Recent advances in arsenic trioxide encapsulated nanoparticlesas drug delivery agents to solid cancers

Since arsenic trioxide (ATO) was first approved as the front line therapy for acute promyelocytic leukemia (APL) 25 years ago, its anti-cancer properties for various malignancies have been under intense investigation. However, the clinical successes of ATO in treating hematological cancers have not been translated to solid cancers. This is due to arsenic’s rapid clearance by the body’s immune system before reaching the tumor site. Several attempts have henceforth been made to increase its bioavailability toward solid cancers without increasing its dosage albeit without much success. This review summarizes the past and current utilization of ATO in the medical field with primary focus on the implementation of nanotechnology for ATO delivery to solid cancer cells. Different approaches that have been employed to increase arsenic’s efficacy, specificity and bioavailability to solid cancer cells were evaluated and compared. The potential of combining different approaches or tailoring delivery vehicles to target specific types of solid cancers according to individual cancer characteristics and arsenic chemistry was proposed and discussed

Modelling and validating three dimensional human normal cervix and cervical cancer tissues in vitro

Objective: The use of three dimensional in vitro systems in cancer research is a promising path for developing effective anticancer therapies. The aim of this study was to engineer a functional 3-D in vitro model of normal and cancerous cervical tissue. Methods: Normal epithelial and immortalized cervical epithelial carcinoma cell lines were used to construct 3-D artificial normal cervical and cervical cancerous tissues. De-epidermised dermis (DED) was used as a scaffold for both models. Morphological analyses were conducted by using haematoxylin and eosin staining and characteristics of the models were studied by analysing the expression of different structural cytokeratins and differential protein marker Mad1 using immunohistochemical technique. Results: Haematoxylin and eosin staining results showed that normal cervical tissue had multi epithelial layers while cancerous cervical tissue showed dysplastic changes. Immunohistochemistry staining results revealed that for normal cervix model cytokeratin 10 was expressed in the upper stratified layer of epithelium while cytokeratin 5 was expressed mainly in the middle and basal layer. Cytokeratin 19 was weakly expressed in a few basal cells. Cervical cancer model showed cytokeratin 19 expression in different epithelial layers and weak or no expression for cytokeratin 5 and cytokeratin 10. Mad1 expression was detected in some suprabasal cells. Conclusions: The 3-D in vitro models showed stratified epithelial layers and expressed the same types and patterns of differentiation marker proteins as seen in corresponding in vivo tissue in either normal cervical or cervical cancerous tissue. Findings imply that they can serve as functional normal and cervical cancer models

Effective delivery of arsenic trioxide to HPV-positive cervical cancer cells using optimised liposomes: a size and charge study

Despite the success of arsenic trioxide (ATO) in treating haematological malignancies, its potential to treat solid tumours has not been fully exploited, owing to its dose-limiting toxicity and poor pharmacokinetics. In order to overcome this hurdle, liposomal encapsulation of the drug with different surface charges (neutral, negative, and positive) and sizes (100, 200 and 400 nm) were synthesised and tested on human papilloma virus (HPV)-positive HeLa and HPV-negative HT-3 cervical cancer cell lines. Two epithelial cell lines-human keratinocytes (HK) and human colon cells (CRL-1790)-were used as controls. The synthesised liposomes were tested for their physico-chemical characteristics, drug loading efficiency, and toxicity on the studied cell lines. Neutral liposomes of 100 nm in size were the chosen formulation for delivering ATO into the studied cells, as they showed the least intrinsic cytotoxicity and the highest loading efficiency. The findings demonstrated that the optimised formulation of liposomes was an effective drug delivery method for HPV-infected cervical cancer cells. Furthermore, the toxicity vs. uptake ratio was highest for HeLa cells, while a reduced or minimal toxic effect was observed for non-HPV-infected cervical cancer cells and control cells. These findings may provide a promising therapeutic strategy for effectively managing cervical cancers

Optimisation of folate-mediated liposomal encapsulated arsenic trioxide for treating HPV-positive cervical cancer cells in vitro

High-risk human papilloma virus (HPV) infection is directly associated with cervical cancer development. Arsenic trioxide (ATO), despite inducing apoptosis in HPV-infected cervical cancer cells in vitro, has been compromised by toxicity and poor pharmacokinetics in clinical trials. Therefore, to improve ATO’s therapeutic profile for HPV-related cancers, this study aims to explore the effects of length of ligand spacers of folate-targeted liposomes on the efficiency of ATO delivery to HPV-infected cells. Fluorescent ATO encapsulated liposomes with folic acid (FA) conjugated to two different PEG lengths (2000 Da and 5000 Da) were synthesised, and their cellular uptake was examined for HPV-positive HeLa and KB and HPV-negative HT-3 cells using confocal microscopy, flow cytometry, and spectrophotometer readings. Cellular arsenic quantification and anti-tumour efficacy was evaluated through inductively coupled plasma-mass spectrometry (ICP-MS) and cytotoxicity studies, respectively. Results showed that liposomes with a longer folic acid-polyethylene glycol (FA-PEG) spacer (5000 Da) displayed a higher efficiency in targeting folate receptor (FR) + HPV-infected cells without increasing any inherent cytotoxicity. Targeted liposomally delivered ATO also displayed superior selectivity and efficiency in inducing higher cell apoptosis in HPV-positive cells per unit of arsenic taken up than free ATO, in contrast to HT-3. These findings may hold promise in improving the management of HPV-associated cancers

Modelling and validating three-dimensional human breast and cancerous human breast tissues in vitro

In this study three dimensional (3-D) in vitro models of normal breast and breast cancer tissues were developed to mimic closely the in vivo tissue microenvironment and therefore providing reliable models for in vitro studies as well as testing of novel cancer therapies. Normal and cancerous human breast cell lines were used to construct 3-D artificial tissues, where de-epidermalised dermis (DED) was used as a scaffold for both models. Morphological analyses were conducted using haematoxylin and eosin staining. Biomarkers including keratin 5 and 19 as well as α smooth muscle actin and mucin 1 were used to confirm and validate the reliability of the proposed models using immunohistochemical techniques. Findings suggest that the 3-D in vitro models described in this work can serve as functional models of both human normal and cancerous breast tissues. Multiple structures similar to ducts and lobules of human breast in vivo were observed in 3-D in vitro models by the use of H&E, some breast cancer colonies seen in the cancerous 3-D model were similar to the ducto-lobular structures observed in normal 3-D model of the breast but the former cells were more loosely connected, irregular and largely disorganized. The established 3-D in vitro model of normal breast showed the development of ducto-lobular structures composed of an inner cell layer which was stained positive with α mucin 1 antibody, a biomarker that is characteristic for luminal cells; and also an outer basal layer of cells that was stained positive for α smooth muscle actin, a biomarker of myoepithelial cells.. Keratin staining in 3-D in vitro models also resembled the pattern observed in vivo where keratin 5 was detected in both luminal and myoepithelial cells of normal breast model (NTERT cells), whereas keratin 19 was present in breast cancer model (C2321 cells). These 3-D models successfully recapitulate both normal and pathological tissue architecture of breast tissue and has the potential for various applications in the evaluation of breast cancer progression and treatment

A large-scale proteogenomics study of apicomplexan pathogens-Toxoplasma gondii and Neospora caninum

Proteomics data can supplement genome annotation efforts, for example being used to confirm gene models or correct gene annotation errors. Here, we present a large‐scale proteogenomics study of two important apicomplexan pathogens: Toxoplasma gondii and Neospora caninum. We queried proteomics data against a panel of official and alternate gene models generated directly from RNASeq data, using several newly generated and some previously published MS datasets for this meta‐analysis. We identified a total of 201 996 and 39 953 peptide‐spectrum matches for T. gondii and N. caninum, respectively, at a 1% peptide FDR threshold. This equated to the identification of 30 494 distinct peptide sequences and 2921 proteins (matches to official gene models) for T. gondii, and 8911 peptides/1273 proteins for N. caninum following stringent protein‐level thresholding. We have also identified 289 and 140 loci for T. gondii and N. caninum, respectively, which mapped to RNA‐Seq‐derived gene models used in our analysis and apparently absent from the official annotation (release 10 from EuPathDB) of these species. We present several examples in our study where the RNA‐Seq evidence can help in correction of the current gene model and can help in discovery of potential new genes

Smart green charging scheme of centralized electric vehicle stations

This paper presses a smart charging decision-making criterion that significantly contributes in enhancing the scheduling of the electric vehicles (EVs) during the charging process. The proposed criterion aims to optimize the charging time, select the charging methodology either DC constant current constant voltage (DC-CCCV) or DC multi-stage constant currents (DC-MSCC), maximize the charging capacity as well as minimize the queuing delay per EV, especially during peak hours. The decision-making algorithms have been developed by utilizing metaheuristic algorithms including the Genetic Algorithm (GA) and Water Cycle Optimization Algorithm (WCOA). The utility of the proposed models has been investigated while considering the Mixed Integer Linear Programming (MILP) as a benchmark. Furthermore, the proposed models are seeded using the Monte Carlo simulation technique by estimating the EVs arriving density to the EVS across the day. WCOA has shown an overall reduction of 13% and 8.5% in the total charging time while referring to MILP and GA respectively

Evaluation of complication rates after coronary artery bypass surgery using administrative data

Our objectives were (1) to determine if studying hospital complication rates after coronary artery bypass graft (CABG) surgery provides information not available when only mortality is studied, and (2) to reexplore the utility of ICD-9-CM administrative data for CABG outcomes assessment. Using data from Massachusetts, we identified CABG cohorts from 1990 and 1992 to respectively develop and validate multivariate risk adjustment models predicting in-hospital mortality and complications. The resulting models had good discrimination and calibration. In 1992, adjusted hospital complication rates ranged widely from 13.0% to 57.6%, while mortality rates ranged from 1.4% to 6.1%. Hospitals with high complication rates tended to have high mortality (r = 0.74, p = 0.006), but 2 of the 12 hospitals studied ranked quite differently when judged by complications rather than mortality. We conclude that (1) complications after CABG occur frequently and may provide information about hospital quality beyond that obtained from hospital mortality rates, and that (2) administrative data continue to be a promising resource for outcomes research

The Attenuation Capability ofSelected Steel Alloys for Nuclear Reactor Applications

Neutronsand gamma ray attenuation of different steel grades (SS304, SS304L, SS316L, SS430, a modified high manganese-nitrogen austenitic stainless steel, and developed cobalt-free Maraging steel) was measured to study their capability to be used as nuclear reactor materials. The hardness and microstructure of the studied steel alloys were carried out using Vickers hardness and optical microscope respectively.Neutron and gamma rays measurements were carried out using a narrow beam transmissions geometry method. Measurements and calculations of gamma ray attenuation coefficients were carried out at energies 238.63, 338.28, 583.19, 911.2, 968.97, 1173.23, 1332.49, and 2614.51 keV. The transmitted gamma rays were detected by the Hyper Pure Germanium detector (HPGe), while, the neutron flux emitted from 241Am-Be neutron source was used to measure the neutron removal cross section for both slow and total neutrons. The transmitted beam of neutrons was measured under a good geometric conditions using 3He counter.A good agreement between experimental data of mass attenuation coefficients and theoretical results calculated by the WinXcom computer program (version 3.1) was obtained