Chemoprevention of Familial Melanoma

Bleaching agents 4-tertiary butyl phenol (4-TBP) and monobenzyl ether of hydroquinone (MBEH) have been known to cause occupational vitiligo This project answers whether agents 4-TBP and MBEH can be used for prophylactic treatment of familial melanoma by being specifically toxic to melanocytes and activating an immune response against distant pigment cells. Cytotoxic experiments reveal that similar to 4-TBP, MBEH induces specific melanocyte death. To compare death pathways initiated by 4-TBP and MBEH, classical apoptotic hallmarks were evaluated in treated melanocytes. MBEH induced cell death without activating the caspase cascade or DNA fragmentation, showing that the death pathway is non-apoptotic. Release of High Mobility Group Box-1 protein by MBEH-treated melanocytes and ultrastructural features further confirmed a necrotic death pathway mediated by MBEH. A negative correlation between MBEH-induced cell death and cellular melanin content supports a cytoprotective role for melanin. Moreover, MBEH exposure upregulated the levels of melanogenic enzymes in cultured melanocytes whereas 4-TBP reduced the expression of the same. Insensitivity of melanoma cell lines to either agent in comparison with melanocytes further supported the need for prophylactic therapy. Successful prophylaxis will likely require a systemic immune response in order to eradicate all melanocytes; therefore, immune infiltrates in response to these agents was assessed in vivo. C57BL/6 wild type as well as k14-SCF transgenic, mice were topically treated with either agent. MBEH induced significant skin depigmentation in both strains, not observed upon 4-TBP treatment. A significant increase in the migration of Langerhans cells towards the dermis in human skin explants, upon MBEH treatment, suggested selective elicitation of an immune response. Cytokine expression patterns in skin treated with MBEH supported activation of a Th1-mediated immune response corresponding to an influx of T cells and macrophages. Importantly, despite insensitivity of tumor cells to MBEH-induced cytotoxicity, significantly retarded tumor growth was observed in B16 challenged k14-SCF mice pretreated with MBEH, likely due to an abundance of cytotoxic T cells accompanied by an increased expression of Th1 and Th17 cytokines. . In conclusion topical application of MBEH and not 4-TBP generates a two tierd response that constitutes a candidate prophylactic treatment of familial melanoma

Real-time Monitoring for the Next Core-Collapse Supernova in JUNO

Core-collapse supernova (CCSN) is one of the most energetic astrophysical events in the Universe. The early and prompt detection of neutrinos before (pre-SN) and during the SN burst is a unique opportunity to realize the multi-messenger observation of the CCSN events. In this work, we describe the monitoring concept and present the sensitivity of the system to the pre-SN and SN neutrinos at the Jiangmen Underground Neutrino Observatory (JUNO), which is a 20 kton liquid scintillator detector under construction in South China. The real-time monitoring system is designed with both the prompt monitors on the electronic board and online monitors at the data acquisition stage, in order to ensure both the alert speed and alert coverage of progenitor stars. By assuming a false alert rate of 1 per year, this monitoring system can be sensitive to the pre-SN neutrinos up to the distance of about 1.6 (0.9) kpc and SN neutrinos up to about 370 (360) kpc for a progenitor mass of 30$M_{\odot}$ for the case of normal (inverted) mass ordering. The pointing ability of the CCSN is evaluated by using the accumulated event anisotropy of the inverse beta decay interactions from pre-SN or SN neutrinos, which, along with the early alert, can play important roles for the followup multi-messenger observations of the next Galactic or nearby extragalactic CCSN.Comment: 24 pages, 9 figure

Evaluation of the effect of titanium dioxide and gold nanoparticles surface treatment on the flexural strength of polymethyl methacrylate heat cure denture base resin

Aim: The purpose of this study was to evaluate the effect of Titanium dioxide and Gold nanoparticles surface treatment on the flexural strength of Polymethyl methacrylate (PMMA) Heat cure denture base resins.Materials and methods: A total of thirty PMMA Heat cure denture base resin test samples were fabricated of size 65 x 10 x 2.5 mm (rectangular shaped) according to ADA specification no.2. The samples were divided into three groups as Conventional PMMA heat cure denture base resin samples (GROUP I, n = 10 CONTROL), PMMA Heat cure denture base resin samples coated with Titanium dioxide nanoparticles (GROUP II, n = 10) and PMMA Heat cure denture base resin samples coated with Gold nanoparticles (GROUP III, n = 10). GROUP II and GROUP III PMMA Heat cure denture base resin test samples were coated by Magnetron sputtering. Flexural strength of GROUP I, GROUP II and Group III was evaluated by a three-point bend test using a Universal testing machine and the mean values were obtained.Results: The Mean flexural strength of GROUP I, GROUP II and GROUP III samples were 114.79 MPa, 142.48 MPa and 154.70 MPa respectively. On comparative evaluation of the flexural strength among the three groups GROUP III PMMA Heat cure denture base resin samples exhibited the highest flexural strength followed by GROUP II and least by GROUP I. The statistical analysis by ANOVA had shown that there is significance in flexural strength among the groups tested (p - value = 0.000*).Conclusion: Within the limitations of the study, PMMA heat cure denture base resin coated with Gold nanoparticles showed the highest flexural strength followed by PMMA Heat cure denture base resin coated with Titanium dioxide nanoparticles. Conventional PMMA Heat cure denture base resin without any surface treatment showed the least flexural strength

Comparative evaluation of the effect of electrolyzed oxidizing water on surface detail reproduction, dimensional stability and Surface texture of poly vinyl siloxane impressions

Aim: The aim of this in vitro study was to comparatively evaluate the effect of chemical disinfectants on the surface detail reproduction, dimensional stability and surface texture of polyvinyl siloxane (PVS) impressions. Materials and Methods: The impressions were then divided into five groups (fifteen samples per group) and subjected to a ten minutes immersion with 2% glutaraldehyde (Group I), 1% sodium hypochlorite (Group II), freshly prepared electrolyzed oxidizing water (EOW) with different pH values - acidic (Group III), alkali (Group IV) and neutral (Group V). The samples were examined pre and post-immersion under visual observation for surface detail reproduction, travelling microscope for measurement of dimensional stability and surface profilometer (3D) for evaluation of surface texture. A standardized master die was fabricated and seventy-five PVS test samples were made. The samples were subjected to immersion disinfection and studied for surface detail reproduction, dimensional stability and surface texture. Post-hoc test, paired t test and ANOVA were used to analyze dimensional stability statistically both within and between the test groups. Results: The surface detail reproduction was satisfactory with both pre and post-immersion test samples. A statistically significant dimensional change was observed post-immersion in Groups II, III and V test samples and a statistically insignificant dimensional change was observed in Groups I and IV test samples. There was a negligible change in surface texture post-immersion in Groups I, III, IV and V test samples with a slight increase in surface roughness post-immersion in Group II samples. Conclusion: In this study, all the test disinfectants produced satisfactory surface detail reproduction on Polyvinyl siloxane impressions. 2% glutaraldehyde and electrolyzed oxidizing water (alkali) have resulted in statistically insignificant dimensional change, while 1% sodium hypochlorite, electrolyzed oxidizing water (acidic) and electrolyzed oxidizing water (neutral) have resulted in statistically significant dimensional changes. All the test disinfectants except 1% sodium hypochlorite showed a reduction in surface roughness (Ra) values

Enhanced bleaching treatment: opportunities for immune-assisted melanocyte suicide in vitiligo

Depigmentation in vitiligo occurs by progressive loss of melanocytes from the basal layer of the skin, and can be psychologically devastating to patients. T cell-mediated autoimmunity explains the progressive nature of this disease. Rather than being confronted with periods of rapid depigmentation and bouts of repigmentation, patients with long-standing, treatment-resistant vitiligo can undergo depigmentation treatment. The objective is to remove residual pigmentation to achieve a cosmetically acceptable result--that of skin with a uniform appearance. In the United States, only the use of mono-benzyl ether of hydroquinone (MBEH) is approved for this purpose. However, satisfactory results can take time to appear, and there is a risk of repigmentation. MBEH induces necrotic melanocyte death followed by a cytotoxic T-cell response to remaining, distant melanocytes. As cytotoxic T-cell responses are instrumental to depigmentation, we propose that combining MBEH with immune adjuvant therapies will accelerate immune-mediated melanocyte destruction to achieve faster, more definitive depigmentation than with MBEH alone. As Toll-like Receptor (TLR) agonists--imiquimod, CpG, and Heat Shock Protein 70 (HSP 70)--all support powerful Th1 responses, we propose that using MBEH in combination with these agents can achieve superior depigmentation results for vitiligo patient