Inhibitory activity of human lactate dehydrogenase isoform A and B (LDH-A, LDH-B) by new potential anticancer drugs

The glycolysis is the stage of the production of energy by breakdown of glucose in body cells; a chain of chemical events requiring a specific set of enzymes, and resulting in formation of ATP. In aerobic metabolism subsequent sequences produce several times more ATP, thereby providing a greater quantity of energy per molecule of glucose, utilizing oxygen, and producing carbon dioxide and water-comparable to burning organic fuels in air. In anaerobic metabolism glycolysis is the only means of energy production from glucose and lactate is the end-product. This occurs in cells which cannot utilize oxygen, predominately in some components of skeletal muscle, and probably to some extent in all cells when there is a shortage of oxygen Many substances have been developed which inhibit glycolysis, and such glycolytic inhibitors are currently the subject of intense research as anticancer agents. Some glycolytic inhibitors currently being studied as anticancer treatments. Highly invasive tumor cells are characterized by a metabolic switch, known as the Warburg effect. The Warburg effect is the observation that most cancer cells predominantly produce energy by a high rate of glycolysis followed by lactic acid fermentation in the cytosol, rather than by a comparatively low rate of glycolysis followed by oxidation of pyruvate in mitochondria like most normal cells. The latter process is aerobic. Malignant rapidly-growing tumor cells typically have glycolytic rates that are up to 200 times higher than those of their normal tissues of origin; this occurs even if oxygen is plentiful. This dependence on glycolysis also confers a growth advantage to cells present in hypoxic regions of the tumor. One of the key enzymes involved in glycolysis, the muscle isoform of lactate dehydrogenase (LDH-A), is overexpressed by metastatic cancer cells and is linked to the vitality of tumors in hypoxia. Lactate dehydrogenase (LDH) is a widely diffused 2-hydroxyacid oxidoreductase, which promotes the inter-transformation of pyruvate and lactate by using a nicotinamide adenine dinucleotide cofactor (NADH/NAD+). Various isoforms of LDH are presently being considered as promising targets for a range of pathologies, such as cancer and malaria. This enzyme may be considered as a potential target for new anticancer agents, since its inhibition cuts cancer energetic and anabolic supply, thus reducing the metastatic and invasive potential of cancer cells. With colorimetric measurement of inhibition (% relative to control) of the enzymatic activity of LDH-A and LDH-B in the presence of compounds, we have discovered new and efficient N-hydroxyindole-based and Triazole-substituted N-hydroxyindol-2-carboxylates inhibitors of LDH-A, which are isoform-selective (over LDH-B) and competitive with both the substrate (pyruvate) and the cofactor (NADH)

Improving accuracy of corneal power measurement with partial coherence interferometry after corneal refractive surgery using a multivariate polynomial approach

Background: To improve accuracy of IOLMaster (Carl Zeiss, Jena, Germany) in corneal power measurement after myopic excimer corneal refractive surgery (MECRS) using multivariate polynomial analysis (MPA). Methods: One eye of each of 403 patients (mean age 31.53 ± 8.47 years) was subjected to MECRS for a myopic defect, measured as spherical equivalent, ranging from - 9.50 to - 1 D (mean - 4.55 ± 2.20 D). Each patient underwent a complete eye examination and IOLMaster scan before surgery and at 1, 3 and 6 months follow up. Axial length (AL), flatter keratometry value (K1), steeper keratometry value (K2), mean keratometry value (KM) and anterior chamber depth measured from the corneal endothelium to the anterior surface of the lens (ACD) were used in a MPA to devise a method to improve accuracy of KM measurements. Results: Using AL, K1, K2 and ACD measured after surgery in polynomial degree 2 analysis, mean error of corneal power evaluation after MECRS was + 0.16 ± 0.19 D. Conclusions: MPA was found to be an effective tool in devising a method to improve precision in corneal power evaluation in eyes previously subjected to MECRS, according to our results

OCT Applications in Conjunctival Disease

Today the of anterior segment optical coherence tomography (ASOCT) has become an irreplaceable tool in the management of various pathologies and also in many surgical techniques. The cornea has been widely studied in many pathologies with ASOCT, but now also the conjunctival study with ASOCT allows to obtain a detailed imaging of the normal and pathological conjunctiva, so that in many conjunctival diseases the ASOCT is a useful tool to help the clinicians. In this chapter we will briefly discuss the results of the imaging of the oct appearance of the normal conjunctiva with ASOCT and its present and potential use in the conjunctival pathologies

Polycrystallization effects on the nanoscale electrical properties of high-k dielectrics

In this study, atomic force microscopy-related techniques have been used to investigate, at the nanoscale, how the polycrystallization of an Al2O3-based gate stack, after a thermal annealing process, affects the variability of its electrical properties. The impact of an electrical stress on the electrical conduction and the charge trapping of amorphous and polycrystalline Al2O3 layers have been also analyzed

Dielectric Breakdown in Chemical Vapor Deposited Hexagonal Boron Nitride

Insulating films are essential in multiple electronic devices because they can provide essential functionalities, such as capacitance effects and electrical fields. Two-dimensional (2D) layered materials have superb electronic, physical, chemical, thermal, and optical properties, and they can be effectively used to provide additional performances, such as flexibility and transparency. 2D layered insulators are called to be essential in future electronic devices, but their reliability, degradation kinetics, and dielectric breakdown (BD) process are still not understood. In this work, the dielectric breakdown process of multilayer hexagonal boron nitride (h-BN) is analyzed on the nanoscale and on the device level, and the experimental results are studied via theoretical models. It is found that under electrical stress, local charge accumulation and charge trapping/detrapping are the onset mechanisms for dielectric BD formation. By means of conductive atomic force microscopy, the BD event was triggered at several locations on the surface of different dielectrics (SiO2, HfO2, Al2O3, multilayer h-BN, and monolayer h-BN); BD-induced hillocks rapidly appeared on the surface of all of them when the BD was reached, except in monolayer h-BN. The high thermal conductivity of h-BN combined with the one-atom-thick nature are genuine factors contributing to heat dissipation at the BD spot, which avoids self-accelerated and thermally driven catastrophic BD. These results point to monolayer h-BN as a sublime dielectric in terms of reliability, which may have important implications in future digital electronic devices.Fil: Jiang, Lanlan. Soochow University; ChinaFil: Shi, Yuanyuan. Soochow University; China. University of Stanford; Estados UnidosFil: Hui, Fei. Soochow University; China. Massachusetts Institute of Technology; Estados UnidosFil: Tang, Kechao. University of Stanford; Estados UnidosFil: Wu, Qian. Soochow University; ChinaFil: Pan, Chengbin. Soochow University; ChinaFil: Jing, Xu. Soochow University; China. University of Texas at Austin; Estados UnidosFil: Uppal, Hasan. University of Manchester; Reino UnidoFil: Palumbo, Félix Roberto Mario. Comisión Nacional de Energía Atómica; Argentina. Universidad Tecnológica Nacional; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Lu, Guangyuan. Chinese Academy of Sciences; República de ChinaFil: Wu, Tianru. Chinese Academy of Sciences; República de ChinaFil: Wang, Haomin. Chinese Academy of Sciences; República de ChinaFil: Villena, Marco A.. Soochow University; ChinaFil: Xie, Xiaoming. Chinese Academy of Sciences; República de China. ShanghaiTech University; ChinaFil: McIntyre, Paul C.. University of Stanford; Estados UnidosFil: Lanza, Mario. Soochow University; Chin

Hydrogen Peroxide Production in an Electrochemical Flow-by Reactor using Gas Diffusion Electrodes Modified with Organic Redox Catalysts

This paper presents a proposal to use an electrochemical flow-by reactor for hydrogen peroxide electrogeneration using cathodes formed from the incorporation of organic redox catalysts (2-ethylanthraquinone, 2-tert-butylanthraquinone, alizarin, and azobenzene) in the structure of gas diffusion electrodes. These electrodes help circumvent the low solubility of oxygen in aqueous solutions. Organic redox catalysts, which typically contain quinone or azo groups in their structure, were added to the electrode mass in a 10% proportion. The electrodes were used to study the electrogeneration of hydrogen peroxide in situ, in an acid medium (0.1 mol L-1 H2SO4 and 0.1 mol L-1 K2SO4, pH 1), inside an electrochemical flow-by reactor. Comparative analysis among the different catalysts indicated that the best electrode for hydrogen peroxide electrogeneration was the gas diffusion electrode modified with 10% of 2-ethylanthraquinone. With an underflow rate of 200 L h-1, hydrogen peroxide was formed with a maximum yield of 998.12 mg L-1 after 2 h at -2.0 V vs Pt//Ag/AgCl, for which the energy consumption was 11.21 kWh kg-1. The use of the electrochemical flow-by reactor was much more efficient, in that it yielded higher concentrations of hydrogen peroxide with extremely low energy consumption, compared to that obtained when using an electrochemical cell. In addition, for ensuring appropriate usage of the electrodes, optimizing their potential for the maximum generation of hydrogen peroxide, and obtaining the highest efficiency for the reduction of oxygen, a fuzzy algorithm was developed to help support the user’s decision

Landscapes, Art, Parks and Cultural Change

A critical examination of a series of cultural interventions in the Matese mountains north of Naples, deploying artistic practices to re-signify the complexities and memories of the landscape

Understanding current instabilities in conductive atomic force microscopy

Conductive atomic force microscopy (CAFM) is one of the most powerful techniques in studying the electrical properties of various materials at the nanoscale. However, understanding current fluctuations within one study (due to degradation of the probe tips) and from one study to another (due to the use of probe tips with different characteristics), are still two major problems that may drive CAFM researchers to extract wrong conclusions. In this manuscript, these two issues are statistically analyzed by collecting experimental CAFM data and processing them using two different computational models. Our study indicates that: (i) before their complete degradation, CAFM tips show a stable state with degraded conductance, which is difficult to detect and it requires CAFM tip conductivity characterization before and after the CAFM experiments; and (ii) CAFM tips with low spring constants may unavoidably lead to the presence of a ~1.2 nm thick water film at the tip/sample junction, even if the maximum contact force allowed by the setup is applied. These two phenomena can easily drive CAFM users to overestimate the properties of the samples under test (e.g., oxide thickness). Our study can help researchers to better understand the current shifts that were observed during their CAFM experiments, as well as which probe tip to use and how it degrades. Ultimately, this work may contribute to enhancing the reliability of CAFM investigations

Considering REM Sleep Behavior Disorder in the Management of Parkinson's Disease

Rapid eye movement (REM) sleep behavior disorder (RBD) is the result of the loss of physiological inhibition of muscle tone during REM sleep, characterized by dream-enacting behavior and widely recognized as a prodromal manifestation of alpha-synucleinopathies. Indeed, patients with isolated RBD (iRBD) have an extremely high estimated risk to develop a neurodegenerative disease after a long follow up. Nevertheless, in comparison with PD patients without RBD (PDnoRBD), the occurrence of RBD in the context of PD (PDRBD) seems to identify a unique, more malignant phenotype, characterized by a more severe burden of disease in terms of both motor and non-motor symptoms and increased risk for cognitive decline. However, while some medications (eg, melatonin, clonazepam, etc.) and non-pharmacological options have been found to have some therapeutic benefits on RBD there is no available treatment able to modify the disease course or, at least, slow down the neurodegenerative process underlying phenoconversion. In this scenario, the long prodromal phase may allow an early therapeutic window and, therefore, the identification of multimodal biomarkers of disease onset and progression is becoming increasingly crucial. To date, several clinical (motor, cognitive, olfactory, visual, and autonomic features) neurophysiological, neuroimaging, biological (biofluids or tissue biopsy), and genetic biomarkers have been identified and proposed, also in combination, as possible diagnostic or prognostic markers, along with a potential role for some of them as outcome measures and index of treatment response. In this review, we provide an insight into the present knowledge on both existing and future biomarkers of iRBD and highlight the difference with PDRBD and PDnoRBD, including currently available treatment options