The Immune Suppressor IGSF1 as a Potential Target for Cancer Immunotherapy.

The development of first-generation immune-checkpoint inhibitors targeting PD-1/PD-L1 and CTLA-4 ushered in a new era in anticancer therapy. Although immune-checkpoint blockade therapies have shown clinical success, a substantial number of patients yet fail to benefit. Many studies are under way to discover next-generation immunotherapeutic targets. Immunoglobulin superfamily member 1 (IGSF1) is a membrane glycoprotein proposed to regulate thyroid function. Despite containing 12 immunoglobin domains, a possible role for IGSF1, in immune response, remains unknown. Here, our studies revealed that IGSF1 is predominantly expressed in tumors but not normal tissues, and increased expression is observed in PD-L1low non-small cell lung cancer (NSCLC) cells as compared with PD-L1high cells. Subsequently, we developed and characterized an IGSF1-specific human monoclonal antibody, WM-A1, that effectively promoted antitumor immunity and overcame the limitations of first-generation immune-checkpoint inhibitors, likely via a distinct mechanism of action. We further demonstrated high WM-A1 efficacy in humanized peripheral blood mononuclear cells (PBMC), and syngeneic mouse models, finding additive efficacy in combination with an anti-PD-1 (a well-characterized checkpoint inhibitor). These findings support IGSF1 as an immune target that might complement existing cancer immunotherapeutics.

Liposome-assisted penetration and antiaging effects of collagen in a 3D skin model.

BACKGROUND: Collagen is a major component of the extracellular matrix that supports the epidermal layers of the skin; thus, many strategies have been made to enhance the topical delivery of collagen for antiaging purposes. In addition, our previous study indicated that liposome can help the penetration of active ingredients into the skin. AIMS: To produce stable collagen-encapsulated liposomes to improve the topical delivery of collagen. METHODS: Collagen-encapsulated liposomes were fabricated using high-pressure homogenization method. The colloidal stability and adhesion ability were confirmed using dynamic light scattering, and spectrofluorophotometer, respectively. Keratinocyte differentiations of 3D skin before and after treatment with collagen-encapsulated liposomes were confirmed by real-time PCR. RESULTS: In comparison with native collagen, collagen-encapsulated liposomes enhanced collagen retention in artificial membranes by twofold, even after repeated washings with water. In addition, real-time PCR results indicated that 3D skin treated with collagen-encapsulated liposomes exhibited higher levels of collagen, keratin, and involucrin, even after ethanol treatment. CONCLUSION: Liposomes could serve as efficient delivery vehicles for collagen, thereby enhancing its antiaging effects.

Targeting isoforms of RON kinase (MST1R) drives antitumor efficacy.

Recepteur d'origine nantais (RON, MST1R) is a single-span transmembrane receptor tyrosine kinase (RTK) aberrantly expressed in numerous cancers, including various solid tumors. How naturally occurring splicing isoforms of RON, especially those which are constitutively activated, affect tumorigenesis and therapeutic response, is largely unknown. Here, we identified that presence of activated RON could be a possible factor for the development of resistance against anti-EGFR (cetuximab) therapy in colorectal cancer patient tissues. Also, we elucidated the roles of three splicing variants of RON, RON Δ155, Δ160, and Δ165 as tumor drivers in cancer cell lines. Subsequently, we designed an inhibitor of RON, WM-S1-030, to suppress phosphorylation thereby inhibiting the activation of the three RON variants as well as the wild type. Specifically, WM-S1-030 treatment led to potent regression of tumor growth in solid tumors expressing the RON variants Δ155, Δ160, and Δ165. Two mechanisms for the RON oncogenic activity depending on KRAS genotype was evaluated in our study which include activation of EGFR and Src, in a trimeric complex, and stabilization of the beta-catenin. In terms of the immunotherapy, WM-S1-030 elicited notable antitumor immunity in anti-PD-1 resistant cell derived mouse model, likely via repression of M1/M2 polarization of macrophages. These findings suggest that WM-S1-030 could be developed as a new treatment option for cancer patients expressing these three RON variants.

Prediction Model for Future Success of Early Orthopedic Treatment of Class III Malocclusion.

This study aimed to identify predictors for successful post-treatment outcomes in early orthopedic class III malocclusion treatment with a facemask and hyrax expander appliance. The study was performed on lateral cephalograms from 37 patients at the start of treatment (T0), post-treatment (T1), and a minimum of three years after treatment (T2). The patients were grouped as stable or unstable according to the existence of a 2-mm overjet at T2. For statistical analysis, independent t-tests were used to compare the baseline characteristics and measurements of the two groups, considering a significance level of < 0.05. Thirty variables of pretreatment cephalograms were considered during logistic regression analysis to identify predictors. A discriminant equation was established using a stepwise method. The success rate and area under the curve were calculated, with AB to the mandibular plane, ANB, ODI, APDI, and A-B plane angles as predictors. The A-B plane angle was the most significantly different between the stable and unstable groups. In terms of the A-B plane angle, the success rate of early class III treatment with a facemask and hyrax expander appliance was 70.3%, and the area under the curve indicated a fair grade.

Clinical evaluation of the brightening effect of chitosan-based cationic liposomes.

BACKGROUND: Cationic liposomes can enhance the permeability of drugs in 3-D skin. Chitosan is considered a safe material for percutaneous delivery; thus, this study uses chitosan-incorporated cationic liposomes. AIMS: This study investigated the improvement in skin brightness, melanin, and melasma after treatment niacinamide-incorporated chitosan cationic liposomes. METHODS: A skin brightening agent, niacinamide, was formulated into cationic liposomes to facilitate percutaneous absorption and was clinically tested in 21 Korean female subjects. Cationic liposomes were prepared using a high-pressure homogenizer after mixing an oil phase containing lecithin and cholesterol and an aqueous phase containing niacinamide and chitosan. RESULTS: The cationic liposomes exhibited stability over 28 days, with a particle size of 255-275 nm and zeta potential of 10-14 mV. Cationic liposomes containing niacinamide and a control formulation were applied to the left and right side of the face, respectively, twice daily for 28 days. Skin brightness, melanin index, and area of melasma were significantly enhanced where cationic liposomes were used, in comparison with formulations without cationic liposomes, demonstrating a 1.38-2.08-fold improvement. CONCLUSION: Thus, we established that chitosan liposomes augmented the percutaneous absorption of niacinamide and improved the appearance of the skin.

Dual irradiation-triggered anticancer therapeutics composed of polydopamine-coated gold nanoparticles.

The therapeutic efficacy of nanoparticles depends on their ability to release encapsulated photosensitizers. Here, surface-engineered metallic gold nanoparticles (AuNP) were irradiated with dual near-infrared (NIR) light to enhance the release of photosensitizer. Dopamine hydrochloride was surface-polymerized to polydopamine (PDA) layers on AuNP, and chlorin-e6 (Ce6) was chemically tethered to primary amines of PDA. The resulting Ce6-conjugated AuNP were characterized by Raman and X-ray photoelectron spectroscopy and visualized by electron microscopy and light scattering. The generation of reactive oxygen species was increased following dual NIR irradiation at 650 nm and 808 nm, which was attributed to the increased liberation of Ce6. In vitro, dual NIR irradiation significantly enhanced the anticancer effect of Ce6-incorporating AuNP by increasing the population of apoptotic cells. In vivo, tumor xenografted animals exhibited much better tumor suppression when subjected to dual NIR irradiation. Thus, we propose the use of Ce6-incorporating AuNP coupled to dual NIR irradiation for future anticancer treatment of solid tumors.

Comparison Study of the Effects of Cationic Liposomes on Delivery across 3D Skin Tissue and Whitening Effects in Pigmented 3D Skin.

Charged phospholipids are employed to formulate liposomes with different surface charges to enhance the permeation of active ingredients through epidermal layers. Although 3D skin tissue is widely employed as an alternative to permeation studies using animal skin, only a small number of studies have compared the difference between these skin models. Liposomal delivery strategies are investigated herein, through 3D skin tissue based on their surface charges. Cationic, anionic, and neutral liposomes are formulated and their size, zeta-potential, and morphology are characterized using dynamic light scattering and cryogenic-transmission electron microscopy (cryo-TEM). A Franz diffusion cell is employed to determine the delivery efficiency of various liposomes, where all liposomes do not exhibit any recognizable difference of permeation through the synthetic membrane. When the fluorescence liposomes are applied to 3D skin, considerable fluorescence intensity is observed at the stratum cornea and epithelium layers. Compared to other liposomes, cationic liposomes exhibit the highest fluorescence intensity, suggesting the enhanced permeation of liposomes through the 3D skin layers. Finally, the ability of niacinamide (NA)-incorporated liposomes to suppress melanin transfer in pigmented 3D skin is examined, where cationic liposomes exhibit the highest degree of whitening effects.

Recurrence Rate of Herpes Zoster and Its Risk Factors: a Population-based Cohort Study.

BACKGROUND: Herpes zoster (HZ) is generally thought to occur once in a lifetime and recurrence is considered to be limited to immunocompromised individuals. Although HZ recurrence rates seem to be increasing, there have been few studies exploring these rates in the general population. We investigated the recurrence rate and associated risk factors in the general population. METHODS: We used the population-based samples of the National Health Insurance Service database to identify cases of initial HZ episodes from January 1, 2002 to December 31, 2013. We also followed up on these cases through December 31, 2013 to identify recurrence. RESULTS: Overall, the incidence rate of HZ is 5.1 per 1,000 person years and the recurrence rate is 12.0 per 1,000 person years. There were 2,100 recurrent cases out of 39,441 initial episodes with 4.4 years of the mean follow-up period. We identified significant risk factors for recurrence such as old age (51-70 years) (hazard ratio [HR], 1.447; 95% confidence interval [CI], 1.311-1.598), women (1.476; 1.345-1.619), zoster-related pain (ZRP) longer than 30 days (cases of ZRP lasting 31-90 days [1.200; 1.042-1.383], and ZRP lasting longer than 90 days [2.293; 1.990-2.643]). Concurrent hematologic malignancies (2.864; 1.929-4.251), autoimmune diseases (1.466; 1.252-1.715), dyslipidemia (1.390; 1.263-1.530), and hypertension (1.222; 1.107-1.350) were also significant risk factors. CONCLUSION: Our results suggest that the recurrence of HZ is much more common than generally expected, and that the associated risk factors can play an important role in predicting recurrence.

Simvastatin enhances the radiosensitivity of p53­deficient cells via inhibition of mouse double minute 2 homolog.

Simvastatin exhibits anticancer activities, but its molecular mechanisms and radiosensitizing effects relative to p53 status remain unclear. In this study, we investigated whether the combination of simvastatin and ionizing radiation (IR) would enhance the antitumor effects of IR alone in HCT116 p53+/+ and p53­/- colon cancer cells. Using colony formation assays and a xenograft mouse model, we found that simvastatin potently stimulated radiosensitization of HCT116 p53­/- cells and xenograft tumors. The combination of simvastatin with IR decreased G2/M arrest and delayed the repair of IR-induced DNA damage; however, no differences between the HCT116 p53+/+ and p53­/- cells were evident. A further analysis revealed that simvastatin exhibited a novel function, namely, MDM2 suppression, regardless of p53 status. Interestingly, simvastatin induced radiosensitization by enhancing MDM2 suppression and elevating IR-induced p­ATM foci formation compared with IR alone in HCT116 p53­/- cells. Furthermore, simvastatin caused accumulations of the FOXO3a, E-cadherin, and p21 tumor suppressor proteins, which are downstream factors of MDM2, in HCT116 p53­/- cells. In conclusion, simvastatin enhanced radiosensitivity by inducing MDM2 inhibition and increasing tumor suppressor protein levels in radioresistant HCT116 p53­/- cells and xenografts. Overall, our novel findings suggest a scientific rationale for the clinical use of simvastatin as an MDM2 inhibitor and radiosensitizer for p53­deficient colorectal tumor treatments.

Digoxin enhances radiation response in radioresistant A549 cells by reducing protein phosphatase 2A.

Protein phosphatase 2A (PP2A) is a ubiquitous multifunctional enzyme usually known as a tumor suppressor. Recent studies have reported that although inhibition of PP2A leads to acceleration of cell growth, it also induces damaged cells to pass through the cell cycle and renders them sensitive to radiotherapy. Here, we investigated the radiosensitizing effects of digoxin as a PP2A inhibitor in two non-small-cell lung cancer (NSCLC) cell types (H460 and A549) with differential sensitivity to radiation. Digoxin inhibited the proliferation of H460 and A549 cells in a dose-dependent fashion and was especially effective on radioresistant A549 cells. Interestingly, the radiosensitizing effect of digoxin was only present in the radioresistant A549 cells and xenografts. The combination of digoxin and ionizing radiation (IR) significantly reduced clonogenic survival and xenograft tumor growth (P<0.001), compared with IR alone. Digoxin suppressed PP2A protein expression and prevented IR-induced PP2A expression in A549 cells. Digoxin treatment combined with IR allowed the damaged cell to progress through the cell cycle via suppression of cell cycle-related proteins (p53, cyclin D1, cyclin B1, CDK4, and p-cdc2). Moreover, digoxin enhanced IR-induced DNA damage through reduction in levels of repair proteins and elevation of p-ATM foci formation up to 24 h (P<0.001). In conclusion, digoxin has a novel function as a PP2A inhibitor, and combined with IR produces a synergistic effect on radiosensitizing cells, thereby indicating a potentially promising therapeutic approach to radioresistant lung cancer treatment.

Enhanced anticancer effects of a mixture of low-dose mushrooms and Panax ginseng root extracts in human colorectal cancer cells.

Worldwide, colorectal cancer is the third most common cancer in men and the second most common in women. As conventional colorectal cancer therapies result in various side effects, there is a need for adjuvant therapy that can enhance the conventional therapies without complications. In this study, we investigated the anticancer effects of combined mixture of the several medicinal mushrooms and Panax ginseng root extracts (also called Amex7) as an adjuvant compound in the treatment of human colorectal cancer. We observed the in vivo inhibitory effect of Amex7 (1.25, 6.25, and 12.5 ml/kg, oral administration, twice daily) on tumor growth in a mouse model xenografted with HT-29 human colorectal cancer cells. In vitro, at 6, 12, and 24 h after 4% Amex7 treatment, we analyzed cell cycle by flow cytometry and the expression levels of cell cycle progression, apoptosis, and DNA damage repair-related proteins using immunoblotting and immunofluorescence staining in HT-29 cell line. As a result, Amex7 significantly suppressed tumor growth in HT-29 human colorectal cancer cells and xenografts. In vitro, Amex7 induced G2/M arrest through the regulation of cell cycle proteins and cell death by apoptosis and autophagy. Additionally, Amex7 consistently induced DNA damage and delayed the repair of Amex7-induced DNA damage by reducing the level of HR repair proteins. In conclusion, Amex7 enhanced anticancer effects through the induction of G2/M arrest and cell death, including apoptosis and autophagy. Furthermore, Amex7 impaired DNA damage repair. The present study provides a scientific rationale for the clinical use of a combined mixture of medicinal mushrooms and P. ginseng root extracts as an adjuvant treatment in human colorectal cancer.

Intense Pulsed Light Alone and in Combination with Erbium Yttrium-Aluminum-Garnet Laser on Small-to-Medium Sized Congenital Melanocytic Nevi: Single Center Experience Based on Retrospective Chart Review.

BACKGROUND: Treatment of congenital melanocytic nevi (CMN) with intense pulsed light (IPL) has recently produced promising results. OBJECTIVE: To evaluate the clinical and histological outcomes of small-to-medium sized CMN treated with IPL alone and in combination with erbium: yttrium-aluminum-garnet (Er: YAG) laser. METHODS: We performed a retrospective chart review of 26 small-to-medium sized CMN treated as described above. The reduction in visible pigmentation, signs of recurrence and any adverse skin changes were evaluated by two independent clinicians. RESULTS: Seventeen patients completed treatment and were followed-up. Nine were not able to complete treatment due to work, change in residence, and treatment related stress. Ten patients received IPL alone (mean: 10.5 sessions) and 7 underwent treatment with IPL (mean: 7.7 sessions) and Er: YAG/IPL combination therapy (mean: 4.7 sessions). The initial treatment outcome was cleared in 5 patients and excellent in 12. Fourteen patients (82.4%) showed CMN recurrence one year after treatment completion. The histological results from a patient with an excellent clinical outcome showed remnant nevus cells nests in the deep dermis. CONCLUSION: IPL treatment alone and in combination with Er: YAG laser are not definitive treatments for CMN and should not be considered as first-line treatment.

Recognition of sign language with an inertial sensor-based data glove.

Communication between people with normal hearing and hearing impairment is difficult. Recently, a variety of studies on sign language recognition have presented benefits from the development of information technology. This study presents a sign language recognition system using a data glove composed of 3-axis accelerometers, magnetometers, and gyroscopes. Each data obtained by the data glove is transmitted to a host application (implemented in a Window program on a PC). Next, the data is converted into angle data, and the angle information is displayed on the host application and verified by outputting three-dimensional models to the display. An experiment was performed with five subjects, three females and two males, and a performance set comprising numbers from one to nine was repeated five times. The system achieves a 99.26% movement detection rate, and approximately 98% recognition rate for each finger's state. The proposed system is expected to be a more portable and useful system when this algorithm is applied to smartphone applications for use in some situations such as in emergencies.

Arduino-based automation of a DNA extraction system.

There have been many studies to detect infectious diseases with the molecular genetic method. This study presents an automation process for a DNA extraction system based on microfluidics and magnetic bead, which is part of a portable molecular genetic test system. This DNA extraction system consists of a cartridge with chambers, syringes, four linear stepper actuators, and a rotary stepper actuator. The actuators provide a sequence of steps in the DNA extraction process, such as transporting, mixing, and washing for the gene specimen, magnetic bead, and reagent solutions. The proposed automation system consists of a PC-based host application and an Arduino-based controller. The host application compiles a G code sequence file and interfaces with the controller to execute the compiled sequence. The controller executes stepper motor axis motion, time delay, and input-output manipulation. It drives the stepper motor with an open library, which provides a smooth linear acceleration profile. The controller also provides a homing sequence to establish the motor's reference position, and hard limit checking to prevent any over-travelling. The proposed system was implemented and its functionality was investigated, especially regarding positioning accuracy and velocity profile.

Psychometric Properties of a Short Korean Version of the Revised Obsessive Intrusion Inventory.

OBJECTIVE: The Revised Obsessive Intrusion Inventory (ROII) is a 52-item scale that evaluates obsessional intrusive thoughts. The aim of the present study was to validate a short, 20-item Korean version of the ROII (ROII-20). METHODS: Of the 1125 participants who completed the ROII-20, 895 participants completed the scale to examine the factor structure of the scale. A subgroup of these participants (n=53) completed the scale twice to determine test-retest reliability. To establish external validity, 230 participants completed the scale and other questionnaires. RESULTS: Exploratory factor analyses suggested a hierarchical model comprising two higher order factors of autogenous obsessions (resulting from aggressive thoughts and sexual thoughts) and reactive obsessions (resulting from thoughts about contamination, thoughts about accidents, and thoughts about dirt). Confirmatory factor analyses supported this model. The results indicated good internal consistency and test-retest reliability. External validity was supported by relationships with obsessive-compulsive symptoms and general distress. CONCLUSION: The ROII-20 presents good psychometric properties and may be considered as a promising instrument for measuring obsessional intrusions.

2-Hydroxy-3,4-naphthochalcone (2H-NC) inhibits TNFα-induced tumor invasion through the downregulation of NF-κB-mediated MMP-9 gene expression.

The control of tumor metastasis is important for the successful prevention and treatment of cancer. Emerging evidence indicates that various natural and synthetic chalcones exhibit antimetastatic activity through the inhibition of nuclear factor-κB (NF-κB), although the precise mechanism by which this occurs is currently unclear. In this study, 2-hydroxy-3,4-naphthochalcone (2H-NC) was found to reduce tumor necrosis factor alpha (TNFα)-induced MMP-9 mRNA expression and gelatinolytic enzyme activity. These actions were associated with inhibition of RelA/p65 NF-κB activity. In addition, 2H-NC inhibited TNFα-induced invasion of MDA-MB-231 breast cancer cells, as assessed using a three-dimensional spheroid invasion assay. Taken together, these data demonstrate that 2H-NC prevents TNFα-induced tumor cell invasion through downregulation of NF-κB-mediated MMP-9 gene expression, and thereby identify naphthochalcones as a potentially effective class of molecules to use as a platform for the development of antimetastatic agents.

A new synthetic 2'-hydroxy-2,4,6-trimethoxy-5',6'-naphthochalcone induces G2/M cell cycle arrest and apoptosis by disrupting the microtubular network of human colon cancer cells.

Methoxylated chalcones exert antitumor activities. In the present study, we characterized the cytotoxicity of methylated chalcone derivatives against human colon cancer cells. We synthesized a group of methoxychalcones and explored the molecular mechanisms underlying inhibition of tumor growth by these materials. A new synthetic methoxychalcone, 2'-hydroxy-2,4,6-trimethoxy-5',6'-naphthochalcone (named HMNC-74), most effectively inhibited the clonogenicity of SW620 colon cancer cells. Mechanistically, HMNC-74 triggered cell cycle arrest at G2/M phase, followed by an increase in apoptotic cell death. Our results indicate that the cytotoxicity of the novel compound HMNC-74 involves the disruption of microtubular networks.

c-Myb negatively regulates Ras signaling through induction of dual phosphatase MKP-3 in NIH3T3 cells.

Mitogen-activated protein kinase phosphatase-3 (MKP-3) negatively regulates ERK1/2 MAPK in a feedback loop. However, little is known about the molecular mechanism by which Ras signaling induces MKP-3 expression. In the present study, we demonstrate that exogenous expression of constitutively active H-Ras increases the level of MKP-3 mRNA. A transfection study using a series of MKP-3 promoter deletion constructs revealed that the c-Myb binding site is required for Ras-induced transcriptional activation of the MKP-3 gene promoter. Furthermore, we show that c-Myb directly binds to the MKP-3 promoter, as revealed by electrophoretic mobility shift assay and chromatin immunoprecipitation. Knock-down of c-Myb expression using siRNA abrogated Ras-induced MKP-3 promoter activity. These findings propose a novel mechanism through which Ras signaling activates c-Myb-dependent transcriptional activation of the MKP-3 gene.