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S1. Elevated c-MYC activity in MCF7-BrM promotes brain metastasis (related to Fig 1) S2. C-MYC regulates tumor sphere circularity and invasiveness in a HA-collagen matrix (related to Fig 2) S3. c-MYC-mediated recruitment of RAW cells (related to Fig 3) S4. qRT-PCR analysis of c-MYC-regulated genes (related to Fig 4) S5. Association of c-MYC and MYC-BrMFS with BrMFS in the MSK82 dataset (related to Fig 5) S6. BrM-BCCs exhibit elevated TRAIL sensitivity (related to Fig 6)

Background: The mechanisms of epidermal growth factor (EGF) effects EGF receptor inhibitor (EGFRI)-related skin toxicities are as yet unknown. We investigated which mechanisms are involved in EGF’s positive effects. Methods: Two types of EGFRIs, cetuximab and gefitinib, were used to treat the cells or 3d-cultured human skin tissue with recombinant human EGF (rhEGF). The expression levels of skin barrier related proteins, inflammatory cytokines, and antimicrobial peptides (AMPs) were measured by using RT qPCR, ELISA, immunohistochemical (IHC) stain, or immunofluorescence..Results: Using western blot assay, cetuximab decreased EGFR and phosphorylated EGFR (pEGFR) expression. In contrast, rhEGF increased EGFR and pEGFR expression. Also, rhEGF induces EGFR signaling by pAKT and pPI3K expression in gefitinib and rhEGF co-treated cells. Expressions of proliferation and differentiation proteins, both ki-67 and filaggrin, were decreased in EGFRIs -treated tissue. However, in rhEGF and EGFRIs co-treated tissue, those expressions were increased. Pro-inflammatory cytokines, including IL-1α, IL-8, and TNF-α expression, were increased by EGFRIs, and down-regulated by rhEGF. In patients’ tissue evaluation, compared with control, patients’ Ki-67 and EGFR expression were decreased (P=0.015, P=0.001). Patients’ IL-17 and TNF-α expression intensity was higher than that of control group (P=0.038, P=0.037). After treatment with EGF ointment, average values of Ki-67, EGFR, and Melan-A were changed to normal values. Oppositely patients’ proportions of IL-17 and TNF-α were decreased to low stain level.Conclusions: Treatment of rhEGF improved EGFRIs-induced skin eruption via normalizing the proliferation and differentiation of keratinocytes, reducing inflammatory cytokines by the affected EGFRIs.

Background Ablative fractional laser (AFL)-assisted methyl aminolevulinate (MAL) photodynamic therapy (PDT) (AFL-MAL-PDT) has shown significantly higher efficacy and lower recurrence rates at 12 months than conventional methyl aminolevulinate photodynamic therapy (MAL-PDT) for the treatment of Bowen disease (BD). However, long-term follow-up data are not available. Objective To compare the 5-year efficacy and recurrence rates of AFL-MAL-PDT with those of conventional MAL-PDT for the treatment of lower extremity BD. Methods A total of 60 patients with 84 BD lesions were randomly assigned to a single session of AFL-MAL-PDT or 2 sessions of MAL-PDT with a 1-week interval between sessions. Patients were followed up at 3, 12, 24, 36, 48, and 60 months after treatment. Efficacy, recurrence rates, and risk factors for unsuccessful treatments were assessed. Results After 5 years, the overall clearance rate of AFL-MAL-PDT (84.78%) was significantly better than that of MAL-PDT (44.74%) for BD lesions. The recurrence rate was significantly lower for AFL-MAL-PDT (9.3%) than for MAL-PDT (41.38%). Diameters larger than 20 mm and lesions with a history of previous treatment were independent factors for treatment failure. Limitations The small sample size and single-center study design were limitations. Conclusions For patients with lower extremity BD lesions, AFL-MAL-PDT showed significantly higher long-term efficacy and lower recurrence rates than standard MAL-PDT.

Introduction: Reoviruses are replication-competent and selectively infect and destroy cancer cells. Although the most common route of oncolytic virotherapy is intratumoral or intravenous administration, these routes are often not clinically feasible because of tumor inaccessibility, tumor multiplicity, and systemic toxicities. Here, we developed an orally available oncolytic reovirus, RC402, to elicit potent anti-tumor immune responses without the above mentioned limitations and thereby maximize the efficacy of PD-1 immune checkpoint blockade in colon cancer. Method: MC38 or CT26 colon cancer-bearing immunocompetent mice were treated with RC402 and/or anti-PD-1 antibody. Tumor growth was monitored after treatment and comprehensively analyzed by flow cytometry and/or multiplex tissue imaging. Results: RC402 treatment effectively delayed tumor growth regardless of the route of administration (per os as well as intratumorally). In particular, orally administered RC402 was well tolerated without gross toxicity and interacted with intestinal immune cells, eliciting adaptive T cell responses within intestinal lymphoid organs such as Peyer's patch. Most of the RC402 was cleared in the gastrointestinal tract within 10 days of the first treatment, and it was not detectable in the blood stream or major organs after oral administration. However, RC402 selectively induced strong and durable anti-tumor immunity in distant tumor tissues. Oral RC402 monotherapy markedly increased CD8+ cytotoxic T cells and decreased CD4+CD25+Foxp3+ regulatory T cells in distant colon cancers, while there were no significant changes in tumor-associated myeloid cells. Finally, oral RC402 treatment cooperated with anti-PD-1 blockade to further suppress colon cancer growth and augment anti-tumor immunity within the tumor microenvironment, leading to complete regression of tumors and survival benefit of tumor-bearing mice. Conclusion: Our study demonstrates that orally available oncolytic reovirus, RC402, could induce potent anti-cancer immune responses and effectively suppress colon cancer progression in combination with anti-PD-1 blockade. Citation Format: Chan Kim, Hong Jae Chon, Hye Jin Lee, Won Suk Lee, Hannah Yang, Jeong Hun Kim, So Jung Kong, Yu Seong Lee, Seung Joon Lee, Enkhtaivan Gansukh, Ki-Hoon Song, Yeon-Sook Lee, Beodeul Kang. Orally available oncolytic reovirus, RC402, effectively promotes anti-cancer immunity and synergizes with immune checkpoint blockade in colon cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1914.

A significant relationship between arsenic exposure and non-melanoma skin cancer (NMSC) is well known. The toxicity of arsenics which develop NMSC is dependent on their species. Accordingly, total arsenic levels are unreliable for risk assessment of NMSC. However, there are few studies on quantitative exposure assessment of arsenic species in NMSC patients. To validate the contribution of each arsenic species to NMSC, we compared the creatinine-adjusted urinary concentration of arsenic species in NMSC patients and community controls. A total of 124 biopsy-proven NMSC cases and 125 age- and sex-matched community controls, drinking tap water with low-level arsenic concentration (

Acral lentiginous melanoma (ALM) is a distinctive histopathological subtype of melanoma that typically occurs on the palms, soles, and nail beds. Because of their anatomical locations, ALMs are typically diagnosed at late stages, resulting in a poor prognosis.1 Insulin-like growth factor-2 mRNA-binding protein 3 (IMP-3) plays significant roles in cell proliferation, migration, and adhesion by enhancing IGF-2 protein expression in malignant tumours.2 We evaluated the associations between IMP-3 expression and clinicopathological features, including the western blot profile, Ki-67 index, BRAF mutation, and long-term survival, among patients with ALM. This article is protected by copyright. All rights reserved.

Background Sentinel lymph node biopsy (SLNB) is usually performed using a triple technique that includes lymphoscintigraphy (LSG), which involves the injection of a radiolabelled tracer, blue dye injection, and detection of the radioisotope with a gamma probe. However, blue dye injection may cause pathological misinterpretation and obscure clinical margins, especially when combined with Mohs micrographic surgery (MMS) for cutaneous melanoma. Objectives To assess the efficacy of SLNB without blue dye injection in patients who subsequently underwent MMS for melanomas of the lower extremities. Methods We evaluated patients who underwent MMS with or without SLNB using preoperative localization of the primary melanoma via LSG and intraoperative confirmation using a gamma probe between 2010 and 2016. Results Seventy-two patients with melanoma of mean Breslow thickness 3·03 ± 1·44 mm were evaluated. Sixty-five of the 72 patients underwent SLNB, the success rate of which was 98%. The 5-year overall and disease-free survival rates were 78% and 76%, respectively. Conclusions Blue dye injection can be omitted without compromising the accuracy of standard SLNB. Omitting blue dye injection also has marked advantages in MMS for melanoma. What's already known about this topic? Sentinel lymph node biopsy (SLNB) is usually performed using a triple technique including lymphoscintigraphy, which involves the injection of a radiolabelled tracer, blue dye injection, and radioisotope detection using a gamma probe. Blue dye injection may cause pathological misinterpretation and obscure clinical margins. What does this study add? Omitting the dye does not decrease diagnostic accuracy and is particularly advantageous for Mohs micrographic surgery (MMS) in melanomas with clinically indistinct tumour borders. SLNB without blue dye injection is feasible in MMS for melanoma.

Background The efficacy of epidermal growth factor (EGF) receptor (EGFR) inhibitors in patients with non‐small cell lung cancer (NSCLC), pancreatic cancer (PC), or colorectal cancer (CRC) has been demonstrated. However, dermatological reactions to these inhibitors can cause significant physical and psychosocial discomfort. The objective of the present study was to evaluate the efficacy of EGF ointment for EGFR inhibitor‐related skin adverse events (ERSEs). Materials and Methods This placebo‐controlled, double‐blind, multicenter, pilot phase III trial enrolled patients with NSCLC, PC, or CRC treated with EGFR inhibitors. Patients with grade ≥2 ERSEs were included. Patients were randomized to three treatment arms: arm 1, placebo; arm 2, 1 ppm of EGF ointment; and arm 3, 20 ppm of EGF ointment. Patients applied ointment to their skin lesions twice daily. Results Efficacy evaluation was available for 80 patients (9 for PC, 28 for NSCLC, and 43 for CRC). Responses were 44.4% in arm 1, 61.5% in arm 2, and 77.8% in arm 3. There was a linear correlation between EGF concentrations and responses (p = .012). Quality of life (QoL) was assessed for 74 patients. Maximum changes in composite scores by Skindex‐16 after treatment were significantly different among arms (mean ± SD: −5.2 ± 8.6 for arm 1, −11.7 ± 14.2 for arm 2, and − 18.6 ± 17.7 for arm 3; p = .008). EGF arms showed significant improvement in emotions (p = .005) and functioning (p = .044) scores over the placebo arm. Conclusion EGF ointment is effective for managing ERSEs. It can also improve patients’ QoL compared with placebo. Clinical trial identification number. NCT02284139 Implications for Practice Patients with non‐small cell lung cancer, pancreatic cancer, or colorectal cancer who are treated with epidermal growth factor (EGF) receptor (EGFR) inhibitors may experience dermatologic reactions to their treatment. This study investigated the benefit of an EGF ointment in the treatment of these adverse events and observed the ointment to be effective in managing EGFR inhibitor‐related skin adverse events., Epidermal growth factor (EGFR) is an important target for antitumor therapy. This article evaluates the efficacy of EGF ointment for EGFR inhibitor‐related adverse events of the skin.

Standardized methods for collecting smoke and for measuring smoke components in heat not burn tobacco product (HTP) are yet to be established, and there is a lack of consensus as to whether the content of HTP cigarettes can be assayed in the same manner as for conventional cigarettes. Since HTPcigarettes do not generate ash when smoked, we compared the levels of tobacco alkaloids (TAs) and tobacco-specific nitrosamines (TSNAs) of HTP cigarettes before and after aerosol generation. HTP cigarettes were smoked according to two international standardization methods. The TAs and TSNAs contents of the cigarettes were analyzed by UPLC-Q-TOF and UPLC-MSMS, respectively. Smoking was found to significantly decrease the content of nicotine, nornicotine, anatabine, and anabasine by 53 ∼ 100% in all samples, and the maximum inhalable amounts of these entities were determined to be 4.24 mg/cig, 103.52 μg/cig, 258.72 μg/cig, and 33.03 μg/cig, respectively. By contrast, smoking significantly increased the content of NNK and NAB. we suggested that the reduced nicotine content minus the nicotine content remaining in the filter is an amount that could potentially be inhaled during smoking. The increase of NNK and NAB in HTP cigarette after aerosol generation is expected to be caused by the precursor, but more specific behavioral studies should be performed.

Some polypeptide N-acetyl-galactosaminyltransferases (GALNTs) are associated with cancer, but their function in organ-specific metastasis remains unclear. Here, we report that GALNT14 promotes breast cancer metastasis to the lung by enhancing the initiation of metastatic colonies as well as their subsequent growth into overt metastases. Our results suggest that GALNT14 augments the self-renewal properties of breast cancer cells (BCCs). Furthermore, GALNT14 overcomes the inhibitory effect of lung-derived bone morphogenetic proteins (BMPs) on self-renewal and therefore facilitates metastasis initiation within the lung microenvironment. In addition, GALNT14 supports continuous growth of BCCs in the lung by not only inducing macrophage infiltration but also exploiting macrophage-derived fibroblast growth factors (FGFs). Finally, we identify KRAS-PI3K-c-JUN signalling as an upstream pathway that accounts for the elevated expression of GALNT14 in lung-metastatic BCCs. Collectively, our findings uncover an unprecedented role for GALNT14 in the pulmonary metastasis of breast cancer and elucidate the underlying molecular mechanisms.

Background Chronic actinic dermatitis (CAD) has a more complicated pathogenetic basis than others. The clinical grading system and its correlations with the clinical and immunological parameters still remained to be investigated to define the nature of CAD in a more detailed manner. Objectives We investigated correlations of the clinical severity score of CAD (CSS-CAD) with the clinical and immunological parameters. Methods We evaluated 72 patients with CAD and classified them into three groups according to the CSS-CAD. We analysed total IgE level, peripheral blood (PB) eosinophil count, the ratio of Th2cell (CCR4 + CD4 +) percentage over Th1 cell (CXCR3 + CD4 +) percentage (Th2/Th1) and/or the sum of suppressor/cytotoxic T cells. Results The total IgE levels and the percentage of PB eosinophils were higher in the severer group than other groups. A shift towards Th2 from Th2/Th1 balanced status may be affected by total counts of suppressor T cells, and the patient with higher Th2/Th1 ratio than balanced status had the more proportion in the severer CSS-CAD group than other groups. Conclusion The CSS-CAD correlates with total IgE level, PB eosinophil count and a shift towards Th2 immunity from Th2/Th1. So we suggest the Th1/Th2 dysbalance may be affected by the CSS-CAD.

The mechanisms of epidermal growth factor (EGF) affecting EGF receptor inhibitor (EGFRI)-related skin toxicities are as yet unknown. We investigated which mechanisms are involved in EGF&rsquo, s positive effects. Two types of EGFRIs, cetuximab and gefitinib, were used to treat the cells or 3d-cultured human skin tissue with recombinant human EGF (rhEGF). As a result, rhEGF increased EGFR and pEGFR expression. Furthermore, rhEGF induces EGFR signaling by pAKT and pPI3K expression in gefitinib and rhEGF co-treated cells. In addition, rhEGF bound to EGFR after than cetuximab, but cetuximab bound to EGFR more strongly than rhEGF. Moreover, expressions of proliferation and differentiation proteins, both ki-67 and filaggrin, were decreased in EGFRI-treated tissue. However, in rhEGF and EGFRI co-treated tissue, those expressions were increased. Expression of IL-1&alpha, IL-8, and TNF-&alpha, was increased by EGFRIs and down-regulated by rhEGF. Furthermore, hBD-2 and hBD-3 protein expressions were inhibited by cetuximab or gefitinib treatment, and those decrements were increased by rhEGF treatment. In patients&rsquo, tissue evaluation, compared with controls, patients&rsquo, Ki-67 and EGFR expression were decreased (p = 0.015, p = 0.001). Patients&rsquo, IL-17 and TNF-&alpha, expression intensity was higher than that of the control group (p = 0.038, p = 0.037). After treatment with EGF ointment, average values of Ki-67, EGFR, and Melan-A were changed to normal values. Oppositely, patients&rsquo, proportions of IL-17 and TNF-&alpha, were decreased to low stain level. In conclusion, treatment of rhEGF improved EGFRI-induced skin eruption via normalizing the proliferation and differentiation of keratinocytes, reducing inflammatory cytokines by the affected EGFRIs.

Brain metastasis in breast cancer is particularly deadly, but effective treatments remain out of reach due to insufficient information about the mechanisms underlying brain metastasis and the potential vulnerabilities of brain-metastatic breast cancer cells. Here, human breast cancer cells and their brain-metastatic derivatives (BrMs) were used to investigate synthetic lethal interactions in BrMs. First, it was demonstrated that c-MYC activity is increased in BrMs and is required for their brain-metastatic ability in a mouse xenograft model. Specifically, c-MYC enhanced brain metastasis by facilitating the following processes within the brain microenvironment: (i) invasive growth of BrMs, (ii) macrophage infiltration, and (iii) GAP junction formation between BrMs and astrocytes by upregulating connexin 43 (GJA1/Cx43). Furthermore, RNA-sequencing (RNA-seq) analysis uncovered a set of c-MYC–regulated genes whose expression is associated with higher risk for brain metastasis in breast cancer patients. Paradoxically, however, increased c-MYC activity in BrMs rendered them more susceptible to TRAIL (TNF-related apoptosis-inducing ligand)–induced apoptosis. In summary, these data not only reveal the brain metastasis-promoting role of c-MYC and a subsequent synthetic lethality with TRAIL, but also delineate the underlying mechanism. This suggests TRAIL-based approaches as potential therapeutic options for brain-metastatic breast cancer. Implications: This study discovers a paradoxical role of c-MYC in promoting metastasis to the brain and in rendering brain-metastatic cells more susceptible to TRAIL, which suggests the existence of an Achilles' heel, thus providing a new therapeutic opportunity for breast cancer patients.

As with many countries, the Korea government has made a variety of efforts to meet the precautionary principle under the London Convention and Protocol acceded in 1994 and 2009. However, new strategies for the suitable marine dumping of waste materials have since been developed. In this study, the distribution and contamination of heavy metals including Al, Fe, Mn, Li, Co, Cr, Ni, Cu, Zn, As, Cd, Pb and Hg in bottom sediments were analyzed and compared to various criteria in order to evaluate the effectiveness of the management of the East Sea-Jung (ES-Jung) dumping site by the Korea government. The results indicate that the average metal concentrations were significantly lower than Effects Range Low (ERL) values, and generally similar to or lower than the Threshold Effect Levels (TEL) from the Sediment Quality Guidelinces (SQGs). According to analyses of various metal contamination indexes (Enrichment Factor: EF, Pollution Load Index: PLI and the Index of Geoaccumulation: Igeo), most areas were found to be uncontaminated by heavy metals with the exception of several moderately contaminated stations (ESJ 33, 54, 64 and ESJR 20). Heavy metal concentrations in areas grouped as G1, G2, DMDA, N-Ref and S-Ref which showed similar characteristics between 2007-2013 and 2014, were compared. Unexpectedly, most concentrations in the northern reference area (N-Ref) were much higher than those in the actual dumping areas (G1 and G2), may be due to the influences from nearby cities to the west of the ES-Jung site, rather than from the dumping site itself. Additionally, heavy metal concentrations in the dredged material dumping area (DMDA) were found to be low although they have slightly increased over time and those in the southern reference area (S-Ref) were found to have gradually decreased with year. The concentrations of most metals in the East Sea-Jung dumping site were similar to or less than those in the Earth’s crust and approximately the same as those in continental sediments. As a result, this site can be considered as uncontaminated or slightly contaminated. This implies that the efforts made by the Korea government to manage and govern the dumping site through various policies, including ‘the focal point system’, ‘the responsibility zones system’ and ‘the principle of pollution causing party liability’, have been successful.

In general, surface anchoring energy is one of the most important parameters that strongly affect electrooptical performance, especially the optical response time of liquid crystal (LC) displays. In this paper, we proposed a photoalignment method for strong surface anchoring energy by applying double ultraviolet (UV) exposure with a separated bandwidth to a photosensitive polyimide layer with embedded reactive mesogens (RMs) that can increase the anchoring energy during polymerization. We first polymerized the embedded RM molecules using long wavelength UV rays (over 340 nm), and then achieved the ordered photosensitive alignment layer using short UV rays (between 254 and 340 nm). We compared the measured surface anchoring energy and the optical response time by the proposed method with the conventional UV exposure using the in-plane switching LC mode for verification. As a result, we confirmed that the anchoring energy increased two times and the optical response time improved by 22% compared with the conventional pure UV exposure method.

In this research, items and contents of SONAR were derived from investigation of OMS/MP of previously- operated submarines and domestic and international references related to weapon system. Such items and contents were established in detail and were categorized into four separate groups after consulting system design experts and specialists in the field of SONAR's operation. Ultimately, based on wartime and peacetime scenario and operation concept of SONAR, RAM values were obtained through various methods using submarine-operating records and maintenance records for the past eleven years.

Nodal melanocytic nevi (NNs) encountered during sentinel lymph node biopsy (SLB) for malignant melanoma are usually difficult to distinguish from metastatic melanoma. However, NNs have not been well studied in acral lentiginous melanoma (ALM) in Asian populations.To investigate the clinical characteristics and significance of NNs in SLB specimens from patients with ALM.We retrospectively analyzed 84 patients with ALM who underwent SLB between June 2010 and July 2017.Of the 84 patients with ALM, 9 (10.7%) had NNs in their SLB specimens. NNs were significantly more common in SLB specimens than in specimens not obtained by SLB. The presence of pre-existing melanocytic lesions was found to be associated with NNs (P .001). The 5-year overall survival was significantly higher in patients with ALM with NNs than in patients with a positive SLB result (P = .047). Distant recurrence in patients with ALM with NNs was significantly lower than in patients a positive SLB result (P = .03).The small sample size, single-center study design, and retrospective nature of the study were the limitations.In Asian populations, the prevalence of NNs in ALM is similar to that reported in Europe and the United States. The rates of distant recurrence and overall survival in patients with ALM who have NNs are similar to those of patients who do not have metastatic melanoma.

Recent epidemiological studies have reported adverse health effects, including skin cancer, due to low concentrations of arsenic via drinking water. We conducted a study to assess whether low arsenic contaminated ground water affected health of the residents who consumed it. For precise biomonitoring results, the inorganic (trivalent arsenite (As III) and pentavalent arsenate (As V)) and organic forms (monomethylarsonate (MMA) and dimethylarsinate (DMA)) of arsenic were separately quantified by combining high-performance liquid chromatography and inductively coupled plasma mass spectroscopy from urine samples. In conclusion, urinary As III, As V, MMA, and hair arsenic concentrations were significantly higher in residents who consumed arsenic contaminated ground water than control participants who consumed tap water. But, most health screening results did not show a statistically significant difference between exposed and control subjects. We presume that the elevated arsenic concentrations may not be sufficient to cause detectable health effects. Consumption of arsenic contaminated ground water could result in elevated urinary organic and inorganic arsenic concentrations. We recommend immediate discontinuation of ground water supply in this area for the safety of the residents.

In 2014, the concentrations of 13 heavy metals in surface sediments from 14 sampling stations were analyzed and compared to samples from previous years to evaluate the remediation effectiveness of the “rest-year” (RY) system and capping with dredged material at the Yellow Sea-Byung dumping site offshore Korea. Since the 2006 introduction of the RY system, annual variations in metal concentrations at stations within the RY zone have gradually decreased over time. Heavy metal concentrations at most stations were lower than sediment quality guidelines, indicating the success of the RY system. Additionally, the effects of capping the contaminated sediment with dredged materials were investigated. The results indicate that dredged materials successfully capped the contaminated sediment within the dredged material dumping area, as the concentrations of Cr and total organic carbon were significantly reduced. We conclude that dredged materials may be used as capping materials for the remediation of contaminated sediments.

Importance Surgical excision is the standard treatment for cutaneous squamous cell carcinoma (SCC). However, microinvasive SCC (Clark level II) is limited to the papillary dermis, and it should be differentiated from invasive SCC. Ablative fractional laser-primed photodynamic therapy (AFL-PDT) may have enhanced efficacy. Objective To compare 1 session of AFL-PDT with 2 sessions of conventional methyl aminolevulinate-PDT (MAL-PDT) for the treatment of microinvasive SCC. Design, Setting, and Participants A 2-armed, randomized, single-blind, comparative trial of 45 patients with histologically proven microinvasive SCC. Twenty-one patients were randomized to treatment with a single AFL-PDT session, and 24 patients were randomized to 2 MAL-PDT sessions with a 1-week interval between sessions using a computer-generated program. Standard pretreatment such as curettage was not performed prior to PDT owing to a tendency to bleed. The efficacy, recurrence rate, cosmetic outcomes, and safety were assessed 1 week, 3, 12, and 24 months after the last treatment. Interventions AFL was performed with an ablation depth of 550 µm to 600 µm, coagulation level of 1, treatment density of 22%, and a single pulse. Then, MAL cream was applied under occlusion for 3 hours and illuminated by using a red light-emitting diode light at 37 J/cm 2 . A second session of MAL-PDT was administered after 7 days. Main Outcomes and Measures The primary outcome measures were the lesion response at 3 and 12 months, and the recurrence rate 12 months after the last treatment. Results Twenty-one patients (6 men, 15 women) with a mean (SD) age of 76 (6) years were randomized to treatment with a single AFL-PDT session, and 24 patients (11 men, 13 women) with a mean (SD) age of 75 (6) years were randomized to 2 MAL-PDT sessions. The overall complete response rates 3 months after treatment were 84.2% with AFL-PDT and 52.4% with MAL-PDT ( P = .03). These differences in efficacy remained significant at the 24-month follow-up. The recurrence rate was significantly lower with AFL-PDT (12.5%) than with MAL-PDT (63.6%) at 24 months ( P = .006). AFL-PDT and MAL-PDT did not differ significantly with respect to the cosmetic outcomes, adverse events, or pain intensity. Conclusions and Relevance AFL-PDT can be used as an alternative treatment option for patients with microinvasive SCC who are not suitable for surgical treatment. Trial Registration clinicaltrials.gov Identifier:NCT02666534

Oncogenic Ras mutants, frequently detected in human cancers, are high-priority anticancer drug targets. However, direct inhibition of oncogenic Ras mutants with small molecules has been extremely challenging. Here we report the development of a human IgG1 format antibody, RT11, which internalizes into the cytosol of living cells and selectively binds to the activated GTP-bound form of various oncogenic Ras mutants to block the interactions with effector proteins, thereby suppressing downstream signalling and exerting anti-proliferative effects in a variety of tumour cells harbouring oncogenic Ras mutants. When systemically administered, an RT11 variant with an additional tumour-associated integrin binding moiety for tumour tissue targeting significantly inhibits the in vivo growth of oncogenic Ras-mutated tumour xenografts in mice, but not wild-type Ras-harbouring tumours. Our results demonstrate the feasibility of developing therapeutic antibodies for direct targeting of cytosolic proteins that are inaccessible using current antibody technology., Oncogenic RAS mutants are key anti-cancer targets as KRas mutations are very frequent in human cancers. Here, the authors engineer a cytosol-penetrating anti-Ras antibody and demonstrate its ability to block RAS-effector protein interactions inhibiting tumour growth of Ras mutant-driven cancers.

Arsenic is a unique element with distinct physical characteristics and toxicity whose importance in public health is well recognized. The toxicity of arsenic varies across its different forms. While the carcinogenicity of arsenic has been confirmed, the mechanisms behind the diseases occurring after acute or chronic exposure to arsenic are not well understood. Inorganic arsenic has been confirmed as a human carcinogen that can induce skin, lung, and bladder cancer. There are also reports of its significant association to liver, prostate, and bladder cancer. Recent studies have also suggested a relationship with diabetes, neurological effects, cardiac disorders, and reproductive organs, but further studies are required to confirm these associations. The majority of research to date has examined cancer incidence after a high exposure to high concentrations of arsenic. However, numerous studies have reported various health effects caused by chronic exposure to low concentrations of arsenic. An assessment of the health effects to arsenic exposure has never been performed in the South Korean population; thus, objective estimates of exposure levels are needed. Data should be collected on the biological exposure level for the total arsenic concentration, and individual arsenic concentration by species. In South Korea, we believe that biological exposure assessment should be the first step, followed by regular health effect assessments.

We measured Ra isotopes (223Ra and 228Ra) in surface seawater of the northwestern Pacific marginal seas to trace the flow rate and mixing of the Changjiang diluted water (CDW) in the summer of 2012. Based on the horizontal distribution of 223Ra activities, the arrival time of CDW from the river mouth to 450 km offshore northeast was estimated to be 20–35 days, which is similar to that determined in previous studies. Moreover, we successfully calculated the relative contribution of CDW at each sampling station using a salinity and 228Ra diagram. Using this unique method, we found that the relative contribution of CDW was more than 30% in most surface seawaters of the northern East China Sea, the Yellow Sea, and the southern sea off Korea. Our results suggest that CDW is of high significance in the biogeochemistry of surface seawater of these northwestern Pacific marginal seas during the summer monsoon period.

Background: Few studies have compared the efficacy, cosmetic outcomes, and adverse events between 5-aminolevulinic acid photodynamic therapy (ALA-PDT) and methyl aminolevulinate-PDT (MAL-PDT) for actinic keratoses (AKs) in Asian ethnic populations with dark-skin. Objective: We retrospectively compared the long-term efficacy, recurrence rates, cosmetic outcomes, and safety of ALA-PDT versus MAL-PDT for facial AKs in Koreans. Methods: A total of 222 facial AKs in 58 patients were included in this study. A total of 153 lesions (29 patients) were treated with 5-ALA, and 69 lesions (29 patients) with MAL. ALA and MAL creams were applied for 6 hours and 3 hours, respectively; the lesions were then illuminated with a halogen lamp at 150 J/cm 2 for ALA-PDT and a diode lamp at 37 J/cm 2 for MAL-PDT. Results: The complete response rates of ALA-PDT and MAL-PDT were 56.9% and 50.7%, respectively, with no significant difference at 12 months after treatment. No significant difference in recurrence rates was observed between the 2 PDT modalities at either 6 or 12 months after treatment. There was no significant difference in the cosmetic outcomes between the 2 treatment modalities at 12 months after PDT. However, ALA-PDT caused significantly more painful than MAL-PDT (p=0.005). The adverse events were mild to moderate, transient, and self-limiting for both modalities. Conclusion: MAL-PDT was similar to ALA-PDT in terms of long-term efficacy, recurrence rates, cosmetic outcomes, and adverse events; however, it was a significantly less painful procedure than ALA-PDT in our study. (Ann Dermatol 26(3) 321∼331, 2014)

Background: In the majority of melanomas, the RAS/RAF/ MEK/ERK signaling pathway is constitutively activated, due to oncogenic mutations in the BRAF and NRAS genes. The BRAF mutation has been mainly described in Caucasian melanomas. However, there is a lack of study evaluating the status, and the clinical significance, of BRAF mutation in the Asian population. Objective: This study was aimed to determine the frequency of BRAF mutation, and to evaluate the correlation of BRAF status with clinicopathologic features and outcomes, in Korean primary acral lentiginous melanoma (ALM) patients. Methods: ALM samples (n=36) were analyzed for the BRAF V600E mutation, by dual-priming oligonucleotide (DPO) based real-time polymerase chain reaction. The clinicopathologic features and prognosis of the patients were analyzed with BRAF mutation status. Results: The incidence of BRAF V600E mutation was 19.4% (7/36). The BRAF V600E mutations were not associated with clinicopathologic features, except for the age factor. All of the BRAF-mutant patients survived without recurrence or metastasis, and have a better clinical outcome than BRAF wild-type patients. Conclusion: In Korean primary ALM, a low frequency of BRAF mutation was shown; and BRAF mutation presented with a favorable prognosis. These results indicate that other distinctive genetic mechanisms may have more important roles in the development and progression of disease. Further multicenter study with large sample size is firmly needed, to confirm the results of our preliminary study.

Photodynamic therapy (PDT) with methyl aminolevulinate (MAL) is effective for treating multiple actinic keratoses (AKs). Ablative fractional laser (FL) creates vertical channels that may facilitate MAL delivery and improve PDT response.To evaluate the efficacy of FL-assisted PDT (FL-PDT) in treating facial AKs in Korean patients.A prospective randomized non-blinded trial initially evaluated 271 facial AKs in 45 patients. All patients underwent one session of MAL-PDT using a red light-emitting diode lamp at 37 J/cm(2) , and 23 patients with 135 AK lesions were randomly assigned to pre-treatment with a 2940-nm ablative fractional erbium:Yag laser. Patients were followed up at 1, 2 and 4 weeks and every month until 6 and 12 months post-treatment. Response, adverse events, cosmetic outcome and patient satisfaction were documented. Finally, a total of 236 facial AKs in 40 patients were enrolled and analysed in this study.FL-PDT was significantly more effective than MAL-PDT at treating all AK grades (86.9% vs. 61.2%; P 0.001). The efficacy of FL-PDT was most pronounced in treating Olsen grade III AKs (69.4% vs. 32.5%; P = 0.001). FL-PDT also showed a lower lesion recurrence rate than MAL-PDT (9.7% vs. 26.6%; P = 0.004). Excellent or good cosmetic outcome was reported in90% cases. Erythema and hyperpigmentation intensities were higher in the FL-PDT group (P 0.05). Side-effects were more frequent in the FL-PDT group, but these were mild and well tolerated (P 0.05).FL-PDT is effective for treating AKs, especially moderate-to-thick lesions.

Background Cutaneous squamous cell carcinoma (cSCC) usually has ill-defined margins because of its irregular invasive patterns. Objective To evaluate the surgical efficacy of photodynamic diagnosis (PDD) in primary cSCC treated using Mohs micrographic surgery (MMS). Methods & Materials We examined 67 cases of biopsy-proven primary facial cSCC treated with MMS. The 67 SCC were divided into the two groups depending on PDD application: PDD group (n = 38, 56.7%) and non-PDD group (n = 29, 43.3%). We analyzed the differences in surgical features between the PDD and non-PDD groups. Results The PDD group required fewer Mohs stages (1.37 vs 1.83, p = .02) and smaller surgical margins (8.03 vs 11.24 mm, p = .03). PDD showed additional benefits in terms of surgical margin and Mohs stage, especially in low-risk SCC, including thin (≤4 mm), small (≤20 mm), well-differentiated, and nonulcerative tumors (p .05) during MMS. Conclusion PDD can increase surgical efficacy of primary cSCC during MMS. These benefits are more pronounced in low-risk SCC. We recommend PDD as a simple and useful technique for delineating the margins of low-risk SCC before MMS.

Overexpression of insulin-like growth factor binding protein (IGFBP)-3 induces apoptosis of cancer cells. However, preexisting resistance to IGFBP-3 could limit its antitumor activities. This study characterizes the efficacy and mechanism of the combination of recombinant IGFBP-3 (rIGFBP-3) and HDAC inhibitors to overcome IGFBP-3 resistance in a subset of non-small cell lung cancer (NSCLC) and head and neck squamous cell carcinoma (HNSCC) cells. The effects of the combination of rIGFBP-3 and a number of HDAC inhibitors on cell proliferation and apoptosis were assessed in vitro and in vivo by using the MTT assay, a flow cytometry-based TUNEL assay, western blot analyses, and the NSCLC xenograft tumor model. Combined treatment with HDAC inhibitors and rIGFBP-3 had synergistic antiproliferative effects accompanied by increased apoptosis rates in a subset of NSCLC and HNSCC cell lines in vitro. Moreover, combined treatment with depsipeptide and rIGFBP-3 completely suppressed tumor growth and increased the apoptosis rate in vivo in H1299 NSCLC xenografts. Evidence suggests that HDAC inhibitors increased the half-life of rIGFBP-3 protein by blocking protein kinase C (PKC)-mediated phosphorylation and degradation of rIGFBP-3. In addition, combined treatment of IGFBP-3 with an HDAC inhibitor facilitates apoptosis through up-regulation of rIGFBP-3 stability and Akt signaling inhibition. The ability of HDAC inhibitors to decrease PKC activation may enhance apoptotic activities of rIGFBP-3 in NSCLC cells in vitro and in vivo. These results indicated that combined treatment with HDAC inhibitor and rIGFBP-3 could be an effective treatment strategy for NSCLC and HNSCC with highly activated PKC.

Background Vitiligo is an acquired pigmentary disorder caused by the destruction of melanocytes. Two of the major theories regarding the pathogenesis of vitiligo are the autoimmune theory and autocytotoxicity theory, but, the precise pathogenetic mechanism is still not clarified. Objectives We investigated the effects of ET-1, tacrolimus and tumour necrosis factor-α (TNF-α) on proliferation and migration of cultured normal human melanocytes (NHMs). We also sought to clarify the theoretical rationale underlying the topical tacrolimus monotherapy or tacrolimus-UV combination therapy as tools for vitiligo treatment. Methods The effects of ET-1, tacrolimus and TNF-α on proliferation/migration of cultured NHMs were investigated by MTT assay/Boyden chamber transwell migration assay. We also examined roles of CXC-chemokine receptor II (CXCR II) and matrix metalloproteinases (MMPs) in such conditions. Results ET-1 exerted a stimulatory effect on melanocyte proliferation and migration, but, tacrolimus exerted a stimulatory effect only on melanocyte migration higher than ET-1. TNF-α inhibited melanocyte proliferation in a dose-dependent manner. Paradoxically, TNF-α-pretreated NHMs exhibited an enhanced proliferative efficiency after being switched to ET-1. We found CXCRII was highly expressed in TNF-α-incubated melanocytes than the agents-free control, and ET-1 treatment after TNF-α preincubation showed the higher levels of CXCRII expression than the condition incubated with TNF-α alone. Moreover, the greater activities of MMP-2 and MMP-9 induced by tacrolimus than ET-1, reflected tacrolimus would enhance migration stimulatory effect in cultured NHMs. Conclusions Topical tacrolimus can be used an effective agent for vitiligo treatment as monotherapy, maybe due to its migration stimulatory action or TNF-α inhibitory property, and also as a component in combination therapy with UV treatment, considering the more upregulated MMPs activities are induced and the more effective migrations are feasible by itself than ET-1.

We propose a novel approach to achieve a homogeneous alignment of nematic liquid crystal (LC). Two bare substrates are rubbed in antiparallel direction and a mixture of LC and reactive mesogen (RM) is filled into the cell using capillary injection, and then UV is exposed after confirming the clear homogenous alignment. The cell shows an excellent dark state and stable electro-optic on/off switching in the IPS cell, which proves polymerized RM on surfaces plays role of alignment layer. Proposed fabrication method has several advantages such as simple process and low cost for IPS cell because alignment layer as well as the coating process is not required.

Ion movement in liquid crystal displays plays crucial role in residual dc associated with image sticking. This paper investigatesadsorption and desorption of ions at interfaces between liquid crystal and alignment layer depending on resistivity of alignment layer and sign of dielectric anisotropy of liquid crystal in thefringe field switching (FFS) liquid crystal cell. Our studies show that the resistivity of alignment layer mainly determines ion movement such that the one with lower resistivity shows faster absorption and desorption at the interface than that of the one with higher resistivity.

Electrically tunable focusing microlens arrays based on polarization independent optical phase of nano liquid crystal droplets dispersed in polymer matrix are demonstrated. Such an optical medium is optically isotropic which is so-called an optically isotropic liquid crystals (OILC). We not only discuss the optical theory of OILC, but also demonstrate polarization independent optical phase modulation based on the OILC. The experimental results and analytical discussion show that the optical phase of OILC microlens arrays results from mainly orientational birefringence which is much larger than the electric-field-induced birefringence (or Kerr effect). The response time of OILC microlens arrays is fast similar to 5.3ms and the tunable focal length ranges from 3.4 mm to 3.8 mm. The potential applications are light field imaging systems, 3D integrating imaging systems and devices for augment reality. (C) 2015 Optical Society of America

Background Surgical excision is conventionally regarded as the treatment of choice for nodular basal cell carcinoma (nBCC), and methyl aminolevulinate photodynamic therapy (MAL-PDT) has relatively low efficacy for nBCC. However, Er:YAG ablative fractional laser (AFL)-primed MAL-PDT (Er:YAG AFL-PDT) may offer enhanced efficacy for nBCC, especially thin nBCC (thickness ≤2 mm). Objective We compared Er:YAG AFL-PDT with conventional MAL-PDT for thin facial nBCC in Korean patients. Methods Thirty-nine patients (42 lesions) with primary, histologically proven thin nBCCs were randomized to Er:YAG AFL-PDT (single session, n = 20) or conventional MAL-PDT (two sessions, 7 days apart, n = 19). Efficacy, recurrence rate, cosmetic outcomes and safety were assessed 1 week, 3 months and 12 months after the last treatment. Results Three months after the final treatment, overall complete response rates were 84.2% with Er:YAG AFL-PDT and 50% with MAL-PDT (P = 0.026). The recurrence rate was significantly lower with Er:YAG AFL-PDT (6.3%) than with MAL-PDT (55.6%) at 12 months (P = 0.006). Er:YAG AFL-PDT and MAL-PDT did not differ significantly with respect to cosmetic outcomes or safety. Conclusions Er:YAG AFL-PDT can be used as an alternative treatment option for patients who have thin nBCC and are not suitable for surgical treatment.

The efficacy of erlotinib, the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, has been demonstrated in patients with non-small cell lung cancer (NSCLC) and pancreatic cancer (PC). In the present study, we evaluated the effect of epidermal growth factor (EGF) ointment on erlotinib-related skin effects (ERSEs). This was an open-label, non-comparative, multicenter, phase II trial. The patients included those diagnosed with NSCLC or PC who were treated with erlotinib. The effectiveness of the ointment was defined as follows: (1) grade 2, 3, or 4 ERSEs downgraded to ≤grade 1 or (2) grade 3 or 4 ERSEs downgraded to grade 2 and persisted for at least 2 weeks. Fifty-two patients from seven institutes in Korea were enrolled with informed consent. The final assessment included 46 patients (30 males, 16 females). According to the definition of effectiveness, the EGF ointment was effective in 36 (69.2 %) intention to treat patients. There were no statistically significant differences in the effectiveness of the EGF ointment by gender (p = 0.465), age (p = 0.547), tumor type (p = 0.085), erlotinib dosage (p = 0.117), and number of prior chemotherapy sessions (p = 0.547). The grading for the average National Cancer Institute’s Common Terminology Criteria for Adverse Events (NCI-CTCAE) rating of rash/acne and itching improved from 2.02 ± 0.83 to 1.13 ± 0.89 and 1.52 ± 0.84 to 0.67 ± 0.90, respectively (p

Experiments were performed in an optically accessible DI diesel engine to investigate the effects of the addition of dimethoxymethane (DMM) to diesel fuel. The DMM was blended into the baseline diesel fuel to obtain 2% and 4% oxygen by fuel mass. Laser light extinction was used to measure soot variation during combustion as well as exhaust soot levels; NOx, CO2 and CO concentrations in the exhaust were measured using gas analyzers. In addition heat release analysis and direct photography were used to characterize the combustion process. The addition of DMM led to significant reductions in soot, but heat release analysis showed that it also caused significant changes in combustion characteristics, with increases of up to 1.7° of crank angle in ignition delay as well as increases in the fraction of premixed burn. Then, 2-ethylhexylnitrate was used to compensate for the effects on heat release characteristics to determine the relative importance of chemical and heat release effects in reducing soot. A fuel b...