Efficacy and Safety of PrabotulinumtoxinA in Subjects With Benign Masseteric Hypertrophy: A Double-Blind, Randomized, Placebo-Controlled, Multicenter, Phase 3 Trial and Open-Label Extension Study.

BACKGROUND: Despite the widespread use of botulinum toxin (BTX) injection for the treatment of masseter muscle hypertrophy (MMH), there is no standard treatment option. OBJECTIVE: We report the efficacy and safety for BTX in MMH over a period of 48 weeks. METHODS: In double-blinded, placebo-controlled phase 3 trials, 180 patients (randomized 1:1) received treatment with placebo (normal saline) or prabotulinumtoxinA (48 units). Masseter muscle thickness (at maximal clenching and resting positions), 3D imaging analysis, and masseter muscle hypertrophy scale grades were analyzed at each time point. After the 24-week CORE study, all patients who met the same criteria of the CORE study at week 24 (n = 114) received only prabotulinumtoxinA, regardless of previous treatment, for an additional 24 weeks (48 weeks in total) for the open-label extension study. RESULTS: The largest differences in mean and percent changes from baseline in masseter muscle thickness were observed at 12 weeks, and there were significant differences between the 2 groups at all time points (all p < .001). The effect was independent of the number of injections. No serious adverse event was observed. CONCLUSION: PrabotulinumtoxinA could effectively ameliorate MMH without major complications.

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.

Visualizing a Nanoscale Lubricant Layer under Blood Flow.

Tethered-liquid perfluorocarbons (TLPs) are a class of liquid-infused surfaces with the ability to reduce blood clot formation (thrombosis) on blood-contacting medical devices. TLP comprises a tethered perfluorocarbon (TP) infused with a liquid perfluorocarbon (LP); this LP must be retained to maintain the antithrombotic properties of the layer. However, the stability of the LP layer remains in question, particularly for medical devices under blood flow. In this study, the lubricant thickness is spatially mapped and quantified in situ through confocal dual-wavelength reflection interference contrast microscopy. TLP coatings prepared on glass substrates are exposed to the flow of 37% glycerol/water mixtures (v/v) or whole blood at a shear strain rate of around 2900 s-1 to mimic physiological conditions (similar to flow conditions found in coronary arteries). Excess lubricant (>2 µm film thickness) is removed upon commencement of flow. For untreated glass, the lubricant is completely depleted after 1 min of shear flow. However, on optimized TLP surfaces, nanoscale films of lubricants (thickness between 100 nm and 2 µm) are retained over many tens of minutes of flow. The nanoscale films conform to the underlying structure of the TP layer and are sufficient to prevent the adhesion of red blood cells and platelets.

TCOF1 promotes the colorectal cancer progression by stabilizing ß-catenin.

Colorectal cancer (CRC) is one of the highest mortality rates worldwide, and various studies reported to the occurrence of CRC. In particular, the Wnt/ß-catenin pathway is known to be a major factor in the progression of CRC and ß-catenin involved in the expression of its downstream target genes. We searched for TCOF1 through sliver staining to identify a new binding partner for ß-catenin and to investigate the role of the gene involved in CRC. Treacle Ribosome Biogenesis Factor 1 (TCOF1) is a nucleolar protein that regulates the transcription of ribosomal DNA (rDNA). There are many reports of genetic studies on TCOF1 mutations and defects, but its function in CRC remains unknown. We demonstrated that TCOF1 and ß-catenin expression in tissue microarray (TMA) containing 101 individual CRC and 17 adjacent normal samples. Additionally, the effects of TCOF1 knockdown or overexpression were examined proliferation, colony formation assay, western blot, and quantitative real-time PCR (qRT-PCR). TCOF1 knockdown or overexpression regulates cell proliferation about three-fold and the phosphorylation of ß-catenin, cyclin D1 expression levels. Besides, we discovered the mechanism through which TCOF1 regulates the stability of ß-catenin was involved in degradation through proteasome using ubiquitination assay. Finally, we confirmed the interaction of TCOF1 with the tankyrase inhibitor NVP-TNKS656, which destabilizes ß-catenin through in vitro and in vivo. Collectively, this study shows that significantly correlation was observed that TCOF1 and ß-catenin were risk factor for tumor progression. The stability of ß-catenin via regulating TCOF1 expression could be a potential strategy for therapeutic with CRC.

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.

Adipose-derived stem cell exosomes for treatment of dupilumab-related facial redness in patients with atopic dermatitis.

BACKGROUND: Dupilumab facial redness (DFR) is a side effect of dupilumab treatment that has only been recently reported. We previously reported on two patients with DFR who were successfully treated with a topical formulation containing human adipose tissue-derived mesenchymal stem cell-derived exosomes (ASCEs). OBJECTIVES: The study aimed to evaluate the efficacy and safety of ASCEs in DFR. PARTICIPANTS AND METHODS: We performed 12-week prospective study at single center. Twenty adult atopic dermatitis patients diagnosed with DFR were enrolled. They were treated with a topical application of the exosome formulation every week for five consecutive weeks. RESULTS: After exosome treatment, both the average investigator global assessment score and clinical erythema assessment scale scores decreased. 19 patients (95%) were satisfied with the treatment. Compared to baseline, erythema index at week 4 were decreased by 31, 27, 13, and 25 units on the forehead, chin, right and left cheek respectively. The analysis of stratum corneum samples revealed the expression of IL-1α and human thymic stromal lymphopoietin was suppressed after exosome treatment, whereas filaggrin and vascular endothelial growth factor expression increased. CONCLUSIONS: This study suggests topical formulation containing ASCEs can alleviate DFR by downregulating local inflammation and restoring skin barrier function.

Bioinspired Approaches to Engineer Antithrombogenic Medical Devices for Vascular Intervention.

Medical devices form a critical component of health care systems for treating and maintaining patient health. However, devices exposed to blood are prone to blood clotting (thrombosis) and bleeding complications leading to device occlusion, device failure, embolism and stroke, and increased morbidity and mortality. Over the years, developments in innovative material design strategies have been made to help reduce the occurrence of thrombotic events on medical devices, but complications persist. Here, we review material and surface coating technologies that have taken bioinspiration from the endothelium to reduce medical device thrombosis, either by mimicking aspects of the glycocalyx to prevent adhesion of proteins and cells to the material surface or mimicking the bioactive function of the endothelium through immobilized or released bioactive molecules to actively inhibit thrombosis. We highlight newer strategies that take inspiration from multiple aspects of the endothelium or are stimuli responsive, only releasing antithrombotic biomolecules when thrombosis is triggered. Emerging areas of innovation target inflammation to decrease thrombosis without increasing bleeding, and interesting results are coming from underexplored aspects of material properties, such as material interfacial mobility and stiffness, which show that increased mobility and decreased stiffness are less thrombogenic. These exciting new strategies require further research and development before clinical translation, including consideration of longevity, cost, and sterilization, but show capacity for the development of more sophisticated antithrombotic medical device materials.

A Randomized, Prospective, Split-Face Pilot Study to Evaluate the Safety and Efficacy of 532-nm and 1,064-nm Picosecond-Domain Neodymium:Yttrium-Aluminum-Garnet Lasers Using a Diffractive Optical Element for Non-Ablative Skin Rejuvenation: Clinical and Histological Evaluation.

BACKGROUND: The advent of fractionated picosecond (ps) lasers has provided an opportunity to explore new ways of creating microinjuries in the skin to induce skin rejuvenation. OBJECTIVE: To compare the efficacy and safety of diffractive optical element (DOE)-assisted ps neodymium: yttrium-aluminum-garnet (Nd:YAG) lasers with 532-nm and 1,064-nm wavelengths (532-nm and 1,064-nm Nd:YAG P-DOE) using a novel fractional handpiece for the treatment of photoaged skin. METHODS: An ex vivo guinea pig skin experiment was performed by evaluating the histology of the skin after 532-nm Nd:YAG P-DOE irradiation. A randomized, prospective, split-face study was performed on eight subjects with 532-nm and 1,064-nm Nd:YAG P-DOE. RESULTS: Based on the histological evaluation using ex vivo guinea pig skin, a reasonable safety profile and the potential to generate effective skin rejuvenation was observed using the 532-nm Nd:YAG P-DOE. Results demonstrated that both 532- and 1,064-nm Nd:YAG P-DOE were similarly effective in improving skin texture and skin pores; however, 532-nm Nd:YAG P-DOE was more effective in treating dyspigmentation. CONCLUSION: At a preliminary level, this study revealed that 532-nm and 1,064-nm ps Nd:YAG lasers using DOE fractional technology may improve photoaged skin. In conclusion, 532-nm Nd:YAG P-DOE may be especially beneficial for skin with epidermal pigmentary lesions.

Combination of Non-Ablative Fractional Laser with Q-Switched Laser for the Treatment of Becker's Nevus: Efficacy and Limitations.

Becker's nevus (BN) is a benign hamartoma that may present as a distressing cosmetic problem. The treatment of BN poses a significant challenge as current therapeutic modalities are suboptimal and have an increased risk of adverse effects, such as scarring and dyspigmentation. We present the use of non-ablative fractional laser therapy combined with Q-switched Nd:YAG laser as a possible therapeutic option for BN treatment and review relevant literature to discuss its efficacy and limitations.

Treatment of facial pigmented disorders with a 785-nm picosecond Ti:sapphire laser in Asians: A report of three cases.

Since the advent of the theory of selective photothermolysis, the importance of targeting the chromophore and minimizing the surrounding damage has been extensively discussed. Picosecond-domain laser (ps-laser) treatment with a wide range of wavelengths is an emerging option for various pigmented lesions; however, no definitive treatment choice has been confirmed. The authors aimed to investigate the efficacy and safety of a ps-laser with a 785-nm wavelength for the treatment of facial pigmented lesions in Asians. Three Korean patients with facial pigmented lesions were recruited for the study. A 785-nm ps-laser with a fractionated and an unfractionated handpiece was utilized to administer the treatment. The clinical outcome was evaluated by a clinician by comparing pre- and post-treatment photographs. All patients exhibited a significant improvement in pigmented lesions including freckles, lentigines, and melasma, after three to four sessions of treatment. No adverse events, including post-inflammatory hyperpigmentation or hypopigmentation were observed. In conclusion, this novel 785-nm Ti:sapphire ps-laser may be an effective and safe modality for treating pigmented lesions in skin of color.

Mechanisms for Reduced Fibrin Clot Formation on Liquid-Infused Surfaces.

Biomedical devices are prone to blood clot formation (thrombosis), and liquid-infused surfaces (LIS) are effective in reducing the thrombotic response. However, the mechanisms that underpin this performance, and in particular the role of the lubricant, are not well understood. In this work, it is investigated whether the mechanism of LIS action is related to i) inhibition of factor XII (FXII) activation and the contact pathway; ii) reduced fibrin density of clots formed on surfaces; iii) increased mobility of proteins or cells on the surface due to the interfacial flow of the lubricant. The chosen LIS is covalently tethered, nanostructured layers of perfluorocarbons, infused with thin films of medical-grade perfluorodecalin (tethered-liquid perfluorocarbon), prepared with chemical vapor deposition previously optimized to retain lubricant under flow. Results show that in the absence of external flow, interfacial mobility is inherently higher at the liquid-blood interface, making it a key contributor to the low thrombogenicity of LIS, as FXII activity and fibrin density are equivalent at the interface. The findings of this study advance the understanding of the anti-thrombotic behavior of LIS-coated biomedical devices for future coating design. More broadly, enhanced interfacial mobility may be an important, underexplored mechanism for the anti-fouling behavior of surface coatings.

Zn speciation and fate in soils and sediments along the ground transportation route of Zn ore to a smelter.

Assessment of Zn toxicity/mobility based on its speciation and transformations in soils is critical for maintaining human and ecosystem health. Zn-concentrate (56 % Zn as ZnS, sphalerite) has been imported through a seaport and transported to a Zn-smelter for several decades, and smelting processes resulted in aerial deposition of Zn and sulfuric acids in two geochemically distinct territories around the smelter (mountain-slope and riverside). XAFS analysis showed that the mountain-slope soils contained franklinite (ZnFe2O4) and amorphous (e.g., sorbed) species of Zn(II), whereas the riverside sediments contained predominantly hydrozincite [Zn5(OH)6(CO3)2], sphalerite, and franklinite. The mountain-slope soils had low pH and moderate levels of total Zn (~ 1514 ppm), whereas the riverside sediments had neutral pH and higher total Zn (12,363 ppm). The absence of sphalerite and the predominance of franklinite in the mountain-slope soils are attributed to the susceptibility of sphalerite and the resistance of franklinite to dissolution at acidic pH. These results are compared to previous Zn analyses along the transportation routes, which showed that Zn-concentrate spilled along the roadside in dust and soils underwent transformation to various O-coordinated Zn species. Overall, Zn-concentrate dispersed in soils and sediments during transportation and smelting transforms into Zn phases of diverse stability and bioavailability during long-term weathering.

Quantitative Evaluation of Volume Augmentation and Durational Changes in the Anteromedial Cheek with Hyaluronic Acid Fillers Using Three-Dimensional Measurement: 2-Year Results from a Comparative Split-Face Study.

SUMMARY: Hyaluronic acid fillers are widely used for the augmentation of facial soft tissues. Hyaluronic acid fillers can be monophasic or biphasic and have different characteristics, especially regarding volumetric effects and maintenance potential. However, there is paucity of long-term quantitative and objective data on clinical outcomes following hyaluronic acid injection. In this study, the authors evaluated volumetric changes over 2 years and the maintenance potentials of both types of fillers on the anteromedial cheek using objective three-dimensional measurements. This comparative split-face study enrolled participants aged 30 to 50 years who received a midfacial injection of the test filler (Belotero Volume) on one side and a random control filler (Juvéderm, Restylane SubQ, or Yvoire Contour) on the contralateral side. The authors conducted three-dimensional scanning assessments at baseline and after 30 minutes; 3 days; 2, 4, 12, and 24 weeks; and 2 years. The volume augmentation effects for the anteromedial cheek of two monophasic fillers (Belotero Volume and Juvéderm Voluma) were maintained for at least 2 years (81 percent and 66 percent, respectively, compared to the volume at 4 weeks). Two biphasic fillers (Yvoire Contour and Restylane SubQ) maintained over 50 percent volume compared to the volume 4 weeks after injection. Monophasic fillers showed better outcomes than biphasic fillers; however, both types of hyaluronic acid fillers demonstrated superior efficacy, safety, and durability for volumetric augmentation in the anteromedial cheek. Objective data obtained using three-dimensional imaging analysis will enable dermatologists to better demonstrate the results of the procedure to patients, through the provision of visual aids. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II.

CJ14939, a Novel JAK Inhibitor, Increases Oxaliplatin-induced Cell Death Through JAK/STAT Pathway in Colorectal Cancer.

BACKGROUND/AIM: Colorectal cancer is reported to have the highest mortality rate among human malignancies. Although many research results for the treatment of colorectal cancer have been reported, there is no suitable treatment when resistance has developed. Therefore, it is necessary to develop new therapeutic agents. Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling plays an essential role in cell differentiation, proliferation, and survival. Abnormal activation of the JAK/STAT signaling pathway, by gene mutation or amplification, may induce cancer development, and sustained JAK/STAT activation is involved in chemoresistance. While many therapeutic agents have been developed to treat colon cancer, there remains no drug to overcome resistance to chemotherapies. The purpose of this study was to determine the potential of CJ14939 as a novel JAK inhibitor for the treatment of colorectal cancer. MATERIALS AND METHODS: In this study, cell culture, cell death assay, 3- (4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assay, colony formation assay, immunoblot analysis and tumor xenograft were applied. RESULTS: CJ14939 induced cell death, and inhibited phosphorylation of JAK1 and STAT3 in colorectal cancer cells. Furthermore, CJ14939 also promoted oxaliplatin-induced cell death, up-regulated expression of cleaved caspase-3, and down-regulated expression of phospho-JAK1 and phospho-STAT3. In vivo, co-treatment with CJ14939 and oxaliplatin notably reduced tumor growth when compared with CJ14939 or oxaliplatin treatment alone. CONCLUSION: This study identifies the important potential of CJ14939 in colorectal cancer treatment and suggests that combining CJ14939 with oxaliplatin might be a novel therapeutic strategy for patients with colorectal cancer.

A prospective, split-face study comparing 1,064-nm picosecond Nd:YAG laser toning with 1,064-nm Q-switched Nd:YAG laser toning in the treatment of melasma.

BACKGROUND: Recently, a low-fluence picosecond (ps) laser is an emerging option for removing pigmented lesions. OBJECTIVES: We aimed to evaluate the efficacy and safety of a 1,064-nm ps Nd:YAG laser as compared to a 1,064-nm Qs Nd:YAG laser for melasma treatment in an Asian. METHODS: Twenty Korean patients with facial melasma were enrolled and randomly treated with a 1,064-nm ps Nd:YAG laser on one side of the face and 1,064-nm Qs Nd:YAG on the other side at 2-week intervals for five sessions. At each visit, the modified Melasma Area Severity Index (mMASI), patient satisfaction scores, visual analogue scale (VAS) scores, and adverse events were assessed. RESULTS: Both groups showed significant clinical improvement and decreased mMASI scores compared to the baseline. No statistically significant difference was observed in the mMASI score between the two treatment techniques at any time point. The melanin index showed no statistically significant improvement in both groups, and no significant differences were observed in patient satisfaction scores and VAS scores between both modalities. CONCLUSIONS: A 1,064 nm ps Nd:YAG laser is as effective and safe as a conventional 1,064 nm Qs Nd:YAG laser in the treatment of melasma in Asian skin, but no superior outcome was observed.