Chronic toxicity of inhaled thymol in lungs and respiratory tracts in mouse model.

Epinephrine HFA (Primatene® Mist) is a newly formulated asthma metered dose inhaler developed to replace the previous Primatene® Mist CFC. The formulation of Epinephrine HFA contains thymol, a substance recognized to be safe by the FDA. Although the content of thymol contained in Epinephrine HFA is much lower compared to many common foods and medications available, there are no known nonclinical data about the chronic toxicity of thymol through inhalation. Two sequential 6-month studies of identical design were conducted to assess the chronic toxicity of inhaled thymol in mice. Four treatment groups, (a) Air; (b) vehicle control; (c) Article-1 (thymol 0.1%); and (d) Article-2 (thymol 0.5%) were assessed in 128 mice for 26 weeks. The mice were sacrificed at the end of the treatment period and a histopathologic evaluation was performed with respect to lungs, bronchial lymph nodes, nasal passages/nasopharynx, and trachea. Forty-five pathologic assessment parameters (PAPs) were evaluated. In total, 5591 data points from 487 mouse organs were assessed. Chronic toxicity index was calculated for 16 PAPs that had multiple histopathologic abnormal observations. The t tests were conducted for these 16 PAPs (Articles-1 and 2 versus Air and vehicle control, respectively), and all P-values were greater than .05 indicating no significant differences between all treatment groups. An evaluation was also conducted for 25 PAPs that had only a very small number of pathologic abnormalities. No significant differences for chronic toxicity were found when comparing mice under long-term repeated exposure of high doses of inhaled thymol and mice that inhaled no thymol

Pharmacokinetic study of thymol after intravenous injection and high-dose inhalation in mouse model.

Thymol is generally recognized as a safe substance by the FDA and has been widely used in the pharmaceutical, food, and cosmetic industries. Pharmacokinetic (PK) studies of thymol have been previously conducted for oral administration, but there has been no PK study for inhalation administration or intravenous (IV) injection. This study aims at exploring and comparing the inhalation and IV PK profile of thymol in a mouse model. The inhalation PK for mouse model was corrected with fur/skin absorption. Thirty-two male CD-1 mice were randomized into two study arms, Arm-A for intravenous (n = 16) and Arm-B for inhalation (n = 16). The amount of thymol in the mouse serum was measured for Arm-A and for Arm-B at the highest dose. Furthermore, 48 mice were utilized for fur/skin absorption of thymol. In total, 320 mouse serum samples for thymol were analyzed by LC/MS method. After inhalation, the peak concentration of thymol in mouse serum was 42.3 ng/mL (Cmax ) and occurred at 2 minutes (tmax ). The AUC of the inhaled thymol at 0-60 minutes (AUC0-60) was 464 ng/mL/min. From 10-60 minutes post-dose, the PK inhalation curve appeared to be higher than that for the IV injection. This is likely attributed to the effect of absorption of thymol through the fur/skin of mice. After an adjustment by fur/skin absorption, the PK profile for net inhalation closely matched the two-compartment model. In fact, the bioavailability for the net inhalation of thymol was 74% and 77% relative to that for IV injection per AUC0-60min and AUC0-infinite, respectively

Complexity of diatom response to Lateglacial and Holocene climate and environmental change in ancient, deep and oligotrophic Lake Ohrid (Macedonia and Albania)

© Author(s) 2016. Lake Ohrid (Macedonia and Albania) is a rare example of a deep, ancient Mediterranean lake and is a key site for palaeoclimate research in the northeastern Mediterranean region. This study conducts the analysis of diatoms as a proxy for Lateglacial and Holocene climate and environmental change in Lake Ohrid at a higher resolution than in previous studies. While Lake Ohrid has the potential to be sensitive to water temperature change, the data demonstrate a highly complex diatom response, probably comprising a direct response to temperature-induced lake productivity in some phases and an indirect response to temperaturerelated lake stratification or mixing and epilimnetic nutrient availability in others. The data also demonstrate the possible influence of physical limnological (e.g. the influence of wind stress on stratification or mixing) and chemical processes (e.g. the influence of catchment dynamics on nutrient input) in mediating the complex response of diatoms. During the Lateglacial (ca. 12 300-11 800 cal yr BP), the low-diversity dominance of hypolimnetic Cyclotella fottii indicates low lake productivity, linked to low water temperature. Although the subsequent slight increase in small, epilimnetic C. minuscula during the earliest Holocene (ca. 11 800-10 600 cal yr BP) suggests climate warming and enhanced stratification, diatom concentration remains as low as during the Lateglacial, suggesting that water temperature increase was muted across this major transition. The early Holocene (ca. 10 600-8200 cal yr BP) is characterised by a sustained increase in epilimnetic taxa, with mesotrophic C. ocellata indicating high water-temperature-induced productivity between ca. 10 600-10 200 cal yr BP and between ca. 9500-8200 cal yr BP and with C. minuscula in response to low nutrient availability in the epilimnion between ca. 10 200-9500 cal yr BP. During the middle Holocene (ca. 8200-2600 cal yr BP), when sedimentological and geochemical proxies provide evidence for maximum Holocene water temperature, anomalously low C. ocellata abundance is probably a response to epilimnetic nutrient limitation, almost mimicking the Lateglacial flora apart from the occurrence of mesotrophic Stephanodiscus transylvanicus in the hypolimnion. During the late Holocene (ca. 2600 cal yr BP-present), high abundance and fluctuating composition of epilimnetic taxa are probably a response more to enhanced anthropogenic nutrient input, particularly nitrogen enrichment, than to climate. Overall, the data indicate that previous assumptions concerning the linearity of diatom response in this deep, ancient lake are invalid, and multi-proxy analysis is essential to improve understanding of palaeolimnological dynamics in future research on the long, Quaternary sequence

Long-Term Visual Object Tracking Benchmark

We propose a new long video dataset (called Track Long and Prosper - TLP) and benchmark for single object tracking. The dataset consists of 50 HD videos from real world scenarios, encompassing a duration of over 400 minutes (676K frames), making it more than 20 folds larger in average duration per sequence and more than 8 folds larger in terms of total covered duration, as compared to existing generic datasets for visual tracking. The proposed dataset paves a way to suitably assess long term tracking performance and train better deep learning architectures (avoiding/reducing augmentation, which may not reflect real world behaviour). We benchmark the dataset on 17 state of the art trackers and rank them according to tracking accuracy and run time speeds. We further present thorough qualitative and quantitative evaluation highlighting the importance of long term aspect of tracking. Our most interesting observations are (a) existing short sequence benchmarks fail to bring out the inherent differences in tracking algorithms which widen up while tracking on long sequences and (b) the accuracy of trackers abruptly drops on challenging long sequences, suggesting the potential need of research efforts in the direction of long-term tracking.Comment: ACCV 2018 (Oral

Transformational dynamics of BZO and BHO nanorods imposed by Y2O3 nanoparticles for improved isotropic pinning in YBa2Cu3O7−δ thin films

An elastic strain model was applied to evaluate the rigidity of the c-axis aligned one-dimensional artificial pinning centers (1D-APCs) in YBa2Cu3O7-δ matrix films. Higher rigidity was predicted for BaZrO3 1D-APCs than that of the BaHfO3 1D-APCs. This suggests a secondary APC doping of Y2O3 in the 1D-APC/YBa2Cu3O7-δ nanocomposite films would generate a stronger perturbation to the c-axis alignment of the BaHfO3 1D-APCs and therefore a more isotropic magnetic vortex pinning landscape. In order to experimentally confirm this, we have made a comparative study of the critical current density Jc (H, θ, T) of 2 vol.% BaZrO3 + 3 vol.%Y2O3 and 2 vol.%BaHfO3 + 3 vol.%Y2O3 double-doped (DD) YBa2Cu3O7-δ films deposited at their optimal growth conditions. A much enhanced isotropic pinning was observed in the BaHfO3 DD samples. For example, at 65 K and 9.0 T, the variation of the Jc across the entire θ range from θ=0 (H//c) to θ=90 degree (H//ab) is less than 18% for BaHfO3 DD films, in contrast to about 100% for the BaZrO3 DD counterpart. In addition, lower α values from the Jc(H) ∼ H-α fitting were observed in the BaHfO3 DD films in a large θ range away from the H//c-axis. Since the two samples have comparable Jc values at H//c-axis, the improved isotropic pinning in BaHfO3 DD films confirms the theoretically predicted higher tunability of the BaHfO3 1D-APCs in APC/YBa2Cu3O7-δ nanocomposite films

Anti-tumor activity and mechanistic characterization of APE1/Ref-1 inhibitors in bladder cancer

Bladder cancer is the ninth most common cause of cancer-related deaths worldwide. Although cisplatin is used routinely in treating bladder cancer, refractory disease remains lethal for many patients. The recent addition of immunotherapy has improved patient outcomes; however, a large cohort of patients does not respond to these treatments. Therefore, identification of innovative molecular targets for bladder cancer is crucial. Apurinic/apyrimidinic endonuclease 1/redox factor-1 (APE1/Ref-1) is a multifunctional protein involved in both DNA repair and activation of transcription factors through reduction-oxidation (redox) regulation. High APE1/Ref-1 expression is associated with shorter patient survival time in many cancer types. In this study, we found high APE1/Ref-1 expression in human bladder cancer tissue relative to benign urothelium. Inhibition of APE1/Ref-1 redox signaling using APE1/Ref-1-specific inhibitors attenuates bladder cancer cell proliferation in monolayer, in three-dimensional cultures, and in vivo. This inhibition corresponds with an increase in apoptosis and decreased transcriptional activity of NF-κB and STAT3, transcription factors known to be regulated by APE1/Ref-1, resulting in decreased expression of downstream effectors survivin and Cyclin D1 in vitro and in vivo. We also demonstrate that in vitro treatment of bladder cancer cells with APE1/Ref-1 redox inhibitors in combination with standard-of-care chemotherapy cisplatin is more effective than cisplatin alone at inhibiting cell proliferation. Collectively, our data demonstrate that APE1/Ref-1 is a viable drug target for the treatment of bladder cancer, provide a mechanism of APE1/Ref-1 action in bladder cancer cells, and support the use of novel redox-selective APE1/Ref-1 inhibitors in clinical studies. SIGNIFICANCE: This work identifies a critical mechanism for APE1/Ref-1 in bladder cancer growth and provides compelling preclinical data using selective redox activity inhibitors of APE1/Ref-1 in vitro and in vivo

Electric Field-Tuned Topological Phase Transition in Ultra-Thin Na3Bi - Towards a Topological Transistor

The electric field induced quantum phase transition from topological to conventional insulator has been proposed as the basis of a topological field effect transistor [1-4]. In this scheme an electric field can switch 'on' the ballistic flow of charge and spin along dissipationless edges of the two-dimensional (2D) quantum spin Hall insulator [5-9], and when 'off' is a conventional insulator with no conductive channels. Such as topological transistor is promising for low-energy logic circuits [4], which would necessitate electric field-switched materials with conventional and topological bandgaps much greater than room temperature, significantly greater than proposed to date [6-8]. Topological Dirac semimetals(TDS) are promising systems in which to look for topological field-effect switching, as they lie at the boundary between conventional and topological phases [3,10-16]. Here we use scanning probe microscopy/spectroscopy (STM/STS) and angle-resolved photoelectron spectroscopy (ARPES) to show that mono- and bilayer films of TDS Na3Bi [3,17] are 2D topological insulators with bulk bandgaps >400 meV in the absence of electric field. Upon application of electric field by doping with potassium or by close approach of the STM tip, the bandgap can be completely closed then re-opened with conventional gap greater than 100 meV. The large bandgaps in both the conventional and quantum spin Hall phases, much greater than the thermal energy kT = 25 meV at room temperature, suggest that ultrathin Na3Bi is suitable for room temperature topological transistor operation

Markers for the identification of late breast cancer recurrence

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited

Ontology driven integration platform for clinical and translational research

Semantic Web technologies offer a promising framework for integration of disparate biomedical data. In this paper we present the semantic information integration platform under development at the Center for Clinical and Translational Sciences (CCTS) at the University of Texas Health Science Center at Houston (UTHSC-H) as part of our Clinical and Translational Science Award (CTSA) program. We utilize the Semantic Web technologies not only for integrating, repurposing and classification of multi-source clinical data, but also to construct a distributed environment for information sharing, and collaboration online. Service Oriented Architecture (SOA) is used to modularize and distribute reusable services in a dynamic and distributed environment. Components of the semantic solution and its overall architecture are described