydroxy-2-(trialkylsilyl)phenyl triflates are presented as new versatile hydroxyaryne precursors. These are base-activated aryne precursors induced via a C-sp2-to-O 1,3-Brook rearrangement. The reaction of various arynophiles and 3-trialkylsiloxybenzyne generated from 3-hydroxy-2-(trialkylsilyl)phenyl triflate efficiently afforded highly regioselective phenol derivatives. Furthermore, through crossover experiments, the intramolecular mechanism of silyl migration was demonstrated.

Molecular Detection of Dirofilaria immitis Specific Gene from Infected Dog Blood Sample Using Polymerase Chain Reaction.

BACKGROUND: Dirofilaria immitis, a filarial nematode, is the most important parasite-affecting dogs, causing cardiopulmonary dirofilariasis. Current diagnostic tools for detecting D. immitis include morphological assays, antigen detection, and X-ray. Herein, we developed a method for the molecular detection of D. immitis in blood using polymerase chain reaction (PCR). METHODS: The study was conducted at Eulji University, Republic of Korea in 2016. To detect D. immitis-specific gene regions, we aligned the cytochrome c oxidase subunit I (COI) genes of seven filarial nematodes and designed primers targeting the unique region. We used dog glyceraldehyde-3-phosphate dehydrogenase (GAPDH)-targeted primers as the internal control. We conducted PCR-amplified genomic DNA from canine blood samples. The products were confirmed by sequencing. RESULTS: Gene alignment revealed a D. immitis COI-specific gene region, and the activity of designed primers was confirmed by PCR and sequencing. Plasmid DNA made from the PCR products was a positive control. The limit of detection for our method was 50 copies. The D. immitis COI and dog GAPDH genes could be discriminated from blood samples simultaneously. CONCLUSION: This study provides a method for highly specific and sensitive molecular diagnosis of D. immitis used as a diagnostic and therapeutic tool from the early stage of infection.

Gallic acid regulates body weight and glucose homeostasis through AMPK activation.

Gallic acid [3,4,5-trihydroxybenzoic acid (GA)], a natural phytochemical, is known to have a variety of cellular functions including beneficial effects on metabolic syndromes. However, the molecular mechanism by which GA exerts its beneficial effects is not known. Here we report that GA plays its role through the activation of AMP-activated protein kinase (AMPK) and by regulating mitochondrial function via the activation of peroxisome proliferator-activated receptor-γ coactivator1α (PGC1α). Sirtuin 1 (Sirt1) knockdown significantly blunted GA's effect on PGC1α activation and downstream genes, suggesting a critical role of the AMPK/Sirt1/PGC1α pathway in GA's action. Moreover, diet-induced obese mice treated with GA showed significantly improved glucose and insulin homeostasis. In addition, the administration of GA protected diet-induced body weight gain without a change in food intake. Biochemical analyses revealed a marked activation of AMPK in the liver, muscle, and interscapular brown adipose tissue of the GA-treated mice. Moreover, uncoupling protein 1 together with other genes related to energy expenditure was significantly elevated in the interscapular brown adipose tissue. Taken together, these results indicate that GA plays its beneficial metabolic roles by activating the AMPK/Sirt1/PGC1α pathway and by changing the interscapular brown adipose tissue genes related to thermogenesis. Our study points out that targeting the activation of the AMPK/Sirt1/PGC1α pathway by GA or its derivatives might be a potential therapeutic intervention for insulin resistance in metabolic diseases.

Improvement in skin wrinkles using a preparation containing human growth factors and hyaluronic acid serum.

BACKGROUND: Skin aging is accompanied by wrinkle formation. At some sites, such as the periorbital skin, this is a relatively early phenomenon. OBJECTIVE: We evaluated the anti-wrinkle effect of a preparation containing human growth factor and hyaluronic acid serum on periorbital wrinkles (crow's feet). MATERIALS AND METHODS: In total, 23 Korean women (age range: 39-59 years), who were not pregnant, nursing, or undergoing any concurrent therapy, were enrolled in this study. All the patients completed an 8-week trial of twice-daily application of human growth factor and hyaluronic acid serum on the entire face. Efficacy was based on a global photodamage score, photographs, and image analysis using replicas and visiometer analysis every 4 weeks. The standard wrinkle and roughness parameters used in assessing skin by visiometer were calculated and statistically analyzed. RESULTS: Periorbital wrinkles were significantly improved after treatment, with improvements noted both by physician's assessment and visiometer analysis. CONCLUSION: Topical application of human growth factor and hyaluronic acid was beneficial in reducing periorbital wrinkles.

Reduction in facial hyperpigmentation after treatment with a combination of topical niacinamide and tranexamic acid: a randomized, double-blind, vehicle-controlled trial.

BACKGROUND: Facial hyperpigmentation occurs in multiple conditions. In addition, many Asian women desire a lighter skin color. Thus, there is a need for the development of skin lightening agents, and niacinamide and tranexamic acid (TXA) are promising candidates. OBJECTIVE: To assess the effectiveness of a combination of niacinamide and TXA as a topical moisturizing formulation for treatment of irregular facial pigmentation. MATERIALS AND METHODS: A total of 42 Korean women (age range: 30-60 years) who were not pregnant, nursing, or undergoing any concurrent therapy were enrolled in this study for 8 weeks. Subjects used a twice-daily regimen of either a moisturizing cream containing 2% niacinamide + 2% TXA (test formulation; n = 21) or cream vehicles (vehicle control; n = 21) in addition to an assigned sunscreen each morning. Pigmentation was measured objectively using a mexameter and chromameter, in addition to physicians' assessment using clinical photographs. RESULTS: The niacinamide + TXA formulation regimen was significantly (P < 0.05) more effective than the vehicle control formulation regimen in reducing the appearance of pigmentation. CONCLUSION: A formulation containing the combination of niacinamide + TXA reduced the appearance of irregular pigmentation, providing an effect beyond that achieved with sunscreen.

Appropriate timing for thyroidectomy scar treatment using a 1,550-nm fractional erbium-glass laser.

BACKGROUND: Surgical scarring is a common cosmetic problem that occurs in various surgical fields, including dermatology. Many trials have been conducted to determine how to prevent this distressing scar formation. A 1,550-nm fractional erbium-glass laser has been used to improve the appearance of surgical scars, but an appropriate treatment time has not been established. OBJECTIVES: To determine the appropriate time to apply 1,550-nm fractional erbium-glass laser treatment for thyroidectomy scars. MATERIALS AND METHODS: Korean patients with linear surgical suture lines after thyroidectomy (N = 65) were treated using a 1,550-nm fractional erbium-glass laser. Patients were divided into three groups according to postoperative treatment time. Laser treatment was started in 40, 15, and 10 patients 3 weeks, 3 months, and 6 months postoperatively, respectively. Each patient was treated three times at 1-month intervals using the same parameters (14 mJ, 100 spots/cm(2) , 2 passes). RESULTS: Mean Vancouver Scar Scale scores were significantly lower after laser treatment (p < .01), with the greatest difference in the group that began treatment 3 weeks postoperatively. Global assessment also indicated better cosmetic outcomes in the 3-week postoperative treatment group. CONCLUSION: Early postoperative 1,550-nm fractional erbium-glass laser treatment of thyroidectomy scars is more effective than later treatment.

Autoerythrocyte sensitization syndrome presenting with general neurodermatitis.

Autoerythrocyte sensitization syndrome (AES) was first described by Gardner and Diamond in 1955, when four women with painful bruising were depicted. Patients with AES typically present with the development of recurrent, spontaneous, painful ecchymosis, frequently preceded by a prodrome of pain or itching of the skin. The patients are sensitive to their own red blood cells injected intradermally, and underlying coagulopathies are thought to be absent. We introduce a 70-year-old woman presenting with recurrent episodes of painful bruising on the trunk and extremities.

Inhibitory effects of Saururi chinensis extracts on melanin biosynthesis in B16F10 melanoma cells.

Saururus chinensis has been used in folk medicine in Korea for the treatment of edema, jaundice, gonorrhea, and several inflammatory diseases. Saururi chinensis extracts (SCE) have demonstrated anti-inflammatory and anti-oxidant activities, as well as anti-asthmatic, antihypertensive, anti-angiogenic, and therapeutic activities for atopic dermatitis. However, the inhibitory activity of SCE on the melanogenesis signaling pathway is not completely understood. This study examined the effects of SCE on the melanogenesis signaling pathway activated by α-melanocyte-stimulating hormone (α-MSH). We found that SCE inhibited melanin production in a dose-dependent manner without causing cytotoxicity in B16F10 cells. Interestingly, SCE decreased α-MSH-induced tyrosinase activity in B16F10 cells but did not inhibit tyrosinase activity under cell-free conditions. The results of this study indicate that SCE may reduce pigmentation by way of an indirect, nonenzymatic mechanism. We also found that SCE decreased α-MSH-induced microphthalmia-associated transcription factor (MITF) and tyrosinase expression and induced the activation of extracellular signal-regulated kinase (ERK). These results suggest that the depigmenting effect of SCE may result from downregulation of MITF and tyrosinase expression due to increased ERK activity. Thus, our results provide evidence that SCE might be useful as a potential skin-whitening agent.

Treatment of infraorbital dark circles in atopic dermatitis with a 2790-nm erbium: yttrium scandium gallium garnet laser: a pilot study.

BACKGROUND: Although many Asian atopic patients have orbital darkening symptom and the demand to treat this condition is increasing, little has been reported in the literature on the treatment of infraorbital dark circles in atopic dermatitis. OBJECTIVE: To evaluate the clinical efficacy and safety of 2790-nm erbium:yttrium scandium gallium garnet (Er:YSGG) laser therapy for reducing infraorbital dark circles in atopic dermatitis patients. MATERIALS AND METHODS: Ten Korean patients over 21 year with mild atopic dermatitis and infraorbital dark circles were enrolled in this study. Patients who need active atopic dermatitis treatments are excluded because of the possibility of aggravation after laser treatment. They were treated for dark circles using a 2790-nm Er:YSGG laser. The treatment parameters were 1.8-2.2 J/cm² fluence, 6-mm spot size, and 0.3-ms pulse width with 10% overlap over the infraorbital areas once with a 4-week interval between treatments. Efficacy was assessed with a quartile grading score ranging from 0 to 5 by a blinded investigator, and the patients also documented their degree of satisfaction with the same grading score. All possible side effects were evaluated. RESULTS: The clinical assessment showed 74.5% (2.7) and 72.5% (2.5) improvements, and the patient satisfaction scale scores improved an average of 74% (2.4) and 71.5% (2.3) at 2 months and 4 months after treatment, respectively. There were no severe side effects or aggravation of atopic dermatitis. CONCLUSION: Our study suggests that 2790-nm Er:YSGG laser therapy can be effectively and safely used in the treatment of infraorbital dark circles in atopic dermatitis patients.

Acute dystonia by droperidol during intravenous patient-controlled analgesia in young patients.

Patient-controlled analgesia (PCA) is an important means for postoperative analgesia with parenteral opioid. However, postoperative nausea and vomiting (PONV) remains a major problem with a PCA system. Droperidol is used in PCA to prevent PONV. Extrapyramidal reactions by droperidol are, however, occasionally induced. We describe two cases of severe extrapyramidal hypertonic syndrome with an intravenous administration of droperidol in PCA in young patients, following orthopedic surgery.