Nm In Combination Research Articles

Abstract 701: Preclinical data of a novel DNA-PK inhibitor in combination with radiation therapy shows promise in the treatment of established GBM and lung carcinoma cell lines

Abstract Radiation therapy (RT) is a cornerstone of oncologic therapy for the majority of solid malignancies, and unrepaired DNA double-strand breaks are responsible for radiation-induced cytotoxicity. RT-induced DNA lesions can be repaired by multiple mechanisms including homologous recombination (HR) and non-homologous end joining (NHEJ), and disruption of either of these pathways can enhance cytotoxicity. A key component of the NHEJ pathway is the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs), and loss of kinase activity can significantly increase radiosensitivity. Herein we describe the results of our medicinal chemistry campaign to develop a potent and selective DNA-PKcs inhibitor, WNC0901. WNC0901 inhibits DNA-PKcs kinase activity in a cell free system with an IC50 of 0.071 nM and demonstrated at least 30-fold higher sensitivity than other family members (ATM, ATR, mTOR, PI3K). WNC0901 has limited aldehyde oxidase (AO) liability with a T1/2 >2000 min in liver cytosol and is stable for over 120 minutes in the presence and absence of an AO inhibitor. A preliminary pharmacokinetic analysis in wista han rat (IV=2mg/kg, PO=20mg/kg) demonstrated 116% apparent absolute oral bioavailability, 2.6 hour terminal half-life, 33.0 mL/min/kg clearance, and a 2.6% unbound brain-to-plasma partition coefficient (Kpuu). WNC0901 also had favorable pharmacokinetic properties in beagle dog (IV=2mg/kg, PO=20mg/kg) with moderate clearance (8.5 mL/min/kg), high apparent absolute oral bioavailability (131%) with good exposure (AUC=36092 h*ng/mL), moderate half-life (4.28 h), and low protein binding (74.3% fraction unbound). The volume of distribution was moderate in both species (Vss = 1.32 L/kg in wistar han rat and 1.87 L/kg in beagle dog). In cell culture, WNC0901 inhibited autophosphorylation of DNA-PKcs in HT29 cells irradiated with 10 Gy with an IC50 of 32.7 nM and robustly inhibited autophosphorylation in both U251 glioma and A549 lung cancer cell lines at 300 nM in combination with 5Gy. In a clonogenic assay, 5Gy irradiation (10% survival) combined with 100nM WNC0901 demonstrated modestly enhanced cell killing (1.5% survival), and maximal effects were seen at 300nM (0.04% survival, p<0.01). Similar radiosensitizing effects with 300 nM WNC0901 were seen in the A549 cell line (0.2% survival with combination compared to 19% with 5Gy alone, p<0.01). In summary, WNC0901 inhibits DNA-PK kinase activity and provides potent radiosensitization in a GBM and lung cancer cell line. Future studies will assess the combination of WNC0901 and RT in GBM patient-derived xenograft models in vivo. Citation Format: Ann C. Mladek, Danielle L. Burgenske, William F. Elmquist, Wei Zhong, Jann N. Sarkaria. Preclinical data of a novel DNA-PK inhibitor in combination with radiation therapy shows promise in the treatment of established GBM and lung carcinoma cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 701.

Cobalt-modulated dual emission carbon dots for ratiometric fluorescent vancomycin detection.

This work presents a simple yet selective fluorometric protocol for the quantification of vancomycin, an important antibiotic for treating infections caused by Gram-positive bacteria. A novel ratiometric fluorometric method for the determination of vancomycin is developed based on dual emissive carbon dots (DECDs) with emission at 382 nm and 570 nm in combination with Co2+ ions. Upon addition of Co2+ions, the fluorescence at 382 nm of DECDs is enhanced while emission at 570 nm remains constant. In the presence of vancomycin, it complexes with Co2+ leading to quenching of the 382 nm fluorescence due to strong binding with Co2+ in the Co@DECDs system. The DECDs are fully characterized by TEM and different spectroscopic techniques. The proposed ratiometric method is based on measuring fluorescence ratio (F570/F382) against vancomycin concentration and the method exhibits a good linearity range from 0.0 to 120.0 ng mL-1 with a low limit of detection (S/N = 3) of 0.31 ng mL-1. The method shows good selectivity with minimal interference from potential interfering species. This ratiometric fluorometric approach provides a promising tool for sensitive and specific vancomycin detection in clinical applications.

High-Resolution Laser Interference Ablation and Amorphization of Silicon.

The laser interference patterning of a silicon surface via UV femtosecond pulse irradiation, resulting in 350 nm periodic structures, is demonstrated. The structuring process was performed using a laser with a 450 fs pulse duration at a wavelength of 248 nm in combination with a mask projection setup. Depending on the laser fluence, single-pulse irradiation leads to amorphization, structure formation via lateral melt flow or the formation of voids via peculiar melt coalescence. Through multipulse irradiation, combined patterns of interference structures and laser-induced periodic surface structures (LIPSS) are observed.

A randomized trial of improving the effectiveness of physiotherapy treatment of patients with type 2 diabetes mellitus with periodontal-periodontal pathology

BACKGROUND: The severity of chronic periodontitis and related dental complications (gingival pockets accompanied by bleeding gums, pain, tooth mobility, inflammation of the gums, suppuration) in patients with type 2 diabetes mellitus are largely determined by blood sugar parameters, which indicates the importance of modeling treatment to increase efficiency and reduce risks, forming a high medical and social problem.
 AIM: was to evaluate the prospects and efficacy of physiotherapeutic treatment, including intracanale laser exposure in the form of radiation with a wavelength of 810 nm in combination with transchannel galvanophoresis of copper-calcium hydroxide, in patients with type 2 diabetes with periodontal periodontitis.
 MATERIAL AND METHODS: The materials of a retrospective study including 89 patients with type 2 diabetes mellitus with periodontal periodontitis were analyzed. Patients of the first group (Comparison I ― 17 people) received laser exposure intracanally. Patients of the second group (Comparison II ― 18 people) received galvanophoresis with copper-calcium hydroxide transcanally with an active anode. Patients of the third group (Comparison III ― 18 people) received galvanophoresis with copper-calcium hydroxide transcanally from the active Cathode. Patients of the main group (Main I ― 18 people) received complex therapy in the form of laser exposure intracanally and galvanophoresis with copper-calcium hydroxide transcanally from the active Cathode. Patients of the main group (Main II ― 18 people) received complex therapy in the form of laser exposure intracanally and galvanophoresis with copper-calcium hydroxide transcanally with an active anode. The control was carried out on patients without physiotherapeutic treatment, including long-term indicators.
 RESULTS: During dental treatment, all patients with type 2 diabetes had a laboratory-confirmed blood glucose level of 7.51.9 mg% (p 0.05). The hygienic index of FedorovVolodkina ― 5.30.3 points. In 86.5% of patients, supra- and subgingival tartar was detected and in 35.9% of them ― the formation of periodontal pockets with bright red granulations, which required very careful treatment. It has been established that the depot-phoresis with an active cathode provides high anti-inflammatory and analgesic results with mono-exposure. In 29.4% of patients after intracanal monolaser exposure, high anti-inflammatory effects were established, which were accompanied by a decrease in the hygiene index, the index of inflammation, which was lower than after complex laser electrophoresis.
 CONCLUSION: The use of depot-foresis with an active cathode provides higher anti-inflammatory and analgesic results in relation to the apex-foresis of copper-calcium hydroxide (active anode), which, in our opinion, is based on an increase in the activity of physico-chemical reactions of metabolic orientation in the alkaline environment of the oral cavity.

STNM01, the RNA oligonucleotide targeting carbohydrate sulfotransferase 15, as second-line therapy for chemotherapy-refractory patients with unresectable pancreatic cancer: An open label, phase I/IIa trial.

The impact of stroma-targeting therapy on tumor immune suppression is largely unexplored. An RNA oligonucleotide, STNM01, has been shown to repress carbohydrate sulfotransferase 15 (CHST15) responsible for tumor proteoglycan synthesis and matrix remodeling. This phase I/IIa study aimed to evaluate the safety and efficacy of STNM01 in patients with unresectable pancreatic ductal adenocarcinoma (PDAC). This was an open-label, dose-escalation study of STNM01 as second-line therapy in gemcitabine plus nab-paclitaxel-refractory PDAC. A cycle comprised three 2-weekly endoscopic ultrasound-guided locoregional injections of STNM01 at doses of 250, 1,000, 2,500, or 10,000nM in combination with S-1 (80-120mg twice a day for 14 days every 3 weeks). The primary outcome was the incidence of dose-liming toxicity (DLT). The secondary outcomes included overall survival (OS), tumor response, changes in tumor microenvironment on immunohistopathology, and safety (jRCT2031190055). A total of 22 patients were enrolled, and 3 cycles were repeated at maximum; no DLT was observed. The median OS was 7.8 months. The disease control rate was 77.3%; 1 patient showed complete disappearance of visible lesions in the pancreas and tumor-draining lymph nodes. Higher tumoral CHST15 expression was associated with poor CD3+ and CD8+ T cell infiltration at baseline. STNM01 led to a significant reduction in CHST15, and increased tumor-infiltrating CD3+ and CD8+ T cells in combination with S-1 at the end of cycle 1. Higher fold increase in CD3+ T cells correlated with longer OS. There were 8 grade 3 adverse events. Locoregional injection of STNM01 was well tolerated in patients with unresectable PDAC as combined second-line therapy. It prolonged survival by enhancing T cell infiltration in tumor microenvironment. The present study was supported by the Japan Agency for Medical Research and Development (AMED).

The Physiology, Growth and Essential Oil Content of Lemon Balm (Melissa officinalis L.) in Response to Different LED Treatments

Background: Light-emitting diodes (LEDs) are a promising technology that has enormous potential to improve irradiance efficiency and to replace traditionally used horticultural lighting. Compared with traditional light sources (e.g., high-pressure sodium lamps and metal halide lamps) used in crop production, LEDs tends to have long life, generate less heat waste and providing the perfect spectrum for plant growth. Methods: This work sought to investigate the effect of using blue LED lights on growth and development in Lemon balm (Melissa officinalis L.) under sole-source LED lighting spectra. Lighting spectra were provided by differing combinations of LEDs of 4 different peak wavelengths, (Blue 435, Blue 450, Red 663 nm and Green 540 nm) with ratios of (1.95:2.3:1 R: G: B 450 nm (white), 5: 1R: B 450 nm, 2.5:1 R: B 450 nm and 2.5:1 R: B 435 nm) at a PPFD of 95 ìmol m-2 s-1 (PAR). Result: showed that the blue light with a wavelength peak at 435 nm in combination with red light at 663 nm at the ratio of (2.5:1 R: B) and white LEDs enhanced the physiology of lemon balm (i.e., significantly increased assimilation rate, stomatal conductance and transpiration rate), consequently fresh and dry shoot weight increased and the shoot essential oil content.

Evaluating the Efficacy of Platelet Rich Plasma and 1550 nm Fractional Laser in Combination and Alone for the Management of Androgenetic Alopecia.

Androgenetic alopecia (AGA) in men and women is the most common cause of hair loss. Affected individuals may experience psychological distress and social withdrawal. Current treatment options for AGA, such as minoxidil and finasteride, vary in efficacy and have side effects. Platelet-rich plasma (PRP) and photobiomodulation are among treatment options that have gained popularity in recent years. While less is known about the effectiveness of fractional lasers for combating hair loss, research suggests that by creating microscopic thermal injury zones, fractional lasers may cause an increase in hair growth from a wound healing process. In this study, we evaluated the efficacy and safety of PRP and 1550 nm fractional erbium-glass laser as monotherapy or combination treatment for AGA in 60 patients. All patients experienced improvement in AGA, but patients treated with the combination therapy had greater improvement in hair density. Overall, PRP and 1550 nm in combination or alone are good treatment choices for AGA, with no side effects. J Drugs Dermatol. 2022;21(11):1166-1169. doi:10.36849/JDD.6750.

Investigation of thermal and wear behaviour of 3D printed PA-12 nylon polymer spur gears

The study investigates the potential of 3D –printed gears of PA-12 Nylon material which are intended for use in polymer gearing. The gears are made through an additive manufacturing process known SLS (Selective Laser Sintering). Thermal and wear characteristics this set of gears is investigated at varying torque values of 1.6, 2.0, and 2.4 Nm in combination to varying rpm of 800, 1000, 1200 and 1400. The gears are subjected to 1 x 106 load cycles. The gear failed due to a rise in contact surface at 1400 rpm and 2.4 Nm torque. At high torque, there is a decrease in the durability of gear. The specific wear rate is more at low rotational speed in comparison to high speed. At low torque and low rotational speed, there is not any significant sign of failure and gears operate smoothly.

Abstract 5337: Tolinapant (ASTX660) enhances the anti-leukemic activity of Venetoclax and Dexamethasone in T cell acute lymphoblastic leukemia (T-ALL)

Abstract Background: Inhibitors of apoptosis proteins (IAPs) are overexpressed in ALL leading to resistance to apoptosis and chemo-resistance. Tolinapant, a non-peptidomimetic antagonist of the cellular and X-linked inhibitors of apoptosis (cIAP1/2 and XIAP) being evaluated in Phase 1/2 clinical trial [NCT02503423] showed single-agent activity in T-cell lymphoma. Objectives: Herein, we analyzed the preclinical activity of tolinapant in combination with ABT199 and Dexamethasone (DEX) in T-ALL (in vitro and ex-vivo patient derived xenografts (PDX). Results: Using a panel of 8 T-ALL cell lines we analyzed the single agent activity of tolinapant. Loucy and SUP-T11 were most sensitive (IC50 = 190-309 nM). CCRF-CEM and ALL-SIL showed moderate sensitivity (IC50 = 10-18 µM) while Jurkat, MOLT16, MOLT4 and PF382 were resistant. Western blotting (WB) showed decreased levels of cIAP1and cIAP2 with no change in XIAP in response to tolinapant as a single agent. We next investigated the efficacy of tolinapant with Bcl2 inhibitor ABT199. The combination of ABT199 and ASTX660 was synergistic in Loucy cell line with combination index (CI) of 0.14. Cell death was increased to 64±3% in combination v/s 27±0.9% in ABT199. WB showed decreased cIAP2 and increased levels of cleaved caspase 7 and cleaved caspase 9 in combination compared to single agents, suggesting increased apoptosis. Treatment of PDX-derived cells with tolinapant and ABT199 was more effective than monotherapy in inducing apoptosis in CD45+ bulk (46±0.7% to 63±6%, p<0.0001) and leukemia initiating cells (LICs, CD45+ CD7+ CD19- CD34+) (39±3% to 54±8%, p=0.003). Next, we checked the effect of combination of DEX with tolinapant in T-ALL cell lines. CCRF-CEM cell line is from a relapsed patient and is resistant to DEX. The combination was synergistic with CI of 0.26 and cell death of 50±4% compared to 20±3% by DEX. A triple combination of DEX, ABT199 and tolinapant increased apoptotic response to 82.9±1%, compared to DEX+ABT199 dual combination where apoptosis was induced to 52.4±2%. Strong synergy in terms of both cytoreduction as well as apoptosis induction was observed in SUP-T11 cells. Tolinapant sensitized SUP-T11 cells to DEX with ED50 value of 542 nM in combination compared to ~2 µM with DEX treatment. Simultaneous analysis of cell proliferation, stress response and DNA damage using single-cell proteomics analysis showed downregulation of proliferation (Ki-67), stress response (ATF4, LC3B) and increased levels of cleaved PARP, cleaved caspase 3 suggesting increased apoptosis in combination of tolinapant with DEX. Treatment of PDX-derived cells with tolinapant enhanced the cytotoxic effect of DEX in CD45+ bulk (58±2% to 71±0.1%, p<0.0001) and LICs (62±2% to 78±0.9%, p<0.0001). Conclusion: Tolinapant synergizes with the anti-leukemic activity of ABT199 and DEX, establishing a therapeutic rationale for IAP antagonist in T-ALL. Citation Format: Priyanka Sharma, Sujan Piya, Huaxian Ma, Natalia Baran, Muharrem Muftuoglu, Mahesh Basyal, Vivian Ruvolo, George Ward, Tomoko Smyth, Martin J. Sims, Michael Andreeff, Gautam Borthakur. Tolinapant (ASTX660) enhances the anti-leukemic activity of Venetoclax and Dexamethasone in T cell acute lymphoblastic leukemia (T-ALL) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5337.

Evaluation of changes in laser Doppler flowmetry indices in patients with a combined subtype of rosacea under the influence of a course of complex phototherapy

BACKGROUND: The development of new methods for the treatment of rosacea, as well as a combination of various methods of physiotherapy, is of scientific and practical interest. In this work, the assessment of changes in microcirculation indices under complex phototherapy has been carried out.
 AIMS: Тo assess changes in microcirculation indices in patients with a combination of rosacea subtypes according to laser Doppler flowmetry under a course of complex phototherapy.
 MATERIAL AND METHODS: In 20172020 a randomized controlled study of 130 patients with a combination of rosacea subtypes. All patients were divided into 4 groups. In each separate group, laser therapy and 1% metronidazole cream were used (group I); phototherapy and 1% metronidazole cream (group II); complex photolaser therapy and 1% metronidazole cream (group III); in the comparison group (group IV), patients show only 1% metronidazole cream. The treatment, the duration of which was 3 months, included 6 sessions with an interval of 2 weeks. The effectiveness of therapy was assessed according to the data of laser Doppler flowmetry, reflecting changes in the hemodynamics of the microvasculature in the affected skin areas.
 RESULTS: The developed complex method, including exposure to intense pulsed light (intense pulsed light, IPL) 5201100 nm in combination with submillisecond neodymium laser radiation 1064 nm (submilisecond Nd: YAG laser 1064 nm) and daily application of 1% metronidazole cream showed the most pronounced improvement in the state of microcirculation according to laser Doppler flowmetry in comparison with the rest groups. Against the background of the course of complex phototherapy for all patients with the combined subtype of rosacea, statistically significant changes were in the volume of blood flow, modulation coefficients, coefficient of variation. On the contrary, no statistically significant changes were found in the ranges corresponding to active regulatory factors endothelial, neurogenic, myogenic, and passive respiratory and cardiac, as well as in the T index.
 CONCLUSION: After the course of complex phototherapy in the group of patients with a combination of rosacea subtypes, there was a decrease in the severity of clinical manifestations of diseases, as well as an improvement in the main indicators of microcirculation according to laser Doppler flowmetry.

The Impact of Light Spectrum and Intensity on the Growth, Physiology, and Antioxidant Activity of Lettuce (Lactuca sativa L.).

This study focused on the physiology, growth and antioxidant activity response of hydroponically grown lettuce (Lactuca sativa L.) under sole-source LED lighting of differing spectra. Lighting spectra were provided by differing combinations of LEDs of three different peak wavelengths, (Blue 435, Blue 450, and Red 663 nm) with ratios of B450/R663: 1.25 ± 0.1, B450/R663: 1.25 ± 0.1, and B450/R663 1:1 at two light intensities of photosynthetically active radiation (PAR) (270 μmol m−2 s−1 and 60 μmol m−2 s−1). A further experiment was conducted, in which Blue and Red LEDs were supplemented with Green (Blue 450, Red 663, and Green 520 nm) with ratios of B435/R663: 1.25 ± 0.1, B450/R663/G520: 1/0.73/0.26, and B450/R663: 1.25 ± 0.1. LED light intensities under the different spectra were adjusted to deliver the same level of PAR (270 ± 20 μmol m−2 s−1). Results from the first experiment showed that increased fraction of blue 435 nm in combination with red light at 663 nm at high irradiance enhanced the physiology of lettuce (i.e., significantly increased assimilation rate, stomatal conductance and transpiration rate) and increased the yield while having no significant effect on antioxidant activity. At the lower irradiance, the B435/R663 significantly increased antioxidant activity compared to other spectra. Results from the second experiment showed no significant effect of the spectra of LEDs on the physiology and yield of lettuce, but antioxidant activity was very significantly induced by B450/R663 at the ratio of 1.25 ± 0.1. However, the amount was still less than that obtained by B435/R663 1.25 ± 0.1 from the first experiment. This study indicates that LED light with a spectrum of B435/R663 at a ratio of 1.25 ± 0.1 significantly improves lettuce yield and antioxidant activity.

Cyanines comprising barbiturate group facilitate NIR‐light assisted ATRP under anaerobic and aerobic conditions at two wavelengths using Fe(III) catalyst

AbstractCyanines with heptamethine pattern namely 5‐(6‐(2‐(3‐ethyl‐1,1‐dimethyl‐1H‐benzo[e]indol‐2(3H)‐ylidene)ethylidene)‐2‐(2‐(3‐ethyl‐1,1‐dimethyl‐1H‐benzo[e]indol‐3‐ium‐2yl) vinyl) cyclo‐hex‐1‐en‐1‐yl)‐1,3‐dimethyl‐2,6‐dioxo‐1,2,3,6‐tetrahydropyrimidin‐4‐olate comprising a barbiturate group facilitate controlled radical polymerization using FeBr3 in the ppm range applying radiation at 790 nm. Tris(4‐methoylphenyl)phosphine, Tris(2‐pyridylmethyl)amine or tetrabutylammonium bromide served as ligand. The latter showed the best performance resulting in a system needing no amino nitrogen for photo‐ATRP. Ethyl α‐bromophenylacetate worked as initiator. The cyanine interacts with FeBr3 resulting in a new absorption band at 877 nm that also resulted in formation of polymer exhibiting similar molecular weight but higher dispersity compared to that obtained by 790 nm radiation by exposure with a light‐emitting diode (LED) emitting at 870 nm. This explains the reactivity of the system while other cyanines such as 2‐[2‐[3‐[2‐(1,3‐Dihydro‐1,3,3‐trimethyl‐2H‐indol‐2‐ylidene)‐ethylidene]‐2‐(1‐phenyl‐ 1H‐tetrazol‐5‐ylsulfanyl)‐1‐cyclohexen‐1‐yl]‐ethenyl]‐1,3,3‐trimethyl‐3H‐indolium chloride showed no activity by exposure at 790 nm in combination with FeBr3/Br−. Controlled radical polymerization was confirmed by successful chain extension and block copolymerization experiments resulting in polymers, which exhibit a dispersity of about 1.3. Interestingly, the new system comprising the aforementioned barbiturate substituted cyanine, FeBr3/Br− and ethyl α‐bromophenylacetate showed a certain oxygen tolerance. Polymers obtained exhibited similar dispersity as those made under inert conditions.

Immunomodulatory activity seen as a result of photobiomodulation therapy in stimulated primary human fibroblasts

ObjectiveOral biofilms burden host responses by induction of inflammatory mediators, exacerbating periodontal inflammation. Photobiomodulation Therapy (PBMT) has been shown to decrease levels of pro-inflammatory cytokines and chemokines. However, optimal wavelengths and exposure doses have not been established. This study investigated the effects of PBMT on human periodontal ligament fibroblasts (hPDLFs) stimulated with inflammatory mediators (LPS, TNF-α, and IL-1β). MethodsCytotoxic effects of laser wavelengths 660 nm and 810 nm were assessed by measuring their effects on cellular dehydrogenase activity. The study was expanded to include 980 nm, 660 nm + 810 nm, and 810 nm + 980 nm. P.g. LPS, TNF-α, and/or IL-1β were added one hour before irradiation, then exposed to laser irradiation to determine the most appropriate stimulus. The levels of INF-γ, IL-6, IL-8, IL-17A/F, and MCP-1 production in stimulated hPDLFs were measured and analyzed. ResultsP.g. LPS was a poor stimulus for hPDLFs, while TNF-α and IL-1β significantly elevated the analytes. The 660 nm laser treatment induced pro-inflammatory cytokines when stimulated, while 810 nm exhibited significant suppression. IL-1β was the stimulus of choice and the 810 nm wavelength alone exhibited anti-inflammatory effects for all analytes except IL-8, while the 810 nm in combination with 660 nm and/or 980 nm exhibited effects similar to 810 nm alone. ConclusionsThe downregulation of inflammatory mediators by the combination or individual treatment with 810 nm wavelength shows promise for the management of periodontal inflammation. PBMT may lead to the development of a novel approach in the management of periodontal disease.

Evaluation of satellite-based aerosol datasets and the CAMS reanalysis over the ocean utilizing shipborne reference observations

Abstract. Reliable reference measurements over the ocean are essential for the evaluation and improvement of satellite- and model-based aerosol datasets. Within the framework of the Maritime Aerosol Network, shipborne reference datasets have been collected over the Atlantic Ocean since 2004 with Microtops Sun photometers. These were recently complemented by measurements with the multi-spectral GUVis-3511 shadowband radiometer during five cruises with the research vessel Polarstern. The aerosol optical depth (AOD) uncertainty estimate of both shipborne instruments of ±0.02 can be confirmed if the GUVis instrument is cross calibrated to the Microtops instrument to account for differences in calibration, and if an empirical correction to account for the broad shadowband as well as the effects of forward scattering is introduced. Based on these two datasets, a comprehensive evaluation of aerosol products from the Moderate Resolution Imaging Spectroradiometer (MODIS) flown on NASA's Earth Observing System satellites, the Spinning Enhanced Visible and Infrared Imager (SEVIRI) aboard the geostationary Meteosat satellite, and the Copernicus Atmosphere Monitoring Service reanalysis (CAMS RA) is presented. For this purpose, focus is given to the accuracy of the AOD at 630 nm in combination with the Ångström exponent (AE), discussed in the context of the ambient aerosol type. In general, the evaluation of MODIS AOD from the official level-2 aerosol products of C6.1 against the Microtops AOD product confirms that 76 % of data points fall into the expected error limits given by previous validation studies. The SEVIRI-based AOD product exhibits a 25 % larger scatter than the MODIS AOD products at the instrument's native spectral channels. Further, the comparison of CAMS RA and MODIS AOD versus the shipborne reference shows similar performance for both datasets, with some differences arising from the assimilation and model assumptions. When considering aerosol conditions, an overestimation of AE is found for scenes dominated by desert dust for MODIS and SEVIRI products versus the shipborne reference dataset. As the composition of the mixture of aerosol in satellite products is constrained by model assumptions, this highlights the importance of considering the aerosol type in evaluation studies for identifying problematic aspects.

Analysis of photoreactivity and phototoxicity of riboflavin's analogue 3MeTARF

Recent studies focus on usage of blue light of λ = 450 nm in combination with photosensitizers to treat surface skin disorders, including cancers. In search of convenient therapeutic factor we studied riboflavin analogue 3-methyl-tetraacetylriboflavin (3MeTARF) as potential sensitizer. Riboflavin (Rfl) itself, non -toxic in the darkness, upon absorption of UVA and blue light, may act as photosensitizer. However, Rfl efficiency is limited due to its susceptibility to photodecomposition. Riboflavin's acetylated analogue, 3MeTARF, bears substituents in ribose chain, which inhibit intramolecular processes leading to degradation. Upon excitation, this compound, reveals higher photochemical resistance, remaining a good singlet oxygen generator. Thus, being more stable as the sensitizer, might be much more efficient in photodynamic processes. The objective of undertaken study was to elucidate mechanisms of 3MeTARF photoreactivity under the irradiation with blue light in comparison to its mater compound, riboflavin. We approached this goal by using spectroscopic methods, like direct singlet oxygen phosphorescence detection at 1270 nm, EPR spin trapping and oximetry. Additionally, we tested both riboflavin and 3MeTARF phototoxicity against melanoma cells (WM115) and we studied mechanism of photodynamic cell death, as well. Moreover, 3MeTARF induces apoptosis in melanoma cells at ten times lower concentration than riboflavin itself. Our studies confirmed that 3MeTARF remains stable upon blue light activation and is more efficient photosensitizer than Rfl.

BCL-2 Inhibitor Venetoclax Enhances Temozolomide Sensitivity in AML

Introduction: Many older patients with acute myeloid leukemia (AML) are ineligible for intensive chemotherapy due to frailty and co-morbidities; for such patients, existing treatments are often ineffective and new treatments are needed. Temozolomide (TMZ) is an alkylating agent that causes DNA methylation at O6 guanine, generating single strand break leading to apoptosis. However, the efficacy of TMZ depends on the DNA repair protein O6-methylguanine methyltransferase (MGMT), that maintains the genomic integrity by removing the O6-methyl group and restoring guanine nucleobase, thereby enhancing resistance to TMZ. Previous clinical trials in AML found that responses to TMZ correlated with low MGMT expression; however, even in those with low MGMT expression complete response rates were only in the 25% range. BCL-2, an anti-apoptotic protein, is overexpressed in AML cells. Direct inhibition by the selective BCL-2 inhibitor venetoclax (Venet) promotes apoptosis. This study evaluated the ability of Venet to enhance TMZ sensitivity in AML cells, including those with MGMT overexpression. Methods: KG1, MV4-11 and MOLM13 AML cell lines were studied, as well as bone marrow blast cells collected from AML patients. Western blot was used to measure MGMT and BCL-2 expression. The cells were incubated with TMZ at varying concentrations in combination with a fixed concentration of Venet. After 48 hours, cell viability and apoptosis assays were performed using spectrophotometry and flow cytometry, respectively. Synergy was evaluated by the Chou-Talalay method. Cleaved-PARP was measured by Western blot in selected combination doses after 3 hours in MV4-11 and MOLM13 and after 6 hours in KG1. Results: KG1 cells expressing high MGMT demonstrated strong resistance to TMZ; however, co-incubation with 1 uM Venet resulted in a marked enhancement of sensitivity to TMZ. Similarly, in MV4-11 and MOLM13 cell lines, which demonstrated very low or absent MGMT expression. Venet 2.5 nM in combination with TMZ markedly increased the cytotoxicity to TMZ. A synergistic effect was demonstrated in all cell lines with combination index (CI) < 1. Cells overexpressed annexin V and propidium iodide (PI) apoptotic marker after drug combination in all cell lines. Apoptotic effect with the drug combination was verified by cleaved-PARP expression. Most (6/8) AML patient samples which were resistant to TMZ in vitro became sensitized to TMZ in combination with 1 uM Venet, including those with moderate to high MGMT expression. Conclusion: Venetoclax synergizes with TMZ and induces cytotoxicity in all AML cell lines and in most AML patient samples, including those in whom MGMT was highly expressed, by activating apoptotic pathways to trigger cell death. This combination represents a potentially promising new treatment. Further studies evaluating this combination in animal models are in progress. Disclosures Brandwein: Roche: Research Funding; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Otsuka: Honoraria; Jazz Pharma: Consultancy, Honoraria. OffLabel Disclosure: Temozolomide for AML

Combined Technique and Its Clinical and Pathogenetic Evaluation in Treatment of Central Serous Chorioretinopathy Using Subthreshold Microimpulse Laser Irradiation with a Wavelength of 577 nm in Combination with Injections of Platelet Autoplasma

Background. Lack of a holistic understanding of the etiology and pathogenesis of central serous chorioretinopathy (CSH), which determines the conduct of pathogenetic therapy, as well as the lack of effectiveness of treatment methods aimed at developing new pathology methods.Aims. To conduct a comparative therapeutic potential of a combination of subthreshold micropulse laser irradiation (SMILV) with a course of injection of autologous plasma enriched with platelets (TP) in CSH. To evaluate the effectiveness of SMILV with a wavelength of 577 nm with wing-injection injections of TP compared with SMIV monotherapy in the treatment of CSH. Consider issues of modern treatment of CSH, as well as determine the levels of cytokines in the tear fluid of patients with CSH before and after SMILV and SMILV + TP treatment.Methods and methods. The study was conducted on 60 patients (60 eyes) with CSH. Patients were divided into 2 groups: in the comparison group, patients received treatment only SMILV wavelength 577 nm, and in the experimental group – SMILV followed by the introduction of TP. TP was prescribed after 72 hours, 3 injections in the region of the pterygomaxillary fossa on the side of damage to the eyes, with an interval between injections of 72 hours.SMILV was performed on a Supra 577 nm laser machine (Quantel Medical, France) over the entire area of macular edema. Conclusion. Comparative analysis of clinical and functional results of treatment of central serous chorioretinopathy SMILV with a wavelength of 577 nm and a combination of SMILV with injections of autologous plasma enriched with platelets and the outcome of the disease revealed a greater effectiveness of combining SMILV with a course of injections of autologous plasma enriched with platelets.

Radio- and photosensitization of plasmid DNA by DNA binding ligand propidium iodide: Investigation of Auger electron induction and detection of Cherenkov-emission

We investigated whether propidium iodide (PI) enhances DNA damaging effects of ionizing and non-ionizing radiation species (X-rays, alpha-, beta-, auger electron emission and light of various wavelengths, respectively). This biophysical experimental setting allowed us, furthermore, to investigate whether Cherenkov emission can be detected by photodynamic effects and increased DNA damage. Conformation changes of plasmid DNA were detected and quantified by gelelectrophoresis and fluorescence imaging. Hydrogen peroxide, stannous dichloride, and dimethylsulfoxide were used as chemical modulators, Tc-99m, Re-188, Ra-223, and x-ray (32 kV and 200 kV) reflected radiotoxicity and light (λ = 254 nm, 366 nm and 530-575 nm) induced phototoxicity. Radiotracers and x-rays induced dose dependent DNA damage. PI did not serve as radiosensitizer in radioisotopes, while a low effect was detected in X-rays. The phototoxicity was dependent on the wavelengths of light. Light with a wavelength range of 530-575 nm in combination with PI resulted in direct DNA damage. The yield of Cherenkov emission was far below the photon emission of light irradiation and not distinguishable from general radiotoxicity. PI binds to plasmid DNA, is not chemotoxic, and increases radiotoxicity only to minor extent. Phototoxicity and its stimulation by PI is dependent on the wavelength of the light. No kind of energy deposition was capable of inducing an Auger electron cascade. Furthermore, no increase in DNA damage induced by photodynamic effects from Cherenkov emission was detectable.

Fluorescence characteristics of the fuel tracer 1-methylnaphthalene for the investigation of equivalence ratio and temperature in an oxygen-containing environment

In this work, the fluorescence properties of the fuel tracer 1-methylnaphthalene (1-MN) are investigated in a calibration flow cell at elevated temperatures and pressures. This fuel tracer is well suited to investigate mixture formation in diesel engine applications, as 1-MN is a natural diesel fuel component. A tracer-LIF (laser-induced fluorescence) concept is developed that enables temperature measurements using a two-color approach in oxygen-containing gas mixtures. Furthermore, the potential for simultaneous measurement of equivalence ratio (fuel–air ratio, FAR) is evaluated. First, a picosecond Nd:YLF-laser at 263 nm in combination with a spectrograph and a streak unit was used to investigate the spectral fluorescence emission and fluorescence lifetimes. In addition, a nanosecond Nd:YAG-laser at 266 nm was used for fluorescence calibration with regard to equivalence ratio and temperature. All measurements were performed in an oxygen-containing environment at different equivalence ratios, temperatures up to 800 K and pressures up to 2.5 MPa. The dependency of the fluorescence emission on equivalence ratio was studied for varied fuel amount and air concentrations. The calibration data form the basis for investigations of fuel distribution and temperature under realistic engine conditions in an oxygen-containing environment.

Oxidation and molecular properties of microcystin-LR, microcystin-RR and anatoxin-a using UV-light-emitting diodes at 255 nm in combination with H2O2

On the use of UV light emitting diodes (UV-LEDs), emitting at 260–290 nm, has attracted attention for treating cyanotoxins, although most previous studies related with UV/H2O2 process have been used conventional mercury UV lamp (λ = 254 nm). Therefore, the aim of the study was to investigate the UV-LEDs, having a wavelength of 255 nm, coupled with H2O2 process for the removal of microcystin-LR (MC-LR), microcystin-RR (MC-RR), and anatoxin-a (ANTX) and to verify the degradation kinetics, mechanism and impact of water quality parameters in relation to their molecular properties. Among three UV-LEDs (λ = 255, 266, and 280 nm), the shortest one was the most effective to remove MC-LR coincided with its decadic molar absorption coefficient. The degradation rate constants of MC-LR, MC-RR, and ANTX were 0.0644, 0.0241, and 0.0076 cm2 mJ−1, respectively, during the UV-LED/H2O2 process. For MC-LR and MC-RR degradation, reaction with OH is a major mechanism along with direct photolysis as a minor factor. ANTX degradation is predominantly attributed to OH. The second-order rate constant for ANTX is one order of magnitude lower than others because ANTX is recalcitrant to oxidation. The MC-LR degradation occurred at the diene and aromatic ring of Adda, Mdha, and amide bond and the main reactive oxidation site of MC-RR was the Adda chain. In contrast, photo-oxidation transformed ANTX to higher molecular weight compounds via polymerization instead of degradation. When MC-LR, MC-RR, and ANTX were co-present, lower concentration of dissolved organic carbon and higher acidity with bicarbonate was favorable to remove MC-LR and MC-RR according to their scavenging factors and reaction with CO−3. However, ANTX is relatively resistant to degradation at pH 3.2.