National and international standards for honey from
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Barely three months into the new year and we are happy to announce a monumental milestone reached - 150 million downloads.
\n\nThis achievement solidifies IntechOpen’s place as a pioneer in Open Access publishing and the home to some of the most relevant scientific research available through Open Access.
\n\nWe are so proud to have worked with so many bright minds throughout the years who have helped us spread knowledge through the power of Open Access and we look forward to continuing to support some of the greatest thinkers of our day.
\n\nThank you for making IntechOpen your place of learning, sharing, and discovery, and here’s to 150 million more!
\n\n\n\n\n'}],latestNews:[{slug:"intechopen-supports-asapbio-s-new-initiative-publish-your-reviews-20220729",title:"IntechOpen Supports ASAPbio’s New Initiative Publish Your Reviews"},{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"}]},book:{item:{type:"book",id:"1349",leadTitle:null,fullTitle:"Neuroimaging - Cognitive and Clinical Neuroscience",title:"Neuroimaging",subtitle:"Cognitive and Clinical Neuroscience",reviewType:"peer-reviewed",abstract:"The rate of technological progress is encouraging increasingly sophisticated lines of enquiry in cognitive neuroscience and shows no sign of slowing down in the foreseeable future. Nevertheless, it is unlikely that even the strongest advocates of the cognitive neuroscience approach would maintain that advances in cognitive theory have kept in step with methods-based developments. There are several candidate reasons for the failure of neuroimaging studies to convincingly resolve many of the most important theoretical debates in the literature. For example, a significant proportion of published functional magnetic resonance imaging (fMRI) studies are not well grounded in cognitive theory, and this represents a step away from the traditional approach in experimental psychology of methodically and systematically building on (or chipping away at) existing theoretical models using tried and tested methods. Unless the experimental study design is set up within a clearly defined theoretical framework, any inferences that are drawn are unlikely to be accepted as anything other than speculative. 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\r\n\tCurrently, numerous biomaterials-based studies are being conducted, including research into chitin and chitosan, the second most abundant polysaccharide after cellulose. Chitin is obtained at an industrial scale from a variety of natural sources including, crustacean and insect exoskeletons, fungi cell walls, squid pen, etc. Chitosan is biodegradable, biocompatible, non-toxic, water-soluble under acidic conditions, and linear cationic amino polysaccharide derived from the deacetylation of chitin. It contains free amino and hydroxyl groups that can be functionalized by binding with the cationic and anionic groups. It has numerous applications, especially in the environmental remediation, biomedical, pharmaceutical, agriculture, and food industries.
\r\n\r\n\tThis book will present an update of articles addressing isolation, properties, and certain applications of chitin and chitosan, including films, fibers, nanoparticles, composite materials, hydrogels, polymeric complexes, water purification, antimicrobials, textile, cosmetics, biosensors, nanoporous scaffolds, and membranes. We invite world-class researchers from around the world, industry, academia, government, and private research institutions are encouraged to publish research or review articles on chitin and chitosan.
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Bees collect and transform this material with their own specific substances before storing it and leaving it to mature in separate honeycombs [1–3]. Honey is characterized as a semi-liquid product, comprising a complex mixture of carbohydrates, especially the monosaccharides glucose and fructose; and other sugars, enzymes, lactones, wax, pigments, vitamins, amino acids, minerals, organic acids and pollen [4]. Its chemical composition varies according to the bee species, weather conditions, type of soil, physiological state of the colony, nectar source and honey maturity [5]. Its nutritional quality, which occurs due to the presence of minerals and vitamins, sensory properties, medicinal properties such as antioxidant and antiseptic activity, specific therapeutic properties, such as for the treatment of inflammatory and infectious processes, and high energy content attract many consumers [6, 7].
\nIn Brazil, Normative Ruling No. 11 of October 20, 2000, which regulates the standardization of honey for marketing purposes, is based on European laws and approves only honey produced by bees of the Apis genus [3]. The physicochemical analyzes indicated by Brazilian legislation for the identity and quality of honey produced by bees from the Apis genus are moisture, sucrose, reducing sugars, ash, minerals, acidity, diastase activity, color and hydroxymethylfurfural (HMF) content [3]. These analyses contribute to the supervision and control of the quality of honey produced in Brazil and intended for export, and the results are compared with both Brazilian standards and those of international organizations [5, 8], see Table 1. Some concerns exist regarding the quality of domestically produced honey, and such tests allow the quality of imported honey to be inspected [5].
Parameters | Brazil (2000) | Mercosur (1999) | European Union (2001) |
---|---|---|---|
Moisture (%) | Maximum 20.0 | Maximum 20.0 | Maximum 20.0 |
Acidity (meq kg−1) | Maximum 50.0 | Maximum 50.0 | Maximum 50.0 |
Ash (%) | Maximum 0.6 | Maximum 0.6 | – |
Color | Nearly colorless to dark brown | Nearly colorless to dark brown | – |
HMF (mg kg−1) | Maximum 60.0 | Maximum 60.0 | Maximum 60.0 |
Electric conductivity (μS cm−1) | – | – | Maximum 0.8 |
Reducing sugars (%) | Minimum 65.0 | Minimum 65.0 | Minimum 60.0 |
Saccharose (%) | Maximum 6.0 | Maximum 6.0 | Maximum 5.0 |
Diastase activity (Goethe) | Minimum 8.0 | Minimum 8.0 | Minimum 8.0 |
The aim of this chapter is to significantly contribute to the improvement of techniques that evaluate the quality of honey, and to propose an adjustment to the physicochemical parameters established by Brazilian law [3], adding additional analysis such as pH, formaldehyde index (mL kg−1), electric conductivity (mS cm−1), protein (%), total reducing sugars (%), viscosity (mPa s) and water activity. These analyzes can contribute effectively to control the quality of commercially available honey. The analysis required by existing legislation combined with the further analysis proposed by this chapter will allow important parameters for the quality of honey to be determined, such as maturity, purity, deterioration and adulteration.
All analyses were performed in triplicate to provide greater reliability for the results, following the methods described in the below sections.
\nWater content is one of honey’s most important characteristics as it influences its viscosity, specific gravity, maturity, crystallization, flavor, preservation, shelf life and palatability [11–13]. It depends on several factors such as bee species, floral source, honey harvesting time, the degree of maturity achieved in the hive (complete dehydration) and climatic factors [14].
\nMoisture is analyzed to determine the safety of the product, giving a quality criterion that determines the ability of the honey to remain stable and free of fermentation. A high moisture content can lead to crystallization of the product and promote the development of osmophilic microorganisms responsible for fermentation, negatively affecting its sensory characteristics and nutritional properties and reducing the shelf life of the product [15].
\nRefractive index (20°C) | Moisture (%) | Refractive index (20°C) | Moisture (%) |
---|---|---|---|
1.4740 | 25.0 | 1.4865 | 20.0 |
1.4745 | 24.8 | 1.4870 | 19.8 |
1.4750 | 24.6 | 1.4875 | 19.6 |
1.4755 | 24.4 | 1.4880 | 19.4 |
1.4760 | 24.2 | 1.4885 | 19.2 |
1.4765 | 24.0 | 1.4890 | 19.0 |
1.4770 | 23.8 | 1.4895 | 18.8 |
1.4775 | 23.6 | 1.4900 | 18.6 |
1.4780 | 23.4 | 1.4905 | 18.4 |
1.4785 | 23.2 | 1.4910 | 18.2 |
1.4790 | 23.0 | 1.4915 | 18.0 |
1.4795 | 22.8 | 1.4920 | 17.8 |
1.4800 | 22.6 | 1.4925 | 17.6 |
1.4805 | 22.4 | 1.4930 | 17.4 |
1.4810 | 22.2 | 1.4935 | 17.2 |
1.4815 | 22.0 | 1.4940 | 17.0 |
1.4820 | 21.8 | 1.4946 | 16.8 |
1.4825 | 21.6 | 1.4951 | 16.6 |
1.4830 | 21.4 | 1.4956 | 16.4 |
1.4835 | 21.2 | 1.4961 | 16.2 |
1.4840 | 21.0 | 1.4966 | 16.0 |
1.4845 | 20.8 | 1.4971 | 15.8 |
1.4850 | 20.6 | 1.4976 | 15.6 |
1.4855 | 20.4 | 1.4982 | 15.4 |
1.4860 | 20.2 | 1.4987 | 15.2 |
The refractive index of liquids is also temperature dependent. Generally, refractometers are regulated at 20°C [17]. If the temperature of honey is exactly 20°C, the refractive index obtained directly from Table 1 can be applied. However, for measurement at different temperatures, the refractive index should be increased or decreased by a value of 0.00023 for each degree Celsius above or below 20°C, depending on the sample temperature. In the case of refractive index values not included in Table 2, the desired value can be calculated using Eq. (1).
\nwhere y = moisture, x = refractive index.
The pH determined refers to the hydrogen ions present in a solution of honey and can influence the formation of other components such as the production of hydroxymethylfurfural—HMF [19].While pH analysis is useful as an auxiliary variable to estimate the quality of the product and as a parameter for evaluating total acidity, it is not directly related to free acidity due to the actions of the buffer acids and minerals present in honey [20].
\nThe pH of honey ranges between 3.5 and 5.5 depending on its botanical source, the pH of nectar, soil or plant association, and the concentration of different acids and minerals such as calcium, sodium, potassium and other ash constituents [2, 15]. Altered values may indicate fermentation or adulteration [12, 21]. Mandibular substances added to the nectar may also change the pH of honey, a process that begins with the transport of nectar to the hive in the honey vesicle [22].
\nDue to the variations of some organic acids and inorganic ions such as phosphate and based on different sources of nectar, honey acidity can result from the action of the enzyme glucose oxidase produced in the hypopharyngeal glands of bees, producing gluconic acid. This enzyme remains active even during storage affecting the honey after processing due to the quantity of minerals present, and by bacteria during maturation [15, 24, 25]. Organic acids from honey represent less than 0.5% of solids, but have a considerable effect on taste [26].
\nThe formaldehyde content in honey represents, predominantly, amino compounds, allowing the evaluation of peptide content, protein and amino acids [27]. This is an indicative of the presence of nitrogen in honey and is an important adulteration indicator. When low, it can suggest the presence of artificial products, while when excessively high it can show that the bees were fed hydrolyzed protein [28]. Thus, formaldehyde content can be used to prove the authenticity of honey [21].
\nAsh content expresses the richness of honey in mineral content [30–32]. The minerals calcium (Ca), magnesium (Mg), iron (Fe), copper (Cu), cadmium (Cd) and zinc (Zn) in the form of sulfate (SO42−) and chloride (Cl−) [24] are found in small amounts. Minerals influence the color of honey and are present in higher concentrations in dark honey than light-colored honey [14]. They vary depending on the floral origin, region, bee species and type of manipulation [15].
\nwhere m1 = crucible weight with ashes, m2 = crucible weight, m3 = sample weight (mass of honey).
Electrical conductivity is determined by the ability of ions present in a solution to conduct electrons. It has been found to assist in the determination of the botanical origin of honey, as well as correlating with ash content, pH, acidity, minerals, proteins and other substances in honey [30, 34]. Honey conductivity is a great indicator of the adulteration of honey from its original form; whether formed from nectar (with some differentiation according to species) or honeydew [2].
\nWeigh 10 g of honey in a beaker on an analytical balance and transfer it to a 50 mL volumetric flask with distilled water. Take the reading as soon as the conductivity stabilizes. For each change of sample rinse the electrode with distilled water and dry it with absorbent paper.
Color has a direct impact on the price of honey as it influences consumer preference and is of particular importance in the international market [8]. Variations in the color of honey are related to its floral origin, mineral content, storage and product processing, climatic factors during nectar flow and the temperature at which the honey matures in the hive [12], as well as factors such as the proportion of fructose and glucose present, nitrogen content and the instability of fructose in an acid solution [36].
\nColor | Pfund scale (mm)* | Color range (inc)** |
---|---|---|
Water white | From 1 to 8 | 0.030 or less |
Extra white | More than 8–17 | More than 0.030–0.060 |
White | More than 17–34 | More than 0.060–0.120 |
Extra light amber | More than 34–50 | More than 0.120–0.188 |
Light amber | More than 50–85 | More than 0.188–0.440 |
Amber | More than 85–114 | More than 0.440–0.945 |
Dark amber | More than 114 | More than 0.945 |
Pfund scale for determining color.
*Millimeter.
**Incidence—absorbance at 560 nm. Source: Marchini et al. [8].
For this analysis, the honey must be liquid, without crystallization, as crystals tend to change the natural color of honey, making it lighter [8].
Hydroxymethylfurfural (HMF) is an intermediate product of the Maillard reaction, and is formed by the direct dehydration of sugars under acidic conditions, mainly by the decomposition of fructose during heat treatment applied to food [4, 30]. It can be a toxic compound when found in high amounts. In honey, HMF is an indicator of quality which assists in the identification of freshness when in low concentrations. Higher than permitted concentrations may mean that the product has undergone adulteration through the addition of inverted sugar (syrup), has been stored under inappropriate conditions, undergone prolonged storage, been heated, or affected by acidity, water or minerals [12, 36].
\nWeigh 5 g of honey in an analytical balance using a properly labeled 50 mL beaker, dissolve the sample by adding 25 mL of distilled water and then transfer it to a 50 mL volumetric flask. Add 0.5 mL of Carrez solution I and 0.5 mL of Carrez solution II and fill the volumetric flask to the meniscus with distilled water.
\nAdd two drops of ethanol to prevent foaming. Mix the solution and filter using filter paper; discarding the first 10 mL filtered.
\nLabel two test tubes and pipette 5 mL of the filtrate over 5 mL of distilled water in the first (sample) and 5 mL of the filtrate added to 5 mL of 0.2% sodium bisulfite solution in the second tube (blank). Shake the tubes using a vortex mixer. Measure the absorbance in a UV-vis spectrophotometer at wavelengths of 284 and 336 nm using quartz cuvettes.
\nBefore the readings, calibrate the spectrophotometer with a blank reference for each sample evaluated. If absorbance at 284 nm exceeds 0.6 the sample is diluted with water and the blank reference with sodium bisulfite 0.2%, in the same proportions, and the reading is repeated. The HMF content in honey is calculated with Eq. (9) .
\nwhere A284 = absorbance at 284 nm, A336 = absorbance at 336 nm, 149.7 = factor, 5 = theoretical value of sample weight.
Despite little being known about the proteinaceous material present in honey, and its limited occurrence, such materials can be used to detect possible adulterations in commercial products, along with water content and concentration [37]. They are also used as identification parameters for the maturity of honey [38].
\nHoney protein can originate either from animals or plants. Animal protein comes from the bee itself, made up of secretions from the salivary glands, along with products collected during the collection of nectar or the maturation of the honey [11], while the plant origins are the nectar and pollen collected in the field [39].
\nwhere V = volume of HCl spent in titration, M = molarity of hydrochloric acid, fc = correction factor of hydrochloric acid, 6.25 = correction factor for protein, m = sample weight.
Sugars constitute 95% of the dry matter of honey [15], and together with water make up its main components. The monosaccharides glucose and fructose represent around 85% of the carbohydrates present in honey produced by the Apis genus, and are known as reducing sugars, which have the ability to reduce copper ions in an alkaline solution. Fructose has a high hygroscopicity and adds to the sweetness of honey, while glucose, due to its poor solubility, tends to influence crystallization [12]. Normally fructose is predominant as honey with high fructose rates can remain liquid for a long time, or never crystallize [2]. The disaccharides sucrose and maltose represent 10% of the sugars present in honey [41]. Sucrose represents on average 2–3% of the carbohydrates of honey from the Apis genus. When it exceeds this value, it indicates adulterated honey or early harvested honey, with humidity above 20% [19].
\nPreparation of reagents: Fehling A: dissolve 34.65 g of p.a. copper sulfate pentahydrate (CuSO4.5H2O) in distilled water; transfer it to a 1000 mL volumetric flask and complete the volume. Fehling B: dissolve 125 g of p.a. sodium hydroxide (NaOH) in 300 mL of distilled water; in the same solution dissolve 173 g of p.a. tartrate of potassium and sodium (C4H4KNaO6.4H2O); complete the volume to 1000 mL and allow it to stand for 24 hours.
\nwhere V = volume of glucose spent in titration (mL), m = glucose mass (g).\n
Obs.: Total titration time should not exceed 3 min.
\nwhere V = volume spent in titration, 0.05 = correction factor for Fehling’s solution A and B.
\nwhere RS = reducing sugars, TRS = total reducing sugars, 0.95 = reducing factor from total reducing sugars.
Viscosity and the other physicochemical properties of honey depend on many factors, including composition and temperature. One of the most important factors for viscosity is water content, as viscosity generally decreases while water content increases [42]. Studies of this trait are of great importance, as the rheological models obtained are useful for identifying the rheological properties of a fluid with practical quantities such as concentration, temperature, pH and maturation index, among others. This knowledge is essential for quality control in the intermediate control in production lines and for the design of equipment and processes [43].
\nTurn on and reset the equipment, select the specific rotor (rotor 1 or rotor 2 spindles); turn on the water bath at 25°C; place a sufficient volume of the sample in a 250 mL beaker to cover the rotor; wait for the sample to reach the set temperature. Connect the viscometer and take the reading. The standard time to perform the reading is 1 min; the percentage of the viscometer range and the rotation per minute from the equipment vary according to each sample evaluated. After 1 min of rotation, the viscosity of each sample is read directly from the viscometer timer.
As honey contains enzymes in very low quantities, this activity is the result of the joint action of diastase (
Diastase activity is closely related to the structure of the honey and can be modified by denaturing performed by overheating the honey, which seriously compromises its quality [25, 46]. In addition to shelf life and heating the product, another indicator of reduced enzyme levels are honey samples from fast nectar flows, due to the accumulation of the material processed inside the hive.
\nLabel two 50 mL beakers; pipette 5 mL of solution and 10 mL of distilled water into beaker 1, and 20 mL of distilled water into beaker 2. Remove 1 mL aliquots of the solution in each beaker and transfer to another labeled beaker; add 10 mL of the iodine solution 0.0007 N. Prepare five different concentrations so that the correct volume is found. Perform a reading in a spectrophotometer set to the amount of distilled water to be added to the sample, in order to make the reading in the selected absorbance range.
\nWeigh 10 g of honey in a 250 mL beaker using an analytical balance; add 5 mL of buffer and 20 mL of distilled water, homogenize and dissolve; transfer the sample to a 50 mL volumetric flask; add 3 mL of sodium chloride solution 0.5 M; complete the volume with distilled water; pipette 10 mL of this solution into a 250 mL beaker and place it in a water bath at 40°C, wait for 15 min; pipette 5 mL of the starch solution heated to 40°C into the honey solution; mix it and remove 1 mL aliquots to an identified beaker at intervals of 5 min, then quickly add 10 mL of the iodine solution 0.0007 N and complete the volume with distilled water.
\nDetermine the absorbance at 660 nm in a visible spectrophotometer and record the time elapsed between the mixing of the starch solution and the addition of the honey to the iodine. Take aliquots of 1 mL every 5 min to lower the absorbance value to 0235 nm. To determine the time the absorbance took to reach this value, plot an absorbance versus time graph. The results are expressed in the Goethe scale. The diastatic index (DI) is determined according to Eq. (14):
\nwhere t = time.
The concept of water activity has been used to evaluate the interaction of water with other food components, as water is characterized as a major component of many foods [47]. Honey has a low water activity, a parameter which determines the available water in the food and its availability for microbial metabolism, which interferes with the microbial activity in honey. This feature gives the product microbiota stability [48], resulting in quality, preservation and longer shelf life. When there is no water available in food, the water activity measurement is equal to 0.0; however, when the sample consists entirely of pure water, then water activity is equal to 1.0 [49].
\nThe Folin-Ciocalteu assay was designed and standardized for the quantification of total phenols by Singleton et al. [50] and adapted by Daves [51]. The system is characterized by a mixture of sodium tungstate and sodium molybdate salts in an acid medium (hydrochloric acid and phosphoric acid), which has a yellowish color. In the presence of phenolic compounds these salts are reduced, forming complexes (molybdenum-tungsten) and producing a bluish color. The intensity of the blue tone is proportional to the number of hydroxyl or oxidizable groups of phenolic compounds. Absorption occurs at 725 nm. Phenolics determined by Folin-Ciocalteu are often expressed as Gallic acid equivalent (GAE).
\nwhere GAE (mg) from the main solution (mg/mL) = 1.5 mg GAE/mL.
\nPipetted volume from the main solution (mL) = 0.0, 0.1, 0.2, 1.2, 2.2, 4.0, 6.0, 8.0 and 10 mL.
\nAdjust the volume of solutions to 10 mL using water as solvent.
\nTransfer 30 μL of the diluted solutions; 2.370 μL of distilled water and 150 μL of Folin-Ciocalteu reagent to test tubes protected with aluminum foil (put distilled water in the blank sample). After 2 min, add 450 μL of sodium carbonate 15%. Close the tubes and place them in a water bath with stirring in the dark at a temperature of 37°C for 30 min. Measure the absorbance in quartz cuvettes in a spectrophotometer at a wavelength of 725 nm. Plot the Gallic acid concentration (mg/L) on the abscissa (
Standard Gallic acid curve (Gallic acid concentration × absorbance).
Among the active principles present in nature, flavonoids are found in fruits, vegetables, seeds, flowers and bark, wine, cereals and food dyes. The aluminum chloride (AlCl3) colorimetric method is used to obtain the limits of the flavonoid spectra. Interference from other phenolic compounds is frequently present, as the Al3+ cations form stable complexes with free hydroxyl groups of flavonoids. This causes the extension of the conjugated system and consequently a bath chromic shift, or in other words, a shift of the absorption maxima to a longer wavelength region, allowing quantification in a spectrophotometer at 425 nm [52].
\nwhere quercetin in the main solution (mg/mL) = 5.0 mg/mL, volume of the pipetted main solution (mL) = 0.005, 0.010, 0.025, 0.050, 0.075, 0.100, 0.200 and 0.300.
\nAdjust the volume of solution to 10 mL using methanol as solvent.
\nTo obtain the curve, transfer to amber color test tubes or tubes protected with aluminum foil, 250 μL of sample (put methanol in the blank sample); 1000 μL of distilled water; 75 μL NaNO2 5% in water; 600 μL of distilled water. Shake vigorously by vortexing and measure the absorbance in quartz cuvettes at 425 nm in a spectrophotometer. Plot the quercetin concentration (mg/L) on the abscissa (
Standard quercetin curve (quercetin concentration × absorbance).
Antioxidant activity is determined by the scavenging capacity of the free radical DPPH (2,2-diphenyl-1-picrylhydrazyl). The method involves reducing an alcoholic solution of purple DPPH radicals, which, upon receiving an electron or hydrogen radical, changes color from violet to yellow (diphenyl-picryl hydrazine),accompanied by a decrease in absorbance at the wavelength observed [54]. The greater or lesser capacity of the sample to reduce DPPH, or in other words to prevent oxidation, is evidenced by the percentage of DPPH remaining in the system [55]. This free radical, stable at room temperature, is reduced in the presence of an antioxidant molecule, yielding a yellow solution.
\nwhere honey in the main solution (mg/mL) = 80 mg/mL.
\nVolume of the main solution pipetted (mL) = 0.10, 0.15, 0.25, 0.50, 0.75 and 1.00 mL.
\nAdjust the volume of solution to 1.0 mL using methanol as solvent.
\nAfter the preparation, the mix is shaken using a vortex mixer for 15 s and allowed to stand at room temperature in the absence of light for 30 min. Sample absorbance is measured in quartz cuvettes at 515 nm in a spectrophotometer. Results are expressed as a percentage of antioxidant activity (% AA) using Eq. (18):
\nwhere Abssample is sample absorbance; Absblank is the absorbance of the blank control and Abscontrol is the absorbance of the negative control.
\nCalculate the mean EC50 value and standard error. The smaller the value, the higher is the antioxidant activity of the compounds present in the samples analyzed.
\nThe completion of the analyses required under national and international law and those proposed in this chapter are required to determine the quality of honey for marketing, direct human consumption or use as a raw material for the food, cosmetics and pharmaceutical industries.
\nThe results of sensory, physicochemical and functional properties analysis allows us to evaluate if the product meets established standards and demonstrates the features expected from good quality honey.
Hepatocellular carcinoma (HCC) is the fifth most common cancer in males, the seventh in females, and the third leading cause of cancer-related deaths. Each year there are approximately 800,000 fatalities [1, 2, 3]. In developing countries, morbidity and mortality rates are 84% and 83%, respectively [4]. HCC typically occurs in the context of chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, accounting for 85% of all HCC cases globally [3]. Lower risk factors include non-alcoholic fatty liver disease (NAFLD) and chronic alcohol consumption [4].
Tumor evolution is a complex process implying many stages and involving many factors, such as genetic and chromosomal changes. During tumor development, the number, type, extent, and distribution of markers and variants are closely related to the occurrence, progression, invasion, and metastasis of HCC. Therefore, diagnosis and early detection are highly important in management and treatment because it is only possible to cure the disease when the tumor when it is detected at a small size.
Advances in the understanding of tumor biology, combined with the development of molecular methods in looking for new biomarkers in the early detection of the disease, their invasiveness, likelihood of metastasis and recurrence, has led to the discovery and use of several new markers in this disease. In this review, we discuss the results of the studies that we consider the most relevant, and in particular their diagnostic performance for the detection of HCC at an early stage.
Alpha-fetoprotein (AFP) is a large serum glycoprotein that is synthesized in the liver that occurs during fetal life is repressed during adulthood [5]. Therefore, AFP levels often diminish rapidly after birth and remain low throughout adulthood. Since AFP was discovered in the serum of HCC patients in 1964 [6], it has been regarded as the most useful serum protein for patients at risk for HCC [7, 8, 9]. However, the sensitivity and specificity of using AFP for early HCC detection are widely variable as elevated AFP levels are also observed in many other cancers [10]. In addition, AFP levels are below the detection limit in small liver tumors, while it can be above the detection limit when the tumor is large, producing an AFP-negative HCC. AFP is considered to have a screening role in HCC but its role is limited since it does not allow to distinguish between cancerous lesions and some other benign liver damage pathologies, hence causing a high proportion of false positives and false negatives. Patients with hepatitis still have high AFP level even without liver tumors. The positive predictive value of AFP for detecting HCC is 70% for people with hepatitis viruses and 94% for those without. Therefore, AFP is more effective in detecting HCC in cases without hepatitis viruses.
According to the 2010 recommendations of the American Association for the Study of Liver Diseases (AASLD) for the diagnosis and treatment of HCC, the effectiveness of AFP as a test to diagnose HCC was lower than expected. AFP is also increased in biliary carcinoma in the liver or metastases from colon cancer. Biliary cancer in the liver is also quite common in cirrhotic patients, although the incidence of this disease is lower than that of HCC. The fact that these two liver cancers are common in cirrhosis makes it necessary to identify accurately the disease. Because AFP may increase in many cases other than HCC, it is no longer recommended to be used in Europe and the Americas for its diagnosis. The current diagnosis of HCC is based on imaging and histopathology [11]. The Asia Pacific Association for the Study of the Liver (APASL) also stated that AFP alone is not recommended to diagnose HCC. When combined with other methods, the diagnosis threshold of AFP was 200 ng/ml (Table 1) [12].
Marker | Cut-off value | Sensitivity (%) | Specificity (%) | Reference |
---|---|---|---|---|
AFP | >200 ng/ml | 39–45 | 76–94 | ADSSL |
AFP-L3 | AFP-L3/AFP > 15 | 55.3 | 93.9 | Taketa [1] |
GP73 | 85,5 mg/l | 80 | 82 | Schewegle [2] |
GPC3 | n.a. | 55.2 | 84.2 | Jia [3] |
OPN | n.a. | 86 | 86 | Wan [4] |
SCCA | n.a. | 84.2 | 48.9 | Gianneli [5] |
DCP | + AFP | 72.7 74.2 | 90 87.2 | Carr et al. [6] Bertino [7] |
GGT | 5,5 IU/ml | 86 | n.a. | Yao et al. [8] |
hsGGT | n.a. | 74 | n.a. | Cui et al. [9] |
AFU | n.a. | 81.5 | 85.4 | Wang et al. [10] |
TGF-β1 | 800 pg./ml | 95 | n.a. | Song et al. [11] |
TGF-β1 mRNA | > 1,2 μg/l | 89.5 | 94 | Dong et al. [12] |
TSGF | 62 IU/ml | 82 | n.a. | Yin et al. [13] |
IGF-II | 4,1 mg/l | 63 | 90 | Tsai et al. [14] |
HGF | >1 ng/ml | 100 | n.a. | Vejchapipat et al. [15] |
Diagnostic performance of biomarkers for HCC.
AFP exists as three glycoforms, each of them having a different binding capability to lectin
AFP-L3 immunoassay sensitivity has been further improved by higher sensitivity analytical methods and advanced microfluidics-based separation science [15]. “Highly sensitive AFP-L3” (hs-AFP-L3) obtained significantly better results than conventional AFP-L3, even when patients had a single and/or small HCC tumor. The sensitivity and specificity of hs-AFP-L3 were 57% and 63.5%, and 40.4% and 81.1% for conventional AFP-L3 [16]. These results make hs-AFP-L3 a valuable biomarker for detecting early-stage HCC (Table 1).
Glypican-3 (GPC3) is a member of the glycican family of heparan sulfate proteoglycans linked to cell membranes by glycosyl-phosphatidylinositol [17]. It is a fetal glycoprotein that exists on the cell surface to help regulate cell growth during pregnancy. GPC3 is associated with the malignant proliferation of cells but there are currently no studies to prove its association with healthy people and benign conditions. Quite a number of studies have proven the overexpression of GPC3 in malignant diseases such as breast cancer, ovarian cancer, or lung adenocarcinoma [18, 19]. With HCC, its expression is increased through the autocrine/paracrine regulator in conjunction with the Wnt signaling pathway [20]. Some studies have concluded that the sensitivity of GPC3 in HCC diagnosis ranges from 40 to 53%, which is interesting considering that in about 33% of cases, both AFP and DCP serum were within normal limits [21, 22]. GPC3 has been detected in HCC tumor but not in benign liver tissues, so it is likely a marker for early detection of HCC [23]. GPC3 expression does not depend on some clinical features such as tumor size, GPC3 sensitivity in early HCC diagnosis (size <3 cm) was 56% [23]. In a meta-analysis, the sensitivity and specificity of serum GPC3 to diagnose HCC were 55.2% and 84.2%, respectively [24]. A smaller analysis of the early-stage HCC group (BCLC 0 and A or TNM phase I) showed a sensitivity and specificity of GPC3 of 55.1% and 97%, respectively, which are higher than the those obtained with the AFP serum in the same study, that were 34.7% and 87.6%. Combining GPC3 and AFP increased the sensitivity to 76% for early-stage tumors [24]. In short, GPC3 might be a marker for HCC, especially in the early stages, but GPC3 expression also increases in some other malignancies, so the specificity for HCC diagnosis is not high. It can still increase diagnostic sensitivity when combined with other valuable serum markers (Table 1).
Heat shock protein (HSP) is an antiapoptotic protein whose overexpression allows cell survival. It protects cells and stimulates the reparation of tissue damage. A study indicated the positive rate of HSP70 and HSP27 in HCC tissues at 56.3% and 61.9%, respectively [25]. There was a correlation between the stained intensity of HSP70 and tumor size, portal vein invasion, and tumor stage, while HSP27 was only associated with hepatitis B virus (HBV) related HCC. In addition, the overexpression of HSP70 and HSP27 in HCC tumors may lead to increased tumor growth and metastasis (Table 1) [26].
Data suggest that HSP70 can be used as a prognosis indicator for HCC. Its expression was detected in 282 of 392 HCC cases (71.9%), compared to 14 of 115 non-neoplastic liver tissues [27]. The sensitivity and specificity in the detection of HCC have been measured at 57.5% and 85%, respectively [28]. The expression of HSP70 is also correlated with the differentiation and apoptosis of tumor cells. HSP70 promotes cancer cell growth by stabilizing cyclin D1 and suppressing apoptosis in cancer cells by inhibiting the p53 pathway [29, 30]. This information makes HSP70 and HSP27 potential markers of HCC that should be further investigated.
Golgi protein 73 (GP73) is a type II Golgi-specific membrane protein, which is normally expressed in epithelial cells of many human tissue types, but not hepatocytes [31]. A study showed that serum GP73 levels of patients with HBV-related HCC were significantly increased compared to patients with HBV and healthy adults [32, 33]. The sensitivity of diagnosis of HCC (76.9%) was significantly higher than that of AFP (48.6%), suggesting that GP73 can be an effective serum biomarker for the diagnosis of HCC [34]. The combination of GP73 and AFP further increased the sensitivity and specificity to 89.2% and 85.2%, respectively, with an AUC of 0.96 (Table 1).
FC-GP73 further improves the HCC diagnostic performance made with GP73 from 65 to 90 to 90–100%, respectively. Even when GP73 is at a very low level or absent, FC-GP73 is still detectable [35]. These are encouraging data but there is still a lot of work to be done regarding the correlation between GP73 and tumor size, stage, recurrence, and prognosis before this marker can be used.
Squamous cell carcinoma antigen (SCCA) belongs to the high molecular weight protease inhibitor family found in the squamous and granular layers of the normal squamous epithelium. It consists of two different isomers, encoded by two highly homologous genes: SCCA1 being neutral, and SCCA2 acid [36]. SCCA2 has been detected in many malignancies such as cervical, lung, head and neck carcinoma, and it has been used as a valuable diagnostic biomarker in clinical practice [37].
Giannelli et al. showed that SCCA expression was higher in the HCC group than in the cirrhotic group. The sensitivity of SCCA is 84.2%, but the specificity is low at 48.9%. In the small tumor group (≤ 3 cm) the sensitivity and specificity of SCCA were 56.1% and 74.9% with a cut-off of 3.2 ng/ml. In their study of SCCA expression in cells, using immunohistochemistry, Guido et al. demonstrated that SCCA expression in cancerous tissues and dysplasia nodules was much higher than that of newly formed nodules in early HCC diagnosis [38]. SCCA was highly sensitive, but its specificity was quite low. Its expression in early HCC tissue and in dysplasia nodules makes SCCA a valuable complementary marker for HCC diagnosis. An alternative biomarker is an immune complex between SCCA and IgM, SCCA-IgM, whose expression increases in early HCC. The immune complex SCCA-IgM has a higher diagnostic performance than the free SCCA and is also more relevant since it is not found in the serum of healthy people. However, the detection rate of SCCA-IgM immune complex is 18% for chronic hepatitis, 26% for cirrhosis and 70% for HCC [39]. Its sensitivity and specificity for HCC diagnosis are 89% and 50% [40]. The concentration of SCCA-IgM immune complex is constantly increasing in patients with cirrhosis who tend to progress to HCC. Sensitivity and specificity were of higher value than AFP in the studies of Pontisso et al. [37].
Increased serum SCCA in patients with liver disease can be considered a valuable marker for early diagnosis of HCC. Especially the SCCA-IgM immune complex, which is highly sensitive. However, since its specificity is quite low, it must be combined with other markers such as serum AFP or DCP to increase its diagnostic value.
Osteopontin (OPN) is known as a conversion protein and is a glycophosphoprotein associated with integrin, which is overexpressed in many types of malignancies such as lung, breast, and colon cancers [41]. OPN usually manifests in biliary epithelial cells, astrocytes and Kupffer cells, but not in liver cells [42]. However, increased serum OPN expression has been reported in patients with HCC, but not in those with cirrhosis, chronic hepatitis, or healthy controls [43, 44]. In a meta-analysis, the sensitivity and specificity of OPN were 86% for all HCC stages [45]. Shang et al. suggested that serum OPN concentrations at the cut-off level of 91 ng/ml were more sensitive than that of AFP (74% versus 53%) in the diagnosis of HCC. Combining two imprints with an OPN cut-off of 156 ng/ml and an AFP cut-off of 20 ng/ml increased sensitivity and specificity (95% and 96%). The sensitivity and specificity of OPN were 75% and 62% for early HCC, which means the sensitivity was higher than that of AFP, but the specificity lower (46% and 93%). When combined with AFP at the cut-off of 91 ng/ml for OPNs, sensitivity increased to 83% and specificity decreased to 63% [45] (Table 1). Based on such findings, OPN can be considered an important marker in HCC diagnosis, especially for tumors in the early stages, and when combined with AFP to significantly increase sensitivity. However, studies with larger sample populations are needed to confirm its relevance.
Tumor-associated glycoprotein 72 (TAG-72) is a macro-molecular glycoprotein complex, which is rarely expressed in normal tissues, but overexpressed in the majority of human adenocarcinomas, including gastric, colon, and pancreatic cancer. TAG-72 expression is significantly increased in HCC tissues compared to normal liver tissues [46], and it is suspected of promoting tumor invasion and metastasis. A correlation between overexpression of TAG-72 and poor survival in patients with HCC has been observed [46]. This makes TAG-72 a potential prognosis marker for HCC, and anti-TAG-72 monoclonal antibody has been used for tumors clinical detection [47].
Zinc-α2-glycoprotein (ZAG) is a member of the class I major histocompatibility complex (MHC-I) family. It is considered a new adipokine because of its strong amino acid sequence homology with lipid mobilizing factor (LMF). ZAG is downregulated in human obesity [48], but it is upregulated in different cancers such as breast, lung and prostate cancers, making it a potential biomarker for these. The serum proteome of the HCC, liver cirrhosis and healthy adult groups have been analyzed and it was found that the ZAG is overexpressed in the HCC patients suggesting a potential biomarker for the early detection of HCC [49].
Annexin A2 is a calcium-dependent, phospholipid-binding protein found on the surface of endothelial cells and most epithelial cells [50, 51]. Annexin A2 serum concentrations in patients with HCC were often higher than those with benign liver disease, other malignant tumors, or healthy individuals [52, 53, 54]. High annexin A2 levels were observed in 83.2% of early-stage HCC and 78.4% of AFP-negative HCC patients [55]. Annexin A2 sensitivity and specificity were respectively measured at 83.2% and 67.5% in the detection of early-stage HCC, while HCC patients with normal AFP levels were 54.7% and 81.3%, respectively. The diagnostic performance of annexin A2 alone (AUC = 79%) was also greater than for AFP alone (AUC = 73%). As expected, the combination of annexin A2 and AFP further improved the overall diagnostic performance with a sensitivity of 87.4% and a specificity of 68.3%. This makes annexin A2 a potential independent biomarker for detecting early-stage HCC in patients with normal serum AFP.
Des-γ-carboxyprothrombin (DCP) or Prothrombin induced by vitamin K absence II (PIVKA II) is a prothrombin molecule which is synthesized in abnormally high amount in HCC. During malignant transformation in liver cells, vitamin K-dependent carboxylase system weakens [56]. In essence, this is a carboxylation defect that leads to increased DCP synthesis [57]. Serum DCP levels in patients with liver cancer have differed from normal individuals [58]. In a comparative study of cases of chronic hepatitis and liver cirrhosis, DCP showed a sensitivity of 72.7% and a specificity of 90.0%, equivalent to AFP [59]. The combination of these two markers improves HCC diagnosis with a sensitivity and a specificity of 74.2% and 87.2%, respectively [60]. Although DCP has proven to have great potential as a biomarker for early diagnosis of HCC, it needs to be verified by further studies, especially in combination with AFP. In a large multicentre study, the sensitivity of DCP was 56% for early HCC diagnosis. Combining DCP with AFP increased the sensitivity from 65–87% 3 months before HCC diagnosis, but the specificity decreased from 84–69% [61].
Although the diagnostic value of DCP has been studied in Asian countries, its assessments in Western countries, especially in Europe, are still limited. A case–control study to evaluate the performance of serum AFP and DCP concentrations for early HCC diagnosis was conducted in France [62]. The cut-off threshold for serum DCP was 42 mAU/ml and 5.5 ng/ml for AFP, resulting in DCP being better than AFP for early diagnosis of HCC with a sensitivity of 77% compared to a 61% one, and a specificity of 82% compared to a 50% one. The positive forecast value was 76% compared to 51%, and the negative forecast value was 83% compared to 62%. The combination of DCP and AFP improved diagnostic performance. These results further support the value of DCP as a marker for early HCC diagnosis. According to the 2010 recommendations of the Japan Society of Hepatology (JSH), the three biological markers AFP, AFP-L3 and DCP are checked by the state insurance for HCC screening, as a combination of two of the three biomarkers, or all three combined. These three markers help to increase sensitivity without reducing specificity in small liver cancer [63].
γ-Glutamyl transferase (GGT) is a membrane-binding enzyme, which appears in the development of liver cells during pregnancy, its concentration is high throughout pregnancy and decreases immediately after birth. The total GGT concentration increased in chronic liver diseases, HCC, and some extra-liver cancer diseases [63]. A study by Cui et al. on 90 patients with cirrhosis and 120 patients with HCC showed that the sensitivity of HS-GGT was 74%, irrespective of size, and 43.8% for small tumors (<3 cm) [64] (Table 1). The diagnostic value improves when combined with other biomarkers such as AFP, PIVKA II, or AFP-L3. This is a promising sign in the detection of small cancers and can be used in combination with AFP and AFP-L3.
Matrix metalloproteinase (MMP) is an enzyme belonging to the endopeptidase group, which helps regenerate tissue in various pathogenetic processes including tumor progression, and wound healing [65]. Kuo et al. showed that only cases of HBsAg-positive have high levels of MMP-2 expression [66], but the relationship between other markers of HBV and MMP was not clarified. Positive cases with HBeAg showed a high tendency for portal vein thrombosis along with high manifestations of MMP-7 and MMP-9. MMPs have a synergistic effect on HCC generation, proliferation and invasion, through ways that the study did not elucidate [67]. A significantly higher MMP-9/MMP-2 ratio was found in patients with advanced HCC compared to patients at an early stage [68]. The mRNA of MMP-14, MMP-15 and MMP-2 are highly expressed in most HCC cells suggesting an important role of MMPs in the growth, invasion, and metastasis of tumor cells. Selective inhibitors for these MMPs promise to be an effective mean of preventing the growth and metastasis of HCC [69].
Glutamine synthetase (GS) is an enzyme involved in catalyzing the synthesis of glutamine from glutamate and ammonia, it plays an important role in the function of ammonia metabolism and nitrogen balance of the liver [70]. Research by Haupt et al. demonstrated that GSmRNA increased its tissue and protein expression in the serum of HCC patients [71]. In addition, Osada et al. reported increasing GS expression correlated with cancer progression, suggesting GS can play a role in promoting HCC metastases [72].
Alpha L fucosidase (AFU) is a glycosidase responsible for hydrolysing fucoseglycoside bonds of glycoprotein and glycolipids and is found in all mammalian cell lysosomes and is involved in the degenerative reaction of a series of fucoglyco-containing fucoglyco complexes [73]. Serum AFU levels are constantly elevated in cirrhotic patients who tend to progress to HCC. Deugnier et al. found that serum AFU had greater sensitivity and specificity than AFP and that it can be considered a marker for HCC diagnosis. However, the cause of this increased serum AFU activity is still unknown. The most likely explanation is that increased serum AFU activity is a result of an increase in tumor protein synthesis that increases fucoses [74]. Measuring the activity of serum AFU regularly during follow-up of cirrhotic patients provides very useful clinical data in monitoring cirrhosis progression to HCC. Although an increased serum AFU activity was not correlated with tumor size and was common in cases of early HCC, the HCC tumor would appear within a few years in 82% of patients with liver fibrosis if serum AFU activity exceeds 700 nmol/ml/hour. Serum AFU activity increased in 85% of patients at least six months before HCC was detected by a diagnostic imaging method [75]. AFU activity was significantly increased in HCC patients compared with patients with other liver diseases or other cancers. AFU sensitivity is 81.5% and its specificity is 85.4% in HCC diagnosis [76] indicating a promising specific marker for HCC diagnosis.
Cytokines are a heterogeneous group of proteins that play roles of mediators in cellular reactions and activities. They are the product mediating and regulating immune processes of immune cells. Some cytokines also act as potential markers for early diagnosis and treatment of HCC.
Transforming growth factor-β (TGF-β1) is a versatile growth factor associated with proliferation, cell differentiation, embryogenesis, vascular proliferation, invasion and immune activity. One study found that serum TGF-β1 levels increased in the HCC group compared to the group with non-malignant liver disease and the healthy group. With a cut-off of 800 pg./ml, the specificity of TGF-β1 HCC diagnostic serum is above 95%. Taking the same value as the serum AFP at the cut-off of 200 ng/ml, the sensitivity of TGF-β1 is 68%, which is superior to that of AFP (24%). Moreover, in patients with serum AFP within normal limits, increased TGF-β1 levels can be observed in 23% of cases [77]. It has been shown that TGF-β1 and TGF-β1 mRNA can be used as a marker to diagnose and predict HCC due to HBV with a sensitivity and specificity of 89.5% and 94.0% with a cutting level of TGF-β1 > 1.2 g/l [78]. TGF-β1 mediates various biological effects through signal paths and manifestations of TGF-β1 polymorphism may affect tumor susceptibility. The TGF-β1 signaling pathway can be considered as a target for HCC treatment. The subject is currently under study to confirm its role and promises to bring new cancer treatments.
Vascular endothelial growth factor (VEGF) acts as an important factor in the process of tumor formation by forming new blood vessel systems that increase in size and promote invasion and metastasis. Studies have shown that angiogenesis is essential in tumor growth, including HCC, which is often characterized by the proliferation of blood vessels [79]. It has been demonstrated that VEGF expression in HCC tissues has a significantly higher incidence of portal vein thrombosis and a lower average survival time than when VEGF expression is not present [80]. In the study of Xiang et al., VEGF was associated with lymph node metastatic characteristics in HCC. In addition, VEGF expression is closely related to relapse and prognosis. Notably, several manifestations of the VEGF receptor are related to some of the clinical characteristics and prognosis of HCC [81]. Inactivation of VEGF165 increases the expression of the
Interleukin-8 (IL-8) is a multifunctional CXC chemokine that is involved in the immune response of neutrophils in humans including kinetic phenomena, enzyme release and expression of surface adhesion of molecule. IL-8 also has a direct effect on tumor progression, including the proliferation of vascular endothelial cells and formation of new vessels. In addition, IL-8 increases the likelihood of metastases and new tumor formation in the liver [82]. A study showed that IL-8 serum concentrations increased in HCC patients compared to healthy subjects, it was positively correlated with tumor size (≥5 cm), portal vein thrombosis and advanced stage with lymph node metastases [83]. Therefore, it may be a biological marker that plays a useful role in HCC diagnosis and prognosis.
Malignant tumors have the ability to synthesize tumor-specific growth factors, releasing them into the capillaries surrounding the tumor and peripheral blood vessels during their development. Therefore, serum TSGF levels may be a marker of tumor survival. In one study, serum TSGF concentrations were used as a diagnostic marker for HCC with 82% sensitivity at 62 UI/ml [84]. Combined with other cancer markers, TSGF may yield higher diagnostic values with increased sensitivity. Theoretically, preeclampsia is highly expressed in many malignant tumors and HCC, but there are currently too few studies evaluating the role of TSGF in other malignancies to consider it as a potential factor. There are other markers, such as serum insulin-like growth factor-II (IGF-II), which can be used as diagnostic or prognostic markers for HCC. A cut-off of 4.1 mg/l of IGF-II obtained results of 63% sensitivity, 90% specificity and 70% accuracy in early HCC diagnosis with small tumor size. Moreover, the combination of IGF-II and AFP (cut-off value of 50 ng/ml) increases sensitivity up to 80% and accuracy up to 88% [85].
Hepatocyte growth factor (HGF) is a multifunctional element produced in many organs in the body, it affects cell division, cell motility, intracellular invasion, and carcinogenesis [86]. In a study in Japan, serum HGF levels are increased significantly in the HCC group compared with cirrhosis, chronic hepatitis and healthy controls groups. With a cutting level of 0.6 ng/ml, its sensitivity can be up to 100% for any AFP or DCP concentration. The serum HGF concentration ≥ 1.0 ng/ml has a shorter shelf life, so it can be used as a prognostic marker for HCC [87]. The authors suggest that HGF causes proliferation and invasion of cancer cells through the expression of c-met receptors. In addition, increased HGF serum levels along with high expression of serum c-met protein after hepatectomy play an important role in predicting tumor recurrence and metastasis. This can be explained by the fact that HGF can increase the production and size of both normal and malignant liver cells after surgery, leading to tumor recurrence [88].
AFP mRNA is a highly valuable marker only found in active cancer cells, which might be a sign of tumor metastasis. The non-recurrence time of HCC patients with high AFP mRNA expression after surgery was shorter than the group without this marker expression in liver cells (53% compared to 88% after 1 year; 37% compared to 60% after 2 years) [89]. In the advanced HCC stage, the AFP mRNA expression rate reaches 100%, and also acts as a predictor of recurrence after liver resection. However, the use of this marker in HCC diagnosis remains controversial, possibly due to the fact that it also manifests in many other malignancies and non-cancerous liver diseases [90]. Therefore, it could be used for diagnosis and prognosis when combined with other markers.
Gamma-glutamyl transferase mRNA (GGT mRNA) can be found in the blood and peripheral liver cells of healthy individuals, as well as in patients with benign liver disease, benign liver tumors or HCC. It has 3 types: A, B and C. Type A dominates in normal liver cases, non-cancerous liver diseases, benign tumors and secondary liver cancers, while type C is produced by the yolk during pregnancy. In contrast, type B predominates in HCC [91, 92, 93]. During malignant development, expression of GGT mRNA in liver tissues may change from type A to type B [93]. Patients with HCC and high type B expression will have a worse prognosis, with higher odds of a sooner and more serious relapse [94]. Therefore, hepatocellular expression of type B mRNA may be a valuable marker for HCC patients. As in liver tissues, peripheral blood type B expression has also been reported to be significantly higher in HCC patients than in healthy adults [91].
MicroRNAs are small non-coding RNAs that inhibit or accelerate the translation process by attenuating or increasing the synthesis of target mRNAs or by binding to additional chains in the UTR region (3′-untranslated region). In recent years, the link between miRNA and tumor development has become a controversial issue. About 500 miRNA genes have been identified and contribute to control a number of cellular processes including proliferation, differentiation and apoptosis. In malignancy, the function of miRNA is determined to be carcinogenic and tumor suppressant [95]. miRNA can regulate many genes at the same time, they control the replication process and determine the characteristics of the cell. The variety in this functional role allows miRNA to be utilized as a diagnostic marker for early detection of cancer, risk assessment, prognosis and as a new therapeutic target.
Yamamoto et al. have used a global miRNA expression profile in mouse liver development and thus shown that miR-500 (miRNA) is a potential biomarker for HCC [95]. Their work showed that miR-500 is significantly associated with the regulation of liver development and thus is related to cirrhosis progression. The serum miR-21 levels were a valuable marker in distinguishing patients with HCC from those with chronic hepatitis with the sensitivity and specificity of 61.1% and 83.3%, respectively. Compared to the healthy group, the sensitivity and specificity were 87.3% and 92.0%, respectively. Both values are higher than serum AFP concentrations, which have been confirmed as a very valuable biological marker for HCC [96]. Serum miR-15b and miR-130b concentrations are relevant miRNA markers that are highly expressed in HCC. miR-130b has 87.7% sensitivity and 81.4% specificity. In contrast, while the sensitivity of miR-15b is high at 98.3%, its specificity is low at 15.3%. Because the sensitivity of these two factors is rather high, it can be used as a valuable marker in HCC screening and early diagnosis with low AFP levels [97].
A group of markers including seven miRNAs (miR-122, miR-192, miR-21, miR-223, miR-26a, miR-27a and miR-801) has been shown to have a great diagnostic performance for HBV related HCC at an early stage [98]. Although its mechanism and signal path are still unknown, the expression of miRNA-29 may increase the susceptibility of cancer cells to apoptosis and reduce the expression of Mcl-1 and Bcl-2. Indeed, it has the ability to inhibit the formation and growth of cancer cells and is a potential marker in HCC prognosis and treatment [99]. MiR-122 is a specific miRNA found only in HCC, which concentration is inversely correlated with cancer growth and likelihood of invasion and metastasis. An analysis of miRNA markers revealed only tumor miR-21 expression and significantly higher serum miR-21 levels in HCC patients compared to those in chronic liver diseases and healthy control groups. Analysis of ROC curve between HCC and control group showed that sensitivity and specificity were 87.3% and 92% respectively, which is higher than that of serum AFP. Therefore, miR-21 is also a promising marker to support early HCC diagnosis [96].
Some of their features and expressions make miRNA particularly attractive as potential biomarkers. First, many miRNAs exhibit high stability and are easily detectable in peripheral blood of HCC patients. Secondly, miRNAs can be identified in urine, which will be a valuable non-invasive biological marker in detecting and managing HCC. The detection of the expression of some miRNAs in the urine (miR-625, miR-532, miR-618, miR-516-5P and miR-650) has been used for early detection of HCC [100]. However, more research is needed regarding miRNA before it can be used to detect HCC at an early stage.
Like other cancers, HCC is characterized by a gradual accumulation of epigenetic changes. Among these changes, lncRNA has been found to play a significant role in the initiation and progression of HCC. Most lncRNAs express the characteristics of each species and the specific characteristics of the tumor. Increased or decreased expression of lncRNA has been found in cancerous tissues. Meanwhile, some lncRNA are found in urine, blood, and other body fluids. Moreover, the use of lncRNA as a marker for cancer pathology is superior to the coding RNA protein, due to the characteristic expression of lncRNA [101]. The sensitivity and specificity of lncRNA for HCC diagnosis found in some recent studies are quite high, while it has been demonstrated that JPX (just proximal to XIST) can have a sensitivity of up to 100% [102]. The 2-lncRNA signal has a high specificity of 90.62% but a low sensitivity of 60.65%, which could make it a potential marker to confirm an HCC diagnosis [103]. Recent findings suggest that lncRNA may be a potential marker for early diagnosis and monitoring of the risk of malignant progression in patients with chronic and highly specific chronic liver disease. These markers may contribute to the definitive HCC diagnosis without the need for histopathological diagnosis (Table 2).
miRNA/LncRNAs | Diagnostic value | AUC | Sensitivity | Specificity | Reference |
---|---|---|---|---|---|
miR-21 | Differentiate HCC from patients with chronic hepatitis | 61.1% | 83.3% | [16] | |
miR-21 | Differentiate HCC from healthy individuals | 87.3% | 92.0% | [16] | |
miR-130b | Differentiate HCC from healthy individuals | 87.7% | 81.4% | [17] | |
miR-15b | Differentiate HCC from healthy individuals | 98.3% | 15.3% | [17] | |
2-lncRNA | Differentiate HCC from healthy individuals | 0.764 | 60.56% | 90.62% | Yu et al. [18] |
DANCR | Differentiate HCC from cirrhosis and chronic liver | 0.868 | 83.8% | 72.7% | Ma et al. [19] |
MALAT1 (plasma) | Differentiate HCC from patients with liver disease | 0.66 | 51.1% | 89.3% | Konishi et al. [20] |
JPX | Distinguish HCC and control group | 0.814 | 100.0% | 52.4% | Ma et al. [21] |
UCA1 | Distinguish HCC and control group | 0,91 | 91,4% | 88,6% | El-Tawdi et al. [22] |
Diagnostic performance of miRNAs and lncRNAs for HCC.
P53 is an important protein in the P53 signaling pathway and mutation or loss of
Recent reports have shown that
The telomerase reverse transcriptase (hTERT) gene encodes an enzyme that maintains the telomeric DNA length and stabilizes the chromosomes [113]. hTERT is a major determinant of telomerase activity, which plays a key role in protecting cells from apoptosis and transforming into cancerous cells [114]. The reactivation of telomerase activity in cancer may be related to changes that occur during cancer development, including mutations and rearrangements of chromosomes [115].
The frequencies of
In HCC, methylation can occur in two ways: total methylation and partial methylation. Total methylation affects the structural function of the nucleus by promoting chromosome and genome instability, while partial methylation is associated with tumor suppressor genes [122]. Chronic hepatitis virus infections are the cause of DNA methylation aberrations in cancerous tissues. Although several DNA methyltransferase enzymes such as DNMT1, DNMT3A and DNMT3B have been shown to increase their expression in HCC related to hepatitis viruses, their mechanisms remain controversial and unclear [123].
Another potential marker for HCC prognosis is
GSTP1 belongs to the Glutathione S-transferase family, which protects cells against carcinogens, regulates signaling pathways that control cell proliferation and cell death [131]. The methylation in the
Detecting the methylation status of genes in serum provides a promising method for diagnosis of HCC. A study found aberrant methylation in the
A large number of markers have been studied and clinically applied for early diagnosis and monitoring of HCC treatment, of which serum AFP is a widely used with a controversial diagnostic threshold. A number of protein markers such as AFP-L3 and DCP are also being applied to support HCC diagnosis with higher sensitivity and specificity compared to AFP. However, the available marker is neither specific for solely HCC diagnosis nor provides great diagnostic performance for HCC and thus a combination of several serum protein markers can improve the early diagnosis rate. With the development of molecular technology, biomarkers based on miRNA and lncRNA expression, gene mutation (
This study was funded by the Vietnam National Foundation for Science and Technology Development (NAFOSTED; grant number 108.02-2017.15) to Hoang Van Tong. The funder has no role in the study design, data collection and analysis, decision to publish or preparation of the manuscript.
All authors have no conflicts of interest to declare.
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This knowledge can help to better understand the forms of exclusion due to vulnerability in order to develop new forms of social inclusion.",book:{id:"8262",slug:"the-new-forms-of-social-exclusion",title:"The New Forms of Social Exclusion",fullTitle:"The New Forms of Social Exclusion"},signatures:"Rosalba Morese, Sara Palermo, Matteo Defedele, Juri Nervo and Alberto Borraccino",authors:[{id:"214435",title:"Dr.",name:"Rosalba",middleName:null,surname:"Morese",slug:"rosalba-morese",fullName:"Rosalba Morese"},{id:"218983",title:"BSc.",name:"Juri",middleName:null,surname:"Nervo",slug:"juri-nervo",fullName:"Juri Nervo"},{id:"218984",title:"MSc.",name:"Matteo",middleName:null,surname:"Defedele",slug:"matteo-defedele",fullName:"Matteo Defedele"},{id:"233998",title:"Ph.D.",name:"Sara",middleName:null,surname:"Palermo",slug:"sara-palermo",fullName:"Sara Palermo"},{id:"266453",title:"Prof.",name:"Alberto",middleName:null,surname:"Borraccino",slug:"alberto-borraccino",fullName:"Alberto Borraccino"}]},{id:"74550",doi:"10.5772/intechopen.95395",title:"School Conflicts: Causes and Management Strategies in Classroom Relationships",slug:"school-conflicts-causes-and-management-strategies-in-classroom-relationships",totalDownloads:2333,totalCrossrefCites:1,totalDimensionsCites:10,abstract:"Conflicts cannot cease to exist, as they are intrinsic to human beings, forming an integral part of their moral and emotional growth. Likewise, they exist in all schools. The school is inserted in a space where the conflict manifests itself daily and assumes relevance, being the result of the multiple interpersonal relationships that occur in the school context. Thus, conflict is part of school life, which implies that teachers must have the skills to manage conflict constructively. Recognizing the diversity of school conflicts, this chapter aimed to present its causes, highlighting the main ones in the classroom, in the teacher-student relationship. It is important to conflict face and resolve it with skills to manage it properly and constructively, establishing cooperative relationships, and producing integrative solutions. Harmony and appreciation should coexist in a classroom environment and conflict should not interfere, negatively, in the teaching and learning process. This bibliography review underscore the need for during the teachers’ initial training the conflict management skills development.",book:{id:"7827",slug:"interpersonal-relationships",title:"Interpersonal Relationships",fullTitle:"Interpersonal Relationships"},signatures:"Sabina Valente, Abílio Afonso Lourenço and Zsolt Németh",authors:[{id:"324514",title:"Ph.D.",name:"Sabina",middleName:"N.",surname:"Valente",slug:"sabina-valente",fullName:"Sabina Valente"},{id:"326375",title:"Prof.",name:"Abílio Afonso",middleName:"Afonso",surname:"Lourenço",slug:"abilio-afonso-lourenco",fullName:"Abílio Afonso Lourenço"},{id:"329177",title:"Dr.",name:"Zsolt",middleName:null,surname:"Németh",slug:"zsolt-nemeth",fullName:"Zsolt Németh"}]},{id:"55323",doi:"10.5772/intechopen.68873",title:"Positive Psychology: The Use of the Framework of Achievement Bests to Facilitate Personal Flourishing",slug:"positive-psychology-the-use-of-the-framework-of-achievement-bests-to-facilitate-personal-flourishing",totalDownloads:1748,totalCrossrefCites:3,totalDimensionsCites:9,abstract:"The Framework of Achievement Bests, which was recently published in Educational Psychology Review, makes a theoretical contribution to the study of positive psychology. The Framework of Achievement Bests provides an explanatory account of a person’s optimal best practice from his/her actual best. Another aspect emphasizes on the saliency of the psychological process of optimization, which is central to our understanding of person’s optimal functioning in a subject matter. Achieving an exceptional level of best practice (e.g. achieving excellent grades in mathematics) does not exist in isolation, but rather depends on the potent impact of optimization. This chapter, theoretical in nature, focuses on an in‐depth examination of the expansion of the Framework of Achievement Bests. Our discussion of the Framework of Achievement Bests, reflecting a methodical conceptualization, is benchmarked against another notable theory for understanding, namely: Martin Seligman’s PERMA theory. For example, for consideration, one aspect that we examine entails the extent to which the Framework of Achievement Bests could explain the optimization of each of the five components of PERMA (e.g. how does the Framework of Achievement Bests explain the optimization of engagement?).",book:{id:"5761",slug:"quality-of-life-and-quality-of-working-life",title:"Quality of Life and Quality of Working Life",fullTitle:"Quality of Life and Quality of Working Life"},signatures:"Huy P. Phan and Bing H. Ngu",authors:[{id:"196435",title:"Prof.",name:"Huy",middleName:"P",surname:"Phan",slug:"huy-phan",fullName:"Huy Phan"}]},{id:"55349",doi:"10.5772/intechopen.68596",title:"The Development of a Human Well-Being Index for the United States",slug:"the-development-of-a-human-well-being-index-for-the-united-states",totalDownloads:2049,totalCrossrefCites:3,totalDimensionsCites:9,abstract:"The US Environmental Protection Agency (EPA) has developed a human well-being index (HWBI) that assesses the over-all well-being of its population at the county level. The HWBI contains eight domains representing social, economic and environmental well-being. These domains include 25 indicators comprised of 80 metrics and 22 social, economic and environmental services. The application of the HWBI has been made for the nation as a whole at the county level and two alternative applications have been made to represent key populations within the overall US population—Native Americans and children. A number of advances have been made to estimate the values of metrics for counties where no data is available and one such estimator—MERLIN—is discussed. Finally, efforts to make the index into an interactive web site are described.",book:{id:"5761",slug:"quality-of-life-and-quality-of-working-life",title:"Quality of Life and Quality of Working Life",fullTitle:"Quality of Life and Quality of Working Life"},signatures:"J. Kevin Summers, Lisa M. Smith, Linda C. Harwell and Kyle D. Buck",authors:[{id:"197485",title:"Dr.",name:"J. Kevin",middleName:null,surname:"Summers",slug:"j.-kevin-summers",fullName:"J. Kevin Summers"},{id:"197486",title:"Ms.",name:"Lisa",middleName:null,surname:"Smith",slug:"lisa-smith",fullName:"Lisa Smith"},{id:"197487",title:"Ms.",name:"Linda",middleName:null,surname:"Harwell",slug:"linda-harwell",fullName:"Linda Harwell"},{id:"197488",title:"Dr.",name:"Kyle",middleName:null,surname:"Buck",slug:"kyle-buck",fullName:"Kyle Buck"}]},{id:"56529",doi:"10.5772/intechopen.70237",title:"Well-being and Quality of Working Life of University Professors in Brazil",slug:"well-being-and-quality-of-working-life-of-university-professors-in-brazil",totalDownloads:1682,totalCrossrefCites:2,totalDimensionsCites:6,abstract:"This chapter presents a study about the perceptions on quality of working life (QWL) regarding factors and indicator in two public universities in Brazil. It aimed also to analyze their perceptions about university working conditions. This exploratory study is based on quantitative and qualitative analyses. A sample of 715 university professors participated on the research. Data collection was carried out in two steps: online survey and focus groups. There is a moderate negative correlation between psychological well-being and work-related stress. Emotional charge also presents a moderate positive correlation with work-related stress, as well as physical charge and psychological distress. Work-life balance is negatively correlated with physical charge, emotional charge, work-related stress, psychological distress, and burnout. We observed also that 43.6% of the professors reported high levels of work-related stress in their everyday work. The precariousness of university teaching is associated with three main elements, which we defined as the tripod of the precarization of university teaching work. It consists of academic productivism, excess of administrative work and bureaucratic activities, and inadequate working conditions. The operating dynamics of this tripod effect professors’ well-being, their QWL, and even the quality of the work they develop in public universities.",book:{id:"5761",slug:"quality-of-life-and-quality-of-working-life",title:"Quality of Life and Quality of Working Life",fullTitle:"Quality of Life and Quality of Working Life"},signatures:"Alessandro Vinicius de Paula and Ana Alice Vilas Boas",authors:[{id:"175373",title:"Dr.",name:"Ana Alice",middleName:null,surname:"Vilas Boas",slug:"ana-alice-vilas-boas",fullName:"Ana Alice Vilas Boas"},{id:"196534",title:"Dr.",name:"Alessandro Vinicius",middleName:null,surname:"De Paula",slug:"alessandro-vinicius-de-paula",fullName:"Alessandro Vinicius De Paula"}]}],mostDownloadedChaptersLast30Days:[{id:"74550",title:"School Conflicts: Causes and Management Strategies in Classroom Relationships",slug:"school-conflicts-causes-and-management-strategies-in-classroom-relationships",totalDownloads:2328,totalCrossrefCites:1,totalDimensionsCites:10,abstract:"Conflicts cannot cease to exist, as they are intrinsic to human beings, forming an integral part of their moral and emotional growth. Likewise, they exist in all schools. The school is inserted in a space where the conflict manifests itself daily and assumes relevance, being the result of the multiple interpersonal relationships that occur in the school context. Thus, conflict is part of school life, which implies that teachers must have the skills to manage conflict constructively. Recognizing the diversity of school conflicts, this chapter aimed to present its causes, highlighting the main ones in the classroom, in the teacher-student relationship. It is important to conflict face and resolve it with skills to manage it properly and constructively, establishing cooperative relationships, and producing integrative solutions. Harmony and appreciation should coexist in a classroom environment and conflict should not interfere, negatively, in the teaching and learning process. This bibliography review underscore the need for during the teachers’ initial training the conflict management skills development.",book:{id:"7827",slug:"interpersonal-relationships",title:"Interpersonal Relationships",fullTitle:"Interpersonal Relationships"},signatures:"Sabina Valente, Abílio Afonso Lourenço and Zsolt Németh",authors:[{id:"324514",title:"Ph.D.",name:"Sabina",middleName:"N.",surname:"Valente",slug:"sabina-valente",fullName:"Sabina Valente"},{id:"326375",title:"Prof.",name:"Abílio Afonso",middleName:"Afonso",surname:"Lourenço",slug:"abilio-afonso-lourenco",fullName:"Abílio Afonso Lourenço"},{id:"329177",title:"Dr.",name:"Zsolt",middleName:null,surname:"Németh",slug:"zsolt-nemeth",fullName:"Zsolt Németh"}]},{id:"76968",title:"In the Darkness of This Time: Wittgenstein and Freud on Uncertainty",slug:"in-the-darkness-of-this-time-wittgenstein-and-freud-on-uncertainty",totalDownloads:461,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Both Wittgenstein and Freud experienced the crisis of humanism resulting from the first and second world wars. Although they were both considered to be influential figures, they hardly investigated the ways in which people could cope with the consequences of these crises. However, Wittgenstein and Freud did suggest ways of understanding uncertainties caused by real life events, as well as by the nature of human thought processes. This article will explore the therapeutic ways of dealing with uncertainties common to both thinkers and the different concepts facilitating their methodologies. The central contention of this article is that both Wittgenstein and Freud developed a complex methodology, acknowledging the constant and unexpected changes humans have deal with, whilst also offering the possibility of defining “hinge propositions” and “language-games” which can stabilize our consciousness.",book:{id:"10814",slug:"anxiety-uncertainty-and-resilience-during-the-pandemic-period-anthropological-and-psychological-perspectives",title:"Anxiety, Uncertainty, and Resilience During the Pandemic Period",fullTitle:"Anxiety, Uncertainty, and Resilience During the Pandemic Period - Anthropological and Psychological Perspectives"},signatures:"Dorit Lemberger",authors:[{id:"325725",title:"Dr.",name:"Dorit",middleName:null,surname:"Lemberger",slug:"dorit-lemberger",fullName:"Dorit Lemberger"}]},{id:"76565",title:"Introductory Chapter: The Transition from Distress to Acceptance of Human Frailty - Anthropology and Psychology of the Pandemic Era",slug:"introductory-chapter-the-transition-from-distress-to-acceptance-of-human-frailty-anthropology-and-ps",totalDownloads:393,totalCrossrefCites:0,totalDimensionsCites:0,abstract:null,book:{id:"10814",slug:"anxiety-uncertainty-and-resilience-during-the-pandemic-period-anthropological-and-psychological-perspectives",title:"Anxiety, Uncertainty, and Resilience During the Pandemic Period",fullTitle:"Anxiety, Uncertainty, and Resilience During the Pandemic Period - Anthropological and Psychological Perspectives"},signatures:"Fabio Gabrielli and Floriana Irtelli",authors:[{id:"174641",title:"Dr.",name:"Floriana",middleName:null,surname:"Irtelli",slug:"floriana-irtelli",fullName:"Floriana Irtelli"},{id:"259407",title:"Prof.",name:"Fabio",middleName:null,surname:"Gabrielli",slug:"fabio-gabrielli",fullName:"Fabio Gabrielli"}]},{id:"77214",title:"The Impact of the COVID-19 Pandemic on the Mental Health of Dentists",slug:"the-impact-of-the-covid-19-pandemic-on-the-mental-health-of-dentists",totalDownloads:390,totalCrossrefCites:1,totalDimensionsCites:1,abstract:"Since March 2020, the COVID-19 disease has declared a pandemic producing a worldwide containment. For months, many people were subjected to strict social isolation away from family and loved ones to prevent disease transmission, leading to anxiety, fear, and depression. On the other hand, many had to close down their businesses and stop working, resulting in financial issues. Previous studies have reported that pandemics, epidemics, and some diseases can lead to mental disorders such as fear, anxiety, stress, and depression. Among those most affected, healthcare workers (HCWs), especially those on the front line, often develop mental health problems. Although there is data available on the management and care of HCWs, little attention has been paid to the mental health and well-being of dentists during the COVID-19 pandemic. Therefore, this chapter aims to review the impact of the COVID-19 pandemic on dentists’ mental health and mental health-related symptoms. Finally, to recommend specific measures to avoid consequent potential implications for dentists, dental students, and dental patients.",book:{id:"10814",slug:"anxiety-uncertainty-and-resilience-during-the-pandemic-period-anthropological-and-psychological-perspectives",title:"Anxiety, Uncertainty, and Resilience During the Pandemic Period",fullTitle:"Anxiety, Uncertainty, and Resilience During the Pandemic Period - Anthropological and Psychological Perspectives"},signatures:"Andrea Vergara-Buenaventura and Carmen Castro-Ruiz",authors:[{id:"346660",title:"M.Sc.",name:"Andrea",middleName:null,surname:"Vergara-Buenaventura",slug:"andrea-vergara-buenaventura",fullName:"Andrea Vergara-Buenaventura"},{id:"419814",title:"MSc.",name:"Carmen",middleName:null,surname:"Castro-Ruiz",slug:"carmen-castro-ruiz",fullName:"Carmen Castro-Ruiz"}]},{id:"55323",title:"Positive Psychology: The Use of the Framework of Achievement Bests to Facilitate Personal Flourishing",slug:"positive-psychology-the-use-of-the-framework-of-achievement-bests-to-facilitate-personal-flourishing",totalDownloads:1748,totalCrossrefCites:3,totalDimensionsCites:9,abstract:"The Framework of Achievement Bests, which was recently published in Educational Psychology Review, makes a theoretical contribution to the study of positive psychology. The Framework of Achievement Bests provides an explanatory account of a person’s optimal best practice from his/her actual best. Another aspect emphasizes on the saliency of the psychological process of optimization, which is central to our understanding of person’s optimal functioning in a subject matter. Achieving an exceptional level of best practice (e.g. achieving excellent grades in mathematics) does not exist in isolation, but rather depends on the potent impact of optimization. This chapter, theoretical in nature, focuses on an in‐depth examination of the expansion of the Framework of Achievement Bests. Our discussion of the Framework of Achievement Bests, reflecting a methodical conceptualization, is benchmarked against another notable theory for understanding, namely: Martin Seligman’s PERMA theory. For example, for consideration, one aspect that we examine entails the extent to which the Framework of Achievement Bests could explain the optimization of each of the five components of PERMA (e.g. how does the Framework of Achievement Bests explain the optimization of engagement?).",book:{id:"5761",slug:"quality-of-life-and-quality-of-working-life",title:"Quality of Life and Quality of Working Life",fullTitle:"Quality of Life and Quality of Working Life"},signatures:"Huy P. Phan and Bing H. Ngu",authors:[{id:"196435",title:"Prof.",name:"Huy",middleName:"P",surname:"Phan",slug:"huy-phan",fullName:"Huy Phan"}]}],onlineFirstChaptersFilter:{topicId:"278",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:90,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:108,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:33,numberOfPublishedChapters:330,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:14,numberOfPublishedChapters:145,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:9,numberOfPublishedChapters:140,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:123,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:112,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:22,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:11,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:"2753-6580",doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}},{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}}]},series:{item:{id:"7",title:"Biomedical Engineering",doi:"10.5772/intechopen.71985",issn:"2631-5343",scope:"Biomedical Engineering is one of the fastest-growing interdisciplinary branches of science and industry. The combination of electronics and computer science with biology and medicine has improved patient diagnosis, reduced rehabilitation time, and helped to facilitate a better quality of life. Nowadays, all medical imaging devices, medical instruments, or new laboratory techniques result from the cooperation of specialists in various fields. The series of Biomedical Engineering books covers such areas of knowledge as chemistry, physics, electronics, medicine, and biology. This series is intended for doctors, engineers, and scientists involved in biomedical engineering or those wanting to start working in this field.",coverUrl:"https://cdn.intechopen.com/series/covers/7.jpg",latestPublicationDate:"August 14th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:12,editor:{id:"50150",title:"Prof.",name:"Robert",middleName:null,surname:"Koprowski",slug:"robert-koprowski",fullName:"Robert Koprowski",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYTYNQA4/Profile_Picture_1630478535317",biography:"Robert Koprowski, MD (1997), PhD (2003), Habilitation (2015), is an employee of the University of Silesia, Poland, Institute of Computer Science, Department of Biomedical Computer Systems. For 20 years, he has studied the analysis and processing of biomedical images, emphasizing the full automation of measurement for a large inter-individual variability of patients. Dr. Koprowski has authored more than a hundred research papers with dozens in impact factor (IF) journals and has authored or co-authored six books. Additionally, he is the author of several national and international patents in the field of biomedical devices and imaging. Since 2011, he has been a reviewer of grants and projects (including EU projects) in biomedical engineering.",institutionString:null,institution:{name:"University of Silesia",institutionURL:null,country:{name:"Poland"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:3,paginationItems:[{id:"7",title:"Bioinformatics and Medical Informatics",coverUrl:"https://cdn.intechopen.com/series_topics/covers/7.jpg",isOpenForSubmission:!0,editor:{id:"351533",title:"Dr.",name:"Slawomir",middleName:null,surname:"Wilczynski",slug:"slawomir-wilczynski",fullName:"Slawomir Wilczynski",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000035U1loQAC/Profile_Picture_1630074514792",biography:"Professor Sławomir Wilczyński, Head of the Chair of Department of Basic Biomedical Sciences, Faculty of Pharmaceutical Sciences, Medical University of Silesia in Katowice, Poland. His research interests are focused on modern imaging methods used in medicine and pharmacy, including in particular hyperspectral imaging, dynamic thermovision analysis, high-resolution ultrasound, as well as other techniques such as EPR, NMR and hemispheric directional reflectance. Author of over 100 scientific works, patents and industrial designs. Expert of the Polish National Center for Research and Development, Member of the Investment Committee in the Bridge Alfa NCBiR program, expert of the Polish Ministry of Funds and Regional Policy, Polish Medical Research Agency. Editor-in-chief of the journal in the field of aesthetic medicine and dermatology - Aesthetica.",institutionString:null,institution:{name:"Medical University of Silesia",institutionURL:null,country:{name:"Poland"}}},editorTwo:null,editorThree:null},{id:"8",title:"Bioinspired Technology and Biomechanics",coverUrl:"https://cdn.intechopen.com/series_topics/covers/8.jpg",isOpenForSubmission:!0,editor:{id:"144937",title:"Prof.",name:"Adriano",middleName:"De Oliveira",surname:"Andrade",slug:"adriano-andrade",fullName:"Adriano Andrade",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRC8QQAW/Profile_Picture_1625219101815",biography:"Dr. Adriano de Oliveira Andrade graduated in Electrical Engineering at the Federal University of Goiás (Brazil) in 1997. He received his MSc and PhD in Biomedical Engineering respectively from the Federal University of Uberlândia (UFU, Brazil) in 2000 and from the University of Reading (UK) in 2005. He completed a one-year Post-Doctoral Fellowship awarded by the DFAIT (Foreign Affairs and International Trade Canada) at the Institute of Biomedical Engineering of the University of New Brunswick (Canada) in 2010. Currently, he is Professor in the Faculty of Electrical Engineering (UFU). He has authored and co-authored more than 200 peer-reviewed publications in Biomedical Engineering. He has been a researcher of The National Council for Scientific and Technological Development (CNPq-Brazil) since 2009. He has served as an ad-hoc consultant for CNPq, CAPES (Coordination for the Improvement of Higher Education Personnel), FINEP (Brazilian Innovation Agency), and other funding bodies on several occasions. He was the Secretary of the Brazilian Society of Biomedical Engineering (SBEB) from 2015 to 2016, President of SBEB (2017-2018) and Vice-President of SBEB (2019-2020). He was the head of the undergraduate program in Biomedical Engineering of the Federal University of Uberlândia (2015 - June/2019) and the head of the Centre for Innovation and Technology Assessment in Health (NIATS/UFU) since 2010. He is the head of the Postgraduate Program in Biomedical Engineering (UFU, July/2019 - to date). He was the secretary of the Parkinson's Disease Association of Uberlândia (2018-2019). Dr. Andrade's primary area of research is focused towards getting information from the neuromuscular system to understand its strategies of organization, adaptation and controlling in the context of motor neuron diseases. 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