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.

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.

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.

Role of p53 in transcriptional repression of SVCT2.

SVCT2, Sodium-dependent Vitamin C Transporter 2, uniquely transports ascorbic acid (also known as vitamin C and ascorbate) into all types of cells. Vitamin C is an essential nutrient that must be obtained through the diet and plasma levels are tightly regulated by transporter activity. Vitamin C plays an important role in antioxidant defenses and is a cofactor for many enzymes that enable hormone synthesis, oxygen sensing, collagen synthesis and epigenetic pathways. Although SVCT2 has various functions, regulation of its expression/activity remains poorly understood. We found a p53-binding site, within the SVCT2 promoter, using a transcription factor binding-site prediction tool. In this study, we show that p53 can directly repress SVCT2 transcription by binding a proximal- (~-185 to -171 bp) and a distal- (~-1800 to -1787 bp) p53-responsive element (PRE), Chromatin immunoprecipitation assays showed that PRE-bound p53 interacts with the corepressor-histone deacetylase 3 (HDAC3), resulting in deacetylation of histones Ac-H4, at the proximal promoter, resulting in transcriptional silencing of SVCT2. Overall, our data suggests that p53 is a potent transcriptional repressor of SVCT2, a critical transporter of diet-derived ascorbic acid, across the plasma membranes of numerous essential tissue cell types.

In vivo evaluation of novel particle-free polycaprolactone fillers for safety, degradation, and neocollagenesis in a rat model.

Dermal fillers have become popular due to the increased demand for skin rejuvenation products. Polycaprolactone (PCL), a newly developed bioresorbable medical polymer, has emerged as a durable and safe dermal filler. However, available PCL fillers cause irritation; carrier gels can coagulate PCL particles, block the injection needle, and cause nonhomogeneity of particle suspensions that could be responsible for the observed side effects. To relieve pain, premixing PCL filler with lidocaine. However, this formulation changes the property of the CMC portion of the PCL filler, and possibly results in an uneven suspension of the PCL particles. Hence, a particle-free PCL homogeneously solubilized in water was developed to overcome these limitations. This study aimed to assess the in vivo safety, biodegradability, and neocollagenesis ability of a novel PCL filler, DLMR01 using a rat model. Fillers were characterized after injecting a vehicle control or DLMR01 using a digital camera, folliscope, and a three-dimensional profiling system. Biopsy was performed to evaluate biocompatibility and neocollagenesis. Skin elasticity was measured using a Cutometer. DLMR01 caused no needle occlusion by particle aggregation or laborious injectability. Filler nodules dispersed to surrounding tissues within 6 hours without further granuloma formation. Histological inspection revealed no tissue residual material or foreign body reaction during the 12-week test period. DLMR01 increased dermal thickness, collagen regeneration, and skin elasticity. In conclusion, this study demonstrates the potential of DLMR01 for dermal rejuvenation in a rat model.

Life and death of liquid-infused surfaces: a review on the choice, analysis and fate of the infused liquid layer.

Liquid-infused surfaces (or lubricant-infused surfaces) (LIS) are a new class of functional materials introduced in 2011. Their exceptional properties have earned them a place at the forefront of many fields including anti-biofouling, anti-icing, anti-corrosion, drag reduction, droplet manipulation and drop-wise condensation. Integral to their success is the infused lubricant layer which affords them their properties. In this review, we examine the current state of the literature relating to the lubricant layer. We consider the lubricant through all stages in the surface's lifecycle from design, to use, all the way through to depletion and eventual failure. First, we examine trends in lubricant choice and how to choose a lubricant, including environmental and medical considerations. We then look at the different methods used to infuse lubricant into surfaces and how lubricant depletes from the surface. We then report direct and indirect methods to characterise the thickness and distribution of the lubricant layer. Finally, we examine how droplets interact with LIS and the unique properties afforded by the lubricant before providing an outlook into where research centred on understanding the lubricant layer is heading in the new decade.

Inhibition of JAK1/2 can overcome EGFR-TKI resistance in human NSCLC.

Non-small lung cancer (NSCLC) is the most common cancer in the world. The epidermal growth factor receptor (EGFR) gene is mutated in approximately 10% of lung cancer cases in the US and 50% of lung cancer in Asia. The representative target therapeutic agent, erlotinib (EGFR tyrosine kinase inhibitor; EGFR TKI), is effective in inactivating EGFR in lung cancer patients. However, approximately 50-60% of patients are resistant to EGFR TKI. These populations are associated with the EGFR mutation. To overcome resistance to EGFR TKI, we discovered a JAK1 inhibitor, CJ14939. We investigated the efficacy of CJ14939 in human NSCLC cell lines in vitro and in vivo. Our results showed that CJ14939 induced the inhibition of cell growth. Moreover, we demonstrated that combination treatment with erlotinib and CJ14939 induced cell death in vitro and inhibited tumor growth in vivo. In addition, we confirmed the suppression of phosphorylated EGFR, JAK1, and Stat3 expression in erlotinib and CJ14939-treated human NSCLC cell lines. Our results provide evidence that JAK inhibition overcomes resistance to EGFR TKI in human NSCLCs.

Chemosensitivity to HM90822, a novel synthetic IAP antagonist, is determined by p-AKT-inducible XIAP phosphorylation in human pancreatic cancer cells.

Inhibitor of apoptosis proteins (IAPs) are overexpressed in the majority of cancers and prevent apoptosis by inhibiting caspases. IAPs have therefore attracted considerable attention as potential targets for anticancer therapy. Here, we demonstrated that HM90822 (abbreviated HM822; a new synthetic IAP antagonist) induced apoptotic cell death via proteasome-dependent degradation of BIR2/3 domain-containing IAPs in human pancreatic cancer cells. HM822 inhibited the expression of XIAP and cIAP1/2 proteins in Panc-1 and BxPC-3 cells, which are sensitive to HM822. HM822 also induced IAP ubiquitination and promoted proteasome-dependent IAP degradation. However, cells expressing phospho-XIAP (Ser87) and AKT exhibited resistance to HM822. In other words, the overexpression of AKT-CA (constitutive active form for AKT) or AKT-WT induced resistance to HM822. In addition, in Panc-1 xenograft and orthotopic mouse models, we revealed that tumor growth was suppressed by the administration of HM822. Taken together, these results suggest that HM822 induces apoptosis through ubiquitin/proteasome-dependent degradation of BIR3 domain-containing IAPs. These findings suggest that phospho-XIAP and phospho-AKT may be used as biomarkers for predicting the efficacy of HM822 in pancreatic cancer patients.

In vivo quantitative analysis of advanced glycation end products in atopic dermatitis-Possible culprit for the comorbidities?

Advanced glycation end products (AGEs) interact with the membrane-bound receptor for AGEs (RAGE), consequently amplifying the inflammatory response. Soluble receptor for AGE (sRAGE) and endogenous secretory RAGE (esRAGE) act as decoys for AGE and competitively sequester RAGE ligands, thereby serving a cytoprotective role. Our objective was to investigate AGE expression and their receptors in the serum and skin of patients with atopic dermatitis (AD). In this case-control study, the levels of AGE, sRAGE and esRAGE were measured in the blood samples and corneocytes of 29 adult patients with AD and 12 healthy controls by ELISA. Corneocyte AGE levels increased in the AD group (P = .002). Higher corneocyte AGE levels were observed in the severe AD than in the milder form of AD. No significant difference in serum AGE level was observed in patients with AD and healthy controls. Serum sRAGE markedly decreased in patients with AD (P = .007) and serum esRAGE followed a similar trend. In conclusion, dermal accumulation of AGE in AD may have a role in fuelling skin inflammation. The potential after-effects of reduced neutralizer on systemic risk need further evaluation.

Successful Treatment of Pigmentary Disorders in Asians With a Novel 730-nm Picosecond Laser.

BACKGROUND AND OBJECTIVE: Until recently, quality-switched nanosecond lasers have been the workhorse lasers in treating pigmented lesions. However, the recently commercialized picosecond lasers have provided physicians with a novel method to manage pigmented lesions. Most recently, the first picosecond laser with a 730-nm wavelength was developed to specifically target melanin and melanocytes. STUDY DESIGN/MATERIALS AND METHODS: We report on two Asian patients with freckles, lentigines, and melasma who were successfully treated with a novel 730-nm Ti:Sapphire picosecond laser (Picoway®; Syneron Candela, Corp). The clinical outcome was measured by the global percent of clearance, which was evaluated by blinded observers by comparing the post-treatment photographs with the baseline photographs. RESULTS: In both patients, a significant pigmentary reduction was achieved with only one treatment session. In both patients, the treatments were well tolerated with minimal discomfort even without topical anesthesia. No post-inflammatory hyperpigmentation or repigmentation was observed until the 6-week follow-up. The pigmentary conditions treated included freckles, lentigines, and melasma. Both subjects showed clinical improvement, with the best results observed for the treatment of freckles such that 95% of the lesions achieved excellent response (75-94% lightening). CONCLUSION: The results of this case report indicate that a novel 730-nm Ti:Sapphire picosecond laser may be effective and safe in treating pigmentary disorders in darker-skinned patients. Therefore, further well-designed, prospective clinical trials are warranted to establish the potential of 730-nm picosecond lasers and determine the optimal treatment parameters in comparison to existing laser and light modalities. Lasers Surg. Med. © 2020 Wiley Periodicals LLC.

Targeting ß-catenin overcomes MEK inhibition resistance in colon cancer with KRAS and PIK3CA mutations.

BACKGROUND: Mitogen-activated protein kinases (MEK 1/2) are central components of the RAS signalling pathway and are attractive targets for cancer therapy. These agents continue to be investigated in KRAS mutant colon cancer but are met with significant resistance. Clinical investigations have demonstrated that these strategies are not well tolerated by patients. METHODS: We investigated a biomarker of response for MEK inhibition in KRAS mutant colon cancers by LC-MS/MS analysis. We tested the MEK inhibitor in PIK3CA wild(wt) and mutant(mt) colon cancer cells. In addition, we tested the combinational effects of MEK and TNKS inhibitor in vitro and in vivo. RESULTS: We identified ß-catenin, a key mediator of the WNT pathway, in response to MEK inhibitor. MEK inhibition led to a decrease in ß-catenin in PIK3CA wt colon cancer cells but not in mt. Tumour regression was promoted by combination of MEK inhibition and NVP-TNS656, which targets the WNT pathway. Furthermore, inhibition of MEK promoted tumour regression in colon cancer patient-derived xenograft models expressing PIK3CA wt. CONCLUSIONS: We propose that inhibition of the WNT pathway, particularly ß-catenin, may bypass resistance to MEK inhibition in human PIK3CA mt colon cancer. Therefore, we suggest that ß-catenin is a potential predictive marker of MEK inhibitor resistance.

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.

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.

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.

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.