\r\n\tThis book will aim to survey the most recent diagnostic techniques as well as the most promising therapeutic options we can count on to deal with optic nerve disorders. The audience of the book is quite wide and it aims at being the main entry to this fascinating topic for students, clinicians, and researchers.
",isbn:"978-1-80356-774-7",printIsbn:"978-1-80356-773-0",pdfIsbn:"978-1-80356-775-4",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,isSalesforceBook:!1,isNomenclature:!1,hash:"e3d02512ccae0638a73c5c2839e50015",bookSignature:"Prof. Felicia M. Ferreri",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11704.jpg",keywords:"Toxic Neuropathy, Ethambutol, Methanol, Leber Neuropathy, Congenital Anomalies, Coloboma, Optic Disc Excavation, Systemic Anomalies, Optic Disc Swelling, Anterior ION, Posterior ION, ION Variants",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"March 25th 2022",dateEndSecondStepPublish:"June 2nd 2022",dateEndThirdStepPublish:"August 1st 2022",dateEndFourthStepPublish:"October 20th 2022",dateEndFifthStepPublish:"December 19th 2022",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"2 months",secondStepPassed:!0,areRegistrationsClosed:!0,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,biosketch:"Prof. Felicia M. Ferreri graduated summa cum laude from the University of Messina, Italy in 1998. 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From chapter submission and review to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. 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\n
1. Introduction
\n
Asthma is a heterogeneous inflammatory disorder of the airways characterized by chronic deregulated inflammation, bronchial hyperreactivity, and symptoms of recurrent wheezing, coughing, and shortness of breath. Its prevalence has increased considerably over the past three decades, particularly in Western countries. Asthma is a major public health problem that affects 300 million people worldwide [1, 2].
\n
Airway hyperresponsiveness (AHR), one of the hallmarks of asthma, directly results from excessive contraction of airway smooth muscle cells (aSMC). The degree of AHR always correlates with asthma severity and the need for therapy [3, 4]. Regular treatment of chronic asthma consists of a combination of inhaled anti-inflammatory corticosteroids and long-acting beta2-adrenergic receptor agonists for bronchodilation. However, severe asthma escapes to usual treatments or frequently requires higher doses. In acute asthma, short-acting beta2 agonists or anticholinergics are used as bronchodilators. These drugs are rapidly effective but can be insufficient in some cases of severe acute asthma attack. Despite available therapies, many patients with severe asthma remain uncontrolled and the number of asthma deaths is still elevated [5]. There is thus an obvious need for new drugs acting through other pathways to prevent or reverse AHR and decrease severe asthma attacks, hospitalizations and deaths.
\n
The molecular mechanisms regulating aSMC contraction and proliferation involved in AHR are still largely unknown. Understanding the intracellular signaling pathways responsible for AHR is thus essential to identify new targets and design new treatments. In this way, the Rho protein Rac1 has been identified as a promising candidate.
\n
The Rho/Rac proteins constitute a family of small GTPases of more than 25 members in mammals. So far, the best characterized members of this family include the members of the Rho (RhoA, RhoB, RhoC), Rac (Rac1, Rac2, RhoG), and Cdc42 (Cdc42) subfamilies. Rho/Rac proteins share a common structure (40–95% identity) composed of a six-stranded mixed β sheet flanked by five α helices. The core G domain is made up of five polypeptide loops (G1–G5) involved in nucleotide, regulators and effectors interactions. Like the majority of Ras superfamily GTPases, most members of the Rho/Rac family behave as molecular switches that cycle between inactive (GDP-bound) and active (GTP-bound) states. In basal conditions, these proteins are inactive and sequestered in the cytosol due to their binding to Rho GDP dissociation inhibitors (RhoGDIs). Upon cell stimulation, Rho proteins became GTP-bound, translocate to the plasma membrane after release from RhoGDI, and interact with their primary effector molecules to trigger different signal transduction pathways. In addition to RhoGDIs, the activation/inactivation cycle of Rho/Rac proteins is regulated by a complex set of regulatory proteins that include GDP/GTP exchange factors (GEFs) and GTPase activating protein (GAPs) (Figure 1). Interaction of Rho/Rac protein with a GEF promotes the exchange of GDP for GTP molecules, thus leading to the rapid activation of Rho/Rac proteins during cell stimulation events. By contrast, GAPs promote the hydrolysis of the bound GTP molecules to GDP, thus allowing the transfer of the GTPases back to the inactive state at the end of the stimulation cycle [6].
\n
Figure 1.
Activation cycle of Rho/Rac proteins and their regulatory proteins. Activation of Rho/Rac proteins is mediated by a guanine nucleotide exchange factor (GEF) leading to GTP loading and to the translocation of Rho/Rac proteins to the plasmatic membrane. This active configuration of Rho/Rac proteins promotes effector interactions. To “turn off” the cycle, a GTPase-activating protein (GAP) accelerates the intrinsic GTPase activity of Rac, allowing Rac to return to its inactive state in the cytosol. The guanine nucleotide-dissociation inhibitor (GDI) binds specifically to GDP-bound Rho/Rac proteins, prolonging the inactive state and sequestering the GTPase in the cytosol.
\n
During the last decade, Rho/Rac protein signaling pathways have been recognized as major regulators of essential cellular functions. Rac1 is a key regulator of cytoskeletal structure and dynamics, leading to lamellipodia and ruffle formations [6, 7]. Thanks to this last function, Rac1 controls cellular migration and adhesion. Recently, we demonstrated that Rac1 regulates vascular SMC contraction, and consequently modulates arterial pressure [8]. Accordingly, we hypothesized that Rac1 could also be involved in aSMC contraction. We demonstrated that the specific SMC deletion of Rac1 (SM-Rac1-KO) in mice prevents bronchoconstriction ex and in vivo. Our results showed that the decreased expression or activity of Rac1 in aSMC impairs agonist-induced rise in intracellular Ca2+ concentration through a mechanism involving Rac1-dependant control of PLC activity. Interestingly, Rac1 deficiency has no impact on the respiratory system in basal, physiological condition. However, deletion of Rac1 expression in aSMC or nebulization of the Rac inhibitor NSC23766 prevented AHR in an allergic asthma model in mouse. These data indicate that (1) Rac1 is a critical component in aSMC contraction and (2) inhibition of Rac1 activity or expression may represent a novel therapeutic approach for patients with airway AHR such as asthma.
\n
Unfortunately, the currently available drugs that inhibit Rac1 (EHT 1864 and NSC23766) have low affinity and induce critical off-target effects, thus highlighting the obvious need to discover new Rac inhibitors [9, 10].
\n
In this chapter we describe how a published flow cytometry assay was taken and converted to a 1536 well format suitable for high throughput screening (HTS) to enable the screening of 500,000 compounds in the AstraZeneca Global HTS Centre to attempt to find new Rac1 inhibitors. We describe the whole protocol from receiving assay ready plates through to the data analysis and discuss the criteria that are important for an assay to be suitable for a high throughput screen by flow cytometry and describe the validation process we go through prior to starting a high throughput screening campaign.
\n
\n
\n
2. Assay development
\n
Several papers have demonstrated the utility of a bead-based flow cytometric GTP-binding assay for screening GTPase targets for small molecule inhibitors in both singleplex and multiplex formats [11, 12, 13]. As part of AstraZeneca’s Open Innovation initiative, we collaborated with researchers at l’Institut du thorax to identify small molecule inhibitors of Rac1 GTPase. We therefore set out to develop a bead-based assay for screening Rac1 in a singleplex fashion (Figure 2) for a screening campaign in 1536 well plates on an iQue® Screener HD. The Intellicyt iQue® Screener HD is a flow cytometer with an autosampler able to sample from 96, 384 and 1536 well plates. Using proprietary technology the instrument separates well samples with an air bubble allowing the software to determine what sample comes from what well making the instrument a true high throughput instrument.
\n
Figure 2.
Pictorial representation of GST-Rac1 bound to GSH beads. Inhibitors of fluorescent GTP binding result in decreased FL1-H signal.
\n
The assay is based on glutathione-coated beads used to capture GST-tagged Rac1. Bodipy-labeled GTP (FL-GTP, ThermoFisher Scientific), is then used as a tracer for the detection of compounds that compete with its binding to the GTPase resulting in a decreased fluorescence signal.
\n
We purchased commercially-available glutathione coated particles (GSH beads, size 4.0–4.9 μm, Spherotech) that have glutathione covalently coupled to their surface and glutathione S-transferase tagged Rac1 protein (human wild type) (GST-Rac1, ThermoFisher Scientific) and bound the GST-Rac1 onto the GSH beads overnight. Assay development was performed in 384 well plates before miniaturizing the assay for 1536 well plates. We optimized the concentration of FL-GTP to use in the assay to achieve the largest signal to background window and also confirmed that FL-GTP did not bind to unconjugated beads to demonstrate Rac1/GTP binding specificity. Based on the data shown in Figure 3 and associated table, 100 nM FL-GTP was selected.
\n
Figure 3.
Optimization of FL-GTP concentration and confirmation of binding specificity. (A) Unconjugated or Rac1-coated beads were incubated with varying amounts of FL-GTP in the presence or absence of 0.5 mM unlabeled GTP and bead fluorescence measured on the iQue®. \n\n\n: Rac1 coated beads in the presence of 0.5 mM unlabeled GTP, \n\n\n: bare beads, and \n\n\n: Rac1 coated beads. (B) Signal to background table for each concentration of FL-GTP.
\n
To validate that the beads were coated with GST-Rac1 and that they would bind bodipy-labeled GTP the prepared beads were mixed with serial dilutions of unlabeled GTP (ThermoFisher Scientific) as a competitor followed by the addition of FL-GTP. To prepare the assay, 5 μL of coated beads were dispensed into wells on a 384 well plate followed by 5 μL of buffer containing unlabeled GTP in serial dilutions in triplicate, then 5 μL of 100 nM FL-GTP was added for a final volume of 15 μL and incubated for 30 min. The methods described in Refs. [11, 12, 13] included a final incubation for up to 60 min at 4°C. We wanted to be able to prepare and incubate the plates at room temperature (RT) for large scale screening, so we incubated plates both at 4°C or RT and then read the plates on the iQue Screener HD immediately after incubation or after 2 h at RT to determine if the signal window was still adequate for screening at that time. The beads are not fluorescently labeled, therefore exhibit low fluorescence intensity in the FL-1 channel (excitation 488 nm; emission filter 530/30 nm). Beads with bound FL-GTP exhibit a marked increase in fluorescence (approximately 200–500 fold). Inhibitors of GTP binding decrease the FL-1 fluorescence which is the measured signal for the samples read on the iQue® Screener HD. For analysis, beads were gated on forward scatter height (FSC-H) vs. side scatter height (SSC-H), then doublets were excluded by gating on the singlet population on forward scatter height vs. forward scatter area (FSC-A). Figure 4 shows representative data for the gating scheme and the decrease in bead fluorescence with three concentration response curves (0–333.3 μM unlabeled GTP).
\n
Figure 4.
Gating scheme for Rac1 assay. (A) Beads gated on FSC-H versus SSC-H, (B) then on FSC-H versus FSC-A for singlet beads, (C) time-resolved serial dilution curves (time versus log(Median FL1-H fluorescence) of singlet beads. Wells treated with 0–333.3 μM unlabeled GTP show decreasing FL-GTP bound to beads (data in triplicate).
\n
Addition of unlabeled GTP was able to compete with FL-GTP under all assay conditions in a concentration-dependent manner (Figure 5). Samples incubated at 4°C and read immediately afterward showed the highest binding of FL-GTP as well as the greatest decrease in fluorescence in the presence of unlabeled GTP. All other conditions showed a slight increase in FL-GTP intensity, but very similar competition curves. Assay Z′ was greater than 0.75 for all conditions. These data in a final volume of 15 μL demonstrated that the assay was adequate to move forward with miniaturization, so the assay was tested again in small volumes using 2 μL of GST-Rac1 coated beads, 2 μL of buffer containing unlabeled GTP in serial dilutions, and 2 μL of FL-GTP for a total assay volume of 6 μL in low volume 384 well plates. The miniaturized assay was comparable to the preliminary tests (data not shown) so we moved forward with miniaturization to 1536 well plates.
\n
Figure 5.
Comparison of incubation on competition of FL-GTP. Bead fluorescence measured by competition of FL-GTP by unlabeled GTP. GST-Rac1 coated beads with FL-GTP were incubated in the presence of varying amounts of unlabeled GTP in triplicate. Dotted lines indicate bead fluorescence in the presence of no unlabeled GTP. \n\n\n: incubated at 4°C for 30 min, \n\n\n: incubated at RT for 30 min, \n\n\n: incubated at 4°C for 30 min then stored for 2 h at RT and \n\n\n: incubated at RT for 30 min then stored for 2 h at RT.
\n
The challenge for us was to perform the assay in a 1536-well format in order to minimize both cost and timelines of the screen.
\n
Miniaturization to 1536 well format was first performed by using blank GSH beads to test dispensing, inter-well shake speeds, and sip times. Runs were repeated under various conditions to determine the optimum protocol. During these runs it was determined that it was best to use the bead sample buffer 0.1% (w/v) BSA in NP-HPS (30 mM HEPES pH 7.2, 100 mM KCl, 20 mM NaCl, 0.01% NP-40) supplemented with 1 mM DTT to prime the system before acquisition and during inter-well shaking. We found that we could decrease the sip time during which the sample probe aspirates from the well to 0.5 s per well, resulting in the acquisition of an entire 1536 well plate in under 50 min. Once the iQue® Screener HD protocol was optimized with blank GSH beads, we ran 3 separate plates with ½ of the plate with negative control (sample buffer) and ½ of the plate with positive control (unlabeled GTP). Briefly, the assay was performed by dispensing 2 μL of GST-Rac1 coated beads to each well of a 1536 well plate, followed by either 2 μL of sample buffer (negative control) or 2 μL of 500 μM unlabeled GTP (positive control; final concentration 166.7 μM). Finally, 2 μL FL-GTP was added to each well, then the plate was heat sealed with a pierceable foil seal and incubated at RT for 30 min. Each plate’s Z′ factor was calculated as greater than 0.5 with an average of 0.68 across the three plates (Figure 6).
\n
Figure 6.
Representative data from 1536 well Rac1 assay. (A) Beads gated on FSC-H versus SSC-H, (B) then on FSC-H versus FSC-A for singlet beads, (C) time-resolved data (time versus log(Median FL1-H fluorescence) of singlet beads. Wells treated with 0 or 166.7 μM unlabeled GTP show decreasing FL-GTP bound to beads.
\n
We optimized the coating of Rac1 on the beads by testing the signal strength and assay window achieved over a 15 fold range of initial protein concentration from saturation down to zero (Table 1).
\n
\n
\n
\n
\n
\n
\n\n
\n
Rac1 concentration (μM)
\n
Max signal
\n
Min signal
\n
Z′
\n
S/B
\n
\n\n\n
\n
5
\n
107,304
\n
15,623
\n
0.57
\n
6.87
\n
\n
\n
2.5
\n
106,718
\n
14,885
\n
0.82
\n
7.17
\n
\n
\n
1.25
\n
66,630
\n
8559
\n
0.79
\n
7.79
\n
\n
\n
0.625
\n
39,836
\n
5630
\n
0.60
\n
7.08
\n
\n
\n
0.3175
\n
21,087
\n
3518
\n
0.24
\n
5.99
\n
\n\n
Table 1.
Optimization of bead coating. Beads were coated with various concentrations of Rac1, incubated with FL-GTP and the bead fluorescence measured on the iQue®. Max refers to signal in the absence of 0.5 mM unlabeled GTP, min refers to signal in the presence of 0.5 mM unlabeled GTP.
\n
The aim was to identify the optimum concentration to use while maintaining best signal to background ratio. Following optimization i.e. check that the assay was suitable for running at large scale, the assay was validated by running a set of 7000 core compounds and a set of 3000 low molecular weight compounds (LMW) (mol.wt. below 325) (see Section 3) on 2 separate occasions to assess variability. These compounds encompass the diversity of the collections that will be screened. Running an HTS campaign is a costly and fairly demanding process. For this reason we need to ensure an assay is robust (Z′ factor greater than 0.5, signal to background greater than 3, low coefficient of variation across whole plate) and reproducible i.e. active compounds will be found repeatedly if the assay was run multiple times. We therefore defined a set of criteria we need to satisfy prior to embarking on a screen [14]. Core compounds were run at 12.5 μM and LMW at 100 μM. We use an in-house designed Tibco Spotfire® tool to analyze the data and visualize the repeatability of the assay. Validation showed the assay was performing well resulting in good agreement between the repeat runs as depicted in Figure 7 which shows a Bland-Altman plot comparing data from the 2 runs; the average difference is 0.3 and the standard deviation of the difference around 7%. We were confident that this assay was now amenable to full scale screening.
\n
Figure 7.
Bland-Altman plot of validation data.
\n
\n
\n
3. Screening
\n
The iQue® Screener HD increases the capabilities of flow cytometry with rapid sampling and assay miniaturization with a final assay volume of 6 μL per well, using as little as 1 μL per sample with no dead volume. The iQue® Screener HD has an autosampler that delivers samples in an air gap delimited stream to the cytometer engine. The plate loading area is accessible to robotic integration and an easy to use interface allows integration of laboratory automation. The entire plate of data is processed at one time. ForeCyt® software that controls the iQue® Screener HD allows plate level annotation, analysis, and visualization of the acquired data, enabling rapid, high content, multiplexed analysis of cells and beads in suspension. To enable the throughput required, we have linked two iQue® Screener HD to an ACell benchtop automation system (HighRes Biosolutions), as shown in Figure 8, comprising a Nanoserve plate carousel and an ambient nest integrated by the Cellario® scheduling software. This simple small footprint automation system allows unattended operation as well as automatically clean the cytometers at the end of each run and has a capacity of up to 28 plates per working day. We also used a third iQue® Screener HD as a standalone instrument for backup and additional throughput.
\n
Figure 8.
Automation platform used with our iQue® Screener HD. (A) and (B) iQue® Screener HD, (C) ACell robotic arm, (D) NanoServe™ stacker carousel.
\n
Prior to first use, a daily clean was run on the iQue® consisting of 5 min in decontamination solution (Intellicyt), a mildly basic solution, followed by 5 min in cleaning solution (Intellicyt), a mildly acidic and surfactant solution that neutralizes the decontamination solution and a final 10 min in water. This ensures cleaning of the entire fluidics path from probe to detector. Following this procedure a QC test was run to check the performance of the iQue instruments consisting of a 2 min water test to check cleanliness of the system followed by an 8 peak (Intellicyt) and 6 peak (Intellicyt) beads test to check laser alignment and performance of the 4 fluorescence channels. The 8 peak product contains a mixture of several similar size particles with 8 different fluorescence intensities. Every particle contains a mixture of fluorophores that enables their excitation with the blue laser (488 nm) to validate the FL1, FL2 and FL3 channels of the iQue. Similarly, the 6 peak product contains a mixture of particles with 6 different fluorescence intensities excitable by the red laser to validate the FL4 channel.
\n
All compounds for HTS in AstraZeneca are delivered in what are known as assay ready plates. Assay ready plates have the correct volume of compound in them such that on addition of the assay reagents the correct final compound concentration is achieved. Compound volumes are in the nL range and are added by a Labcyte Echo® acoustic dispenser. Using assay ready plates removes the need for intermediate dilution steps to get compounds and vehicle to the correct concentration making plate processing much simpler and faster in HTS screens.
\n
Within the AstraZeneca HTS Centre we have 2 main collections of compounds that we screen. We have what we call the core collection that is screened at a single final concentration of 10 μM or a concentration close to this balancing solubility of the compounds with detecting weaker activity. We also have a low molecular weight collection [15] where we have separated out compounds with molecular weights below 325 Da that pass solubility filters. These compounds are screened at higher concentrations (typically 100 μM) to ensure we detect the activity of these compounds that potentially have better ligand efficiencies than hits that may be found in the core collection.
\n
Rac1-coated beads were prepared by vigorously vortexing the glutathione beads, then transferring 7 mL into a 50 mL centrifuge tube. The beads were centrifuged (1000 × g, 5 min) and the supernatant removed, taking care not to disturb the pellet. 7 mL of wash buffer (0.1%, w/v BSA in NP-HPS) were added and vortexed vigorously to wash the beads. Beads were then incubated at room temperature for 30 min. Lyophilized Rac1 protein was reconstituted to 0.25 mg/mL final concentration (~5 μM) by adding 25 μL of wash buffer and mixing gently until the protein is completely dissolved. After the 30 min incubation of the beads they were pelleted by centrifugation (1000 × g, 5 min) and the supernatant discarded, taking care not to disturb the pellet. Beads were resuspended in 700 μL of wash buffer +175 μL of Rac1 protein to a final concentration of 1 μM. The sample was vortex mixed gently and incubated overnight at 4°C. After incubation at 4°C, beads were washed twice with 14 mL sample buffer (wash buffer +1 mM DTT) pelleted by centrifugation (1000 × g, 5mins) between washes and finally resuspended in 14 mL wash buffer. Labeled beads were stored at 4°C. An accurate bead count was made using the iQue® Screener HD with beads diluted to a density of 1.33 × 106 beads/mL prior to running the assay. The method described here should provide enough beads for 16 plates a day for 6 days.
\n
The primary screen was performed at compound concentration of 12.5 μM (100 μM for LMW) against a diversity collection of 500,000 compounds. All assay ready plates of compounds were prepared by our compound management team. The plate layout included on-board controls in the four central columns (64 wells of either 12.5 μM unlabeled GTP or 1% (v/v) DMSO as inhibitor and neutral controls, respectively). Each remaining well contained a single compound from the library, resulting in single shot screening of 1408 compounds per plate.
\n
To assemble the assay, the Rac1-coated beads were vigorously vortexed to mix and dispensed 3 μL/well to each well of the 1536 well assay ready plate (polypropylene deep well V-bottom microplates, Greiner Bio-One) using a Multidrop™ dispenser and a small tube cassette. Assay ready plates for this assay had 7.5 nL (60 nL for low molecular weight compounds) of a 10 mM stock of compound dispensed to each well. 3 μL/well of 200 nM Bodipy-FL GTP in sample buffer was added and plates were centrifuged (250–500 × g, 10 s) to ensure that samples are at the bottom of the plate and not adhered to the walls of the wells. Plates were sealed using a pierceable heat seal (recommend Thermo Cat No AB-1720 or equivalent) and incubated for 120 min at room temperature shielded from light. Samples were acquired on the iQue® HD Screener using the “Rac1 template” acquisition and analysis template. Rac1 Sample Buffer (0.1% BSA in NP-HPS supplemented with 1 mM DTT) in the iQue HD Buffer station gave the best sampling results. The cytometer protocol was set up with 0.6 s sip time, 0 s up time, standard pump speed, and medium detector speed as can be seen in Figure 9. Reading time per plate is 45 min.
\n
Figure 9.
ForeCyt® protocol on iQue® Screener HD.
\n
In the Intellicyt ForeCyt® software, we acquired flow cytometric light scatter as well as fluorescence emission in the FL1 channel (Ex 488 nm, Em 530 ± 30 nm). We gated on forward scatter and side scatter to identify the bead populations followed by forward scatter area vs. height to identify the singlet bead subpopulation. The median fluorescence of the singlet bead population was then extracted. Data files were exported from the ForeCyt® software as multiple plates in 1536 grid format as a comma-delimited text file. The files were manually imported into Genedata Screener® for analysis.
\n
Data were normalized on a plate by plate basis using the on-board controls to calculate a % effect value and by robust Z Score. Robust Z Score is a derivation of the original Z Score calculation [16] substituting median for average and robust standard deviation for standard deviation and is used routinely for normalization and hit calling in the AstraZeneca HTS Centre alongside the more common 2-point normalizations using positive (inhibitor) and negative (neutral) control wells. By using robust statistical measures the calculation is resistant to outliers which are, of course, the hits in an HTS which can be missed if using the non-robust version of the equation. Robust Z Score is calculated according to the equation below (Eq. (1)) and normalizes individual wells by calculating the number of robust standard deviations the well value is away for the median of the plate central reference. In most HTS screens this central reference is the median of all the compound wells on a plate as >99% of the wells will be inactive and will define the central reference.
x is the measured raw signal value of a well; 〈CR〉 is the median of the measured signal values for the central reference values on a plate; \n\n\n\n〈\n〈\nC\nR\n〉\n〉\n\n\n is the robust standard deviation of the measured signal values for the central reference values on a plate.
\n
Hits were identified using a cut-off of −10 in robust Z score; this corresponded to an approximate change of fluorescence greater than 30% (50% for LMW) from controls.
\n
The primary screen of 500,000 compounds took 4 weeks to complete and some summaries of the data are presented in Figure 10.
\n
Figure 10.
Primary screen data. (A) Distribution plot, (B) box plot, (C) plate view in Genedata Screener® and (D) assay overview in Genedata Screener®.
\n
The screen ran at a throughput of 20 plates per day equivalent to 31,000 compounds per day. The overall distribution in Figure 10 shows a narrow central peak centered on zero with the left tail containing potential hits. This is a typical distribution shape seen in HTS screens and clearly shows that the assay was capable of identifying hits. The box plots shows the stability and consistency of the assay and tightness of the data across multiple plates and also allows visualization of the hits represented as the outliers on the plot. A typical plate analysis is shown depicting the controls in the central columns and a few hits scattered across the plate as dark blue wells with the histogram showing the heat map scale of the robust Z score. The assay overview (Figure 11) shows the whole set of plates (with the low molecular weight collection highlighted) run on one iQue® Screener HD highlighting the hit rate variation with the collection subset. It can be clearly seen that the hit rate in the low molecular weight set, found in the first 32 plates, is elevated above that of the core collections. This can occur due to the higher screening concentration leading to more non-specific inhibition due to common contaminants such as metals which are then ruled out by further downstream assays and SAR analysis Although not shown, the assay signal to background as well as Z′ factor [17] are monitored throughout the screen as markers of data quality and again indicated that this assay was of high quality.
\n
Figure 11.
Primary screen data analysis plots. (A) Number of compounds analyzed per run and (B) hit rate per run.
\n
5870 hits were identified after the primary screen representing a 1.2% overall hit rate. All hits were then tested as 10-point concentration responses (100–0.003 μM) against Rac1 as well as RhoA and CDC42 so we could assess selectivity of the compounds for Rac1. The assay is performed as described for the primary screen. All hits identified in the primary screen were serially diluted 1:3 to construct a 10-point concentration response curve. Compound concentration curves are dispensed using acoustic dispensing into assay ready plates at 150 compound curves per plate. Wells are backfilled with DMSO to keep the DMSO concentration constant in all wells. The plates were sealed and stored in the controlled atmosphere and temperature working plate store before use as for primary screen plates. 1 mM MgCl2 was added to the buffer for the RhoA assay. 82% of the tested compounds were confirmed as active with 44 identified as Rac1 selective using a ≥10 fold ratio of Rac1 IC50 vs. RhoA and Cdc42 as a cutoff. These compounds encompass a variety of chemical structures. Figure 12 shows representative curves of selective and non-selective compounds. Selected hits are being further characterized through a panel of cellular assays by the team at INSERM.
\n
Figure 12.
Representative curves of selective and non-selective compounds.
\n
\n
\n
4. Conclusions
\n
Until recently flow cytometry was considered a powerful technology dedicated to bespoke assays where just a few samples were to be measured. No medium throughput let alone high throughput screen could be run on this technology due to lack of plate handling features, time needed per sample and therefore cellular imaging was the preferred method for any high content screen. Increases of interest in phenotypic screening combined with a desire to access relevant cell models, often suspension cells, and development of plate-based sampling flow cytometers have led to the opportunity to use flow cytometry as a drug screening technology platform. The ability to perform multiplexing where different cells or particles labeled with distinct fluorophores are analyzed in parallel and multiple endpoints are measured leads to in-depth analysis of subpopulations within a sample. Such an approach results in increased productivity by decreasing timelines and cell requirements, two critical parameters for high throughput screening.
\n
We chose to run a screen for Rac1 inhibitors on our iQue® Screener HD as it enabled us to miniaturize and run a simple and robust assay on one of our automation platforms.
\n
We have run a successful 500,000 compound screen using the iQue® HD screener as summarized in Figure 13. By optimizing the protocol, we were able to retain high-quality data while decreasing read time per 1536 well plate to under 50 min. This allowed us to run the primary screen within 4 weeks. Although time is not the most critical criteria we consider it remains an important factor as we need to maintain the overall flow of projects through our portfolio and therefore we must decide on a suitable time frame for completion of each screen.
\n
Figure 13.
Screen summary.
\n
High throughput screening is a key method for the identification of hit and lead compounds and remains at the start of most of our drug discovery programs. As we pursue a wide range of targets we also use a wide range of assays and technologies. We have invested into several iQue® Screener systems as we updated and replaced previous detection systems and to fill a capability gap for screening suspension cells or primary cells in small sample volumes. We have successfully used the iQue® Screener systems in a variety of applications from phenotypic screening to more complex multiplex profiling. The technology has enabled several projects due to the ability to reduce cell requirement, cost and timelines.
\n
The screen we have described here would have not been possible a few years ago but, thanks to the development of high throughput capable instruments, flow cytometry has found its place within the drug discovery process and high throughput screening in AstraZeneca. Although we decided not to multiplex our concentration response assays, it should be noted that the use of flow cytometry technology does allow for such multiplexing and indeed has been described in the literature [12].
\n
\n
Acknowledgments
\n
The authors would like to thank Matthew Collier for his assistance during the high throughput screen and Kim Luu for her technical support with the iQue®.
\n
\n',keywords:"HTS, drug discovery, bead-based assay, GTPase",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/57187.pdf",chapterXML:"https://mts.intechopen.com/source/xml/57187.xml",downloadPdfUrl:"/chapter/pdf-download/57187",previewPdfUrl:"/chapter/pdf-preview/57187",totalDownloads:1069,totalViews:184,totalCrossrefCites:1,totalDimensionsCites:2,totalAltmetricsMentions:0,introChapter:null,impactScore:1,impactScorePercentile:66,impactScoreQuartile:3,hasAltmetrics:0,dateSubmitted:"May 10th 2017",dateReviewed:"September 19th 2017",datePrePublished:"December 20th 2017",datePublished:"June 27th 2018",dateFinished:"October 13th 2017",readingETA:"0",abstract:"High throughput (HT) screening is at the starting point for most drug discovery programs. As the range of targets being pursued widens new technologies have to be deployed to enable assays built to measure the activity of proteins previously deemed challenging. Flow cytometry is a technology providing multi-parametric analysis of single cells or other particles in suspension, such as beads. High throughput (HT) flow cytometry has become a very attractive screening platform for drug discovery. In this chapter we describe a 1536 well format high throughput screen of 500,000 compounds to find inhibitors of Rac1 GTPase to prevent allergic airway hyper-responsiveness in asthma. We discuss the assay development, miniaturization and validation carried out prior to the full screening campaign. We then describe how we have automated our iQue® HD screener instruments and how we proceed with the data analysis and explain why we chose to run this screen on a flow cytometer and how it enabled us to reduce cost and timelines for the project.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/57187",risUrl:"/chapter/ris/57187",book:{id:"6252",slug:"multidimensional-flow-cytometry-techniques-for-novel-highly-informative-assays"},signatures:"Catherine Bardelle, Vincent Sauzeau, Mark B. Carter, Zhaoping Liu,\nGervaise Loirand and David Murray",authors:[{id:"210847",title:"Dr.",name:"Catherine",middleName:null,surname:"Bardelle",fullName:"Catherine Bardelle",slug:"catherine-bardelle",email:"catherine.bardelle@astrazeneca.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"AstraZeneca (United Kingdom)",institutionURL:null,country:{name:"United Kingdom"}}},{id:"212541",title:"Dr.",name:"David",middleName:null,surname:"Murray",fullName:"David Murray",slug:"david-murray",email:"David.Murray@astrazeneca.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"University of Manchester",institutionURL:null,country:{name:"United Kingdom"}}},{id:"218518",title:"Mr.",name:"Mark",middleName:null,surname:"Carter",fullName:"Mark Carter",slug:"mark-carter",email:"mcarter@intellicyt.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"221315",title:"Dr.",name:"Vincent",middleName:null,surname:"Sauzeau",fullName:"Vincent Sauzeau",slug:"vincent-sauzeau",email:"Vincent.Sauzeau@univ-nantes.fr",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"University of Nantes",institutionURL:null,country:{name:"France"}}},{id:"221316",title:"Dr.",name:"Gervaise",middleName:null,surname:"Loirand",fullName:"Gervaise Loirand",slug:"gervaise-loirand",email:"gervaise.loirand@inserm.fr",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"University of Nantes",institutionURL:null,country:{name:"France"}}},{id:"221317",title:"Dr.",name:"Zhaoping",middleName:null,surname:"Liu",fullName:"Zhaoping Liu",slug:"zhaoping-liu",email:"ZLiu@intellicyt.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Assay development",level:"1"},{id:"sec_3",title:"3. Screening",level:"1"},{id:"sec_4",title:"4. Conclusions",level:"1"},{id:"sec_5",title:"Acknowledgments",level:"1"}],chapterReferences:[{id:"B1",body:'Busse WW, Lemanske RF Jr. Asthma. The New England Journal of Medicine. 2001;344(5):350-362\n'},{id:"B2",body:'To T et al. Global asthma prevalence in adults: Findings from the cross-sectional world health survey. BMC Public Health. 2012;12:204\n'},{id:"B3",body:'Cockcroft DW, Davis BE. Mechanisms of airway hyperresponsiveness. The Journal of Allergy and Clinical Immunology. 2006;118(3):551-559. quiz 560-551\n'},{id:"B4",body:'Prakash YS. Airway smooth muscle in airway reactivity and remodeling: What have we learned? American Journal of Physiology. Lung Cellular and Molecular Physiology. 2013;305(12):L912-L933\n'},{id:"B5",body:'Barnes PJ. Immunology of asthma and chronic obstructive pulmonary disease. Nature Reviews. Immunology. 2008;8(3):183-192\n'},{id:"B6",body:'Loirand G et al. Small G proteins in the cardiovascular system: Physiological and pathological aspects. Physiological Reviews. 2013;93(4):1659-1720\n'},{id:"B7",body:'Bustelo XR et al. GTP-binding proteins of the Rho/Rac family: Regulation, effectors and functions in vivo. BioEssays. 2007;29(4):356-370\n'},{id:"B8",body:'Andre G et al. Smooth muscle specific Rac1 deficiency induces hypertension by preventing p116RIP3-dependent RhoA inhibition. Journal of the American Heart Association. 2014;3(3):e000852\n'},{id:"B9",body:'Carrizzo A et al. Rac-1 as a new therapeutic target in cerebro- and cardio-vascular diseases. Current Drug Targets. 2014;15(13):1231-1246\n'},{id:"B10",body:'Halaban R. RAC1 and melanoma. Clinical Therapeutics. 2015;37(3):682-685\n'},{id:"B11",body:'Hong L et al. A Pan-GTPase inhibitor as a molecular probe. PLoS One. 2015;10(8):e0134317\n'},{id:"B12",body:'Surviladze Z et al. Identification of a small GTPase inhibitor using a high-throughput flow cytometry bead-based multiplex assay. Journal of Biomolecular Screening. 2010;15(1):10-20\n'},{id:"B13",body:'Surviladze Z et al. High throughput flow cytometry bead-based multiplex assay for identification of Rho GTPase inhibitors. Methods in Molecular Biology. 2012;827:253-270\n'},{id:"B14",body:'Murray D, Wigglesworth M. Chapter 1 HTS methods: Assay design and optimisation. In: High Throughput Screening Methods: Evolution and Refinement. London: The Royal Society of Chemistry; 2017. p. 1-15\n'},{id:"B15",body:'Wigglesworth MJ et al. Increasing the delivery of next generation therapeutics from high throughput screening libraries. Current Opinion in Chemical Biology. 2015;26:104-110\n'},{id:"B16",body:'Malo N et al. Statistical practice in high-throughput screening data analysis. Nature Biotechnology. 2006;24(2):167-175\n'},{id:"B17",body:'Zhang JH et al. A simple statistical parameter for use in evaluation and validation of high throughput screening assays. Journal of Biomolecular Screening. 1999;4(2):67-73\n'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Catherine Bardelle",address:"catherine.bardelle@astrazeneca.com",affiliation:'
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1. Introduction
Drug-induced liver injury (DILI) represents a large group of hepatic diseases caused by various therapeutical agents.
There are two types of DILI, with differences in pharmacologic mechanism and clinical onset patterns. The first type, the predictable one, named intrinsic or direct, is typically dose-related and affects a large proportion of exposed individuals if the safe amount is exceeded. It produces distinctive liver lesions, and the onset of clinical and laboratory abnormalities is usually after a short time after drug consumption, hours to days. The effects can be also reproduced using routine animal testing [1].
The second type of DILI, the unpredictable one, named idiosyncratic, affects only a small proportion of susceptible individuals exposed to various doses (not dose-related). It produces variable liver injuries, and the onset of clinical and laboratory abnormalities may begin from days to weeks after drug consumption. Usually, the effects cannot be reproduced using routine animal testing [2].
Even the acetaminophen consumption is the cause of the majority of DILI in the USA, in this chapter, our focus will be on injuries induced by oncologic treatment [3]. Despite the chemotherapy possibility of decreasing tumor size and stage, fighting against micrometastatic disease, and prolonging overall survival, it is associated with side effects. The liver is an important organ with a role in drug metabolization and excretion and may be affected when oncologic treatment is initiated.
Several risk factors are associated with a higher incidence of adverse drug reactions, including DILI induced by chemotherapy. Host-related risk factors such as the old age, female sex, HLA class I allele A*33:01, chronic liver disease, and drug-related risk factors such as dose, site of metabolization, and lipophilicity, appear to influence the frequency of occurrence of oncologic treatment hepatic adverse effects. Identifying the risk factors for the development of liver injury after chemotherapy initiation can influence the treatment decision and also improve the patient outcome.
The majority of patients that receive oncological treatment who developed liver injury as adverse reactions are identified by symptoms and/or blood test abnormalities. Elevation of alanine transaminase (ALT), aspartate transaminase (AST), conjugated and total bilirubin (TB), and international normalized ratio (INR) with low values of albumin is frequently revealed in these patients. Symptoms may be absent or nonspecific, or patients can present jaundice, encephalopathy, or coagulopathy manifestation.
DILI, which includes the liver injuries produced by oncological agents, is defined if one of the following criteria is present: (a) more than 5× upper limit of normal ALT value, (b) more than 2× upper limit of normal ALP value (often with the elevation of gamma-glutamyltransferase (GGT)), or (c) more than 3× upper limit of normal ALT value accompanied by more than 2× upper limit of normal TB level value. In practice, there are situations when patients presented with elevated values of the aforementioned blood tests before starting the potential liver harmful treatment, and in this case, the mean of these values replaces the upper limit of normal.
The most recent guidelines of EASL (European Association For The Study Of The Liver) classified DILI in “hepatocellular,” “cholestatic,” or “mixed” types due to the pattern of changes in liver enzymes (Table 1) [2].
DILI pattern
Hepatocellular injury
Cholestatic injury
Mixed injury
Liver biochemical blood tests abnormalities
≥5× ULN elevation in ALT OR Serum activity ALT to ALP is 5 or more.
≥2× ULN elevation in ALP OR Serum activity ALT to ALP is 2 or less.
serum activity of ALT to ALP is between 2 and 5.
Histological abnormalities
Inflammation, necrosis, and apoptosis; severe necrosis involved zone 3.
Canalicular and hepatocelular cholestasis in zone 3.
more similar changes to that of cholestatic than hepatocellular type.
Table 1.
DILI pattern with his associated biochemical blood tests and histological abnormalities, adapted after EASL clinical practice guidelines, 2019: drug-induced liver injury [2].
2. Patterns of oncological-therapy-related liver injury
The most common liver disease patterns induced by oncologic therapy are discussed below, and the agents frequently involved are listed in Tables 2 and 3.
Immunomodulatory agents in chemotherapy and their associated liver-related side effects.
2.1 Steatosis and steatohepatitis
NAFLD affects 10–39% of the global population, and only 2% of these patients are caused by drugs. A common effect of chemotherapy is to increase the amount of hepatocellular fat content. Two entities are described, steatosis and steatohepatitis, often known as chemotherapy-induced acute steatohepatitis, “CASH.” Steatosis is defined by the accumulation of lipids within hepatocytes without inflammatory foci. Steatohepatitis is the lipid accumulation with concurrent inflammation of liver parenchyma on hepatocytes that appear enlarged (ballooning phenomes) and can lead to degeneration [4, 5, 6].
Various therapeutic agents used in oncology can induce steatosis or steatohepatitis. Regimens that contain antitumoral molecules such as 5-fluorouracil, methotrexate, tamoxifen, irinotecan, L-asparaginase, oxaliplatin, mitomycin C, bleomycin sulfate, and dactinomycin were linked with fatty liver transformation [7, 8]. Usually, specific changes are detected after a period of 3–12 months of chemotherapy.
Treatments recommended for patients diagnosed with cancer contain not only antitumoral agents. Associated medication used in oncology can also induce nonalcoholic fatty liver disease. Glucocorticoids used for induction treatment of acute leukemia may cause macrovesicular steatosis [9].
A high number, up to 85%, of patients treated with regimens mentioned above develop CASH due to altered lipoprotein synthesis and therefore abnormal lipid metabolism. The development of steatohepatitis is based on an abnormal function of hepatocyte mitochondria and peroxisomes, inside which the process of oxidation of fatty acids (FAO) takes place. Several chemotherapy agents inhibit free fatty acids (FFA) β-oxidation, which promotes the accumulation of reactive oxygen species (ROS) and lipid peroxidation and increases oxidative stress in hepatocytes. All these processes lead to CASH. At the same time, lipid peroxidation stimulates stellate cell activation, fibrosis, and necrosis of hepatocytes. The intramitochondrial accumulation of tamoxifen leads to the inhibition of FFA β-oxidation, ATP synthesis, and cellular respiration. Another mechanism of steatosis and steatohepatitis is explained by the alteration of lysosomal phospholipid metabolism, which promotes the activation of the adenosine pathway and therefore increases FFA synthesis and also coenzyme A sequestration. This mechanism was observed in patients undergoing treatment with irinotecan and methotrexate. For methotrexate, the increased level of homocysteine due to impaired methylenetetrahydrofolate reductase leads to increased pro-inflammatory cytokines and hepatic stellate cell activation, which promote liver fibrosis. Increased expression of acyl-coenzyme A oxidase 1 (ACOX1) was observed for patients treated with 5-fluorouracil and irinotecan. Inhibition of mitochondrial FFA β -oxidation and reduced expression of carnitine palmitoyl-transferase and ACOX1 induction were observed for irinotecan [10].
ACOX1 is the first limiting enzyme of peroxisomal FAO and may be increased as a response to decreased mitochondrial FFA β-oxidation. A high level of ACOX1 leads to increased expression of pro-inflammatory genes and a high amount of ROS, processes associated with immune cell infiltration. A hepatic steatosis liver can progress to steatohepatitis if contained hepatocytes own altered mitochondrial FFA β-oxidation and high amounts of ROS and inflammation. Mitochondria can be a direct target of every chemotherapy agent via cytotoxicity effect, and every agent can also have multiple pathways to induce steatosis or steatohepatitis [11].
Histologically, there are no marked differences between metabolic steatohepatitis and CASH. Even actually is rare recommended, if liver biopsy is performed on this patient, microvesicular steatosis is usually described. Distribution can be focal, multifocal, or diffuse. Macroscopic, fatty liver has a yellowish appearance and may be enlarged.
Recognition of this liver disease is important for adequate management that improves the prognosis. Usually, clinical manifestations of patients with chemotherapy-induced steatosis and steatohepatitis are subtle. Transaminase levels show elevation of ALT/AST. Steatosis and steatohepatitis liver is characterized by hyperechogenicity with posterior beam attenuation on transabdominal ultrasound examination. On computed tomography, a reduction in liver parenchymal attenuation can be observed when compared with the spleen. With high accuracy, magnetic resonance imaging can quantify the number of lipids in the liver due to spectroscopy and elastography available modes. A reduction in liver signal intensity is described in out-of-phase imaging for patients with steatohepatitis [12, 13, 14]. Delayed regeneration and prolonged liver disfunction were observed in oncologic patients with steatosis and more obvious with steatohepatitis, which was associated with a higher risk of postoperative hepatic failure, infections, and longer period of the intensive-care-unit stay [4, 15]. Repeated chemotherapy cycles are responsible for more severe inflammation, fact that worsens hepatocellular damage and leads to the development of fibrosis, cirrhosis, and liver failure [16, 17]. A limited CASH risk with the best oncologic treatment effects was observed for chemotherapy regimens with a maximum duration of 4 months [18].
For patients diagnosed with cancer, blood lipid and transaminase levels should be performed before initiation and regularly during oncologic treatment. Steatosis and steatohepatitis are in most cases reversible even though they can persist for a few weeks or months after treatment completion [7, 19]. Once the diagnosis was confirmed, the recommendation to stop or continue the administration of oncologic agents with close monitoring relies upon the risk and benefits of this medication. Healthy eating habits and limited high-fat alimentation are recommended to prevent increased blood lipid levels and worsening steatosis or steatohepatitis. Hepatoprotective drug administration, to prevent the worsening damage to the liver, is indicated [20].
Risk factors for CASH occurrence can be patient-related (metabolic syndromes, obesity, diabetes, dyslipidemia, alcohol abuse, preexisting chronic liver disease or hepatic location of the tumor, genetic polymorphism, gut microbiota, and chemotherapy history) or drug-related (cumulative or maximum dose of treatment or combination of more agents) [4]. Special attention is required for women with breast cancer with the A2 allele of CYP17A1 due to the associated increased risk of developing steatosis when treated with tamoxifen [21, 22].
2.2 Focal nodular hyperplasia
Focal nodular hyperplasia is the second most common benign hepatic lesion with unclear pathogenesis. Some explanations for this lesion may include a similar mechanism to focal sinusoidal obstruction syndrome [23].
Some agents used in oncology such as 6-thioguanine and oxaliplatin have an increased risk of inducing nodular hyperplasia and early fibrosis [24, 25]. Focal nodular hyperplasia is characterized by solitary or multiple lesions in liver parenchyma, which usually appear on CT as homogeneous, isodense, or mildly hypodense images. Contrast-enhanced CT shows arterial hyperenhancement, and late enhancement can be seen when a central scar is visible. These lesions may be incorrectly labeled as hypervascular liver metastasis. Characteristic MRI features for focal nodular hyperplasia are nonspherical shape lesions with imprecise margins and particularly hyperenhanced zones in the hepatobiliary phase for specific contrast agents. Signal isointensity on T1- and T2-weighted images, the absence of halo enhancement, and the absence of restriction to water diffusion in the echo-planar sequence are other characteristics that support the diagnosis of focal nodular hyperplasia [23, 26].
2.3 Pseudocirrhosis
Pseudocirrhosis is an imagistic term characterized by hepatic nodularity due to diffuse regenerative nodular hyperplasia but with insignificant fibrosis, different from the classic histopathological attributes of cirrhosis, features that appear after oncologic treatment initiation [27]. Pseudocirrhosis is associated with antineoplastic drugs used for the treatment of metastatic breast, colon, and pancreatic cancers. These agents are oxaliplatin, 5-fluorouracil, gemcitabine, capecitabine, irinotecan, methotrexate, and tamoxifen [28]. It can also appear in patients with carcinoid tumors and Hodgkin lymphoma.
Pseudocirrhosis can represent a cause of portal hypertension and even liver failure, but it lacks the typical clinical and paraclinical features of cirrhosis. The synthetic function of the liver is usually preserved.
On CT examination, pseudocirrhosis looks like macronodular cirrhosis with capsular retraction, diffuse nodularity, lower liver volume, and hypertrophy of the caudate lobe. For up to 9% of cases, signs of portal hypertension, including portosystemic shunts, can appear on imaging evaluation. The severe capsular retraction has been described in some cases of liver metastasis from breast cancer, and those must be excluded due to different treatments and prognoses that are associated with this stage [6, 23].
2.4 Acute hepatitis
Multiple oncological agents are involved in acute hepatitis occurrence, with high-frequency vinblastine, rituximab, etoposide, anastrozole, 6-mercaptopurine, 5-fluorouracil, lapatinib [6, 29, 30]. Even though not routinely indicated, if liver biopsy is performed on patients that underwent treatment with anastrozole, the histopathology report revealed necrosis of hepatocytes limited in acinar zone 3. This zone is related to P450 isoenzymes that are involved in drug metabolism. Histopathological report of liver biopsy of patients treated with lapatinib revealed portal-to-portal and portal-to-central bridging necrosis and hepatocellular necrosis in acinar zone 1 [31, 32]. Etoposide-induced acute hepatitis is described as a viral hepatitis pattern [29].
Clinical manifestation of acute hepatitis can range from mild symptoms to ill-appearing patients. Usually, AST and ALT are markedly increased. Imaging findings are nonspecific and may include hepatomegaly with decreased attenuation, splenomegaly, wall thickening of gallbladder, ascites, and periportal edema. Severe forms of acute hepatitis appear in patients with prior chronic hepatitis B or C due to reactivation when treated with rituximab. Patients with MHC class II alleles HLA-DQA1∗02:01, DQB1∗02:02, or DRB1∗07:01 are at high risk of liver injury if receiving regimens with lapatinib [6, 33].
Acute hepatitis induced by anticancer treatment rapidly improved after drug withdrawal. Liver enzymes and bilirubin return to normal values after a few months of treatment discontinuation [5].
2.5 Hepatic necrosis
Acute liver failure due to hepatic necrosis is a major and worrisome complication of chemotherapy-induced liver injury. Oncologic agents that produce acute hepatitis are more likely to cause hepatic necrosis. Mithramycin, etoposide, and dacarbazine are some of these offending drugs. Mithramycin also known as plicamycin is an antineoplastic antibiotic that has been reported as the most hepatotoxic chemotherapeutic drug capable of causing liver necrosis. Histopathologic reports of the hepatic biopsy reveal centrilobular necrosis.
Clinically, patients with hepatic necrosis develop acute encephalopathy with deterioration of liver synthetic function. Almost all patients receiving plicamycin have increased levels of LDH, aminotransferases, and alkaline phosphatase with normal values of bilirubin. These modifications occur on the first day of treatment, reach the maximum level the next day, and then decrease to normal 3 weeks after treatment cessation. When severe necrosis develops, a computer tomography scan reveals a substantial decrease in the enhancement of liver parenchyma and cystic appearance [6, 34, 35].
2.6 Immune-mediated hepatitis
Metastatic melanoma, non-small-cell lung cancer hepatocellular carcinoma, and urothelial carcinoma are types of cancer that benefit from immunotherapy agents’ efficacy. Side effects are not rare for this class of treatment and are named immune-related adverse effects, including the liver with immune-mediated hepatitis [36].
Immune checkpoints are cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed cell death 1 (PD-1), and programmed cell death ligand 1 (PD-L1). Monoclonal antibodies against these targets are ipilimumab against CTLA-4, pembrolizumab, nivolumab against PD-1 and atezolizumab, avelumab, and durvalumab against PD-L1. From this list, the higher hepatotoxicity was found for CTLA-4 inhibitors, ipilimumab. Patients diagnosed with metastatic melanoma develop immune-mediated hepatitis in 2–9% of cases if they are treated with ipilimumab, and if dacarbazine is associated, the percentage rises up to 31.6% [37, 38].
Immunotherapy contains agents that increase the host’s immune system to fight against tumors, but the subsequent uncontrolled T cell activation is responsible for hepatotoxicity and liver disease. Liver biopsy revealed diffuse T-cell infiltrate, eosinophil infiltration, portal, and periportal inflammation, and spotty or confluent necrosis [39, 40, 41]. Usually, patients are asymptomatic and, in rare cases, fevers, malaise, or symptoms related to fulminant liver failure can be present. Elevation in serum of ALT, AST, and bilirubin occurs especially after ipilimumab. Anti-nuclear, anti-smooth muscle, or other autoimmune hepatitis antibodies are negative. These clinical and paraclinical abnormalities occur from 6 to 14 weeks after immunotherapy initiation or after three doses of this regimen [42, 43]. Some risk factors contribute to a higher chance of liver injury development: a higher dose of treatment, multiple agents association, preexisting liver disease, or autoimmune diathesis [44].
Treatment with corticosteroids or mycophenolate mofetil is indicated for patients with important hepatotoxicity after immunotherapy for cancer [39]. HLA-DRB1*07:01 allele is associated with an increased risk for lapatinib liver injury. Infliximab should not be indicated due to the risk of hepatotoxicity [45, 46].
2.7 Cholestasis
Chemotherapeutic regimens include kinase inhibitors (e.g., erlotinib, sorafenib, nilotinib), thiopurines (6-mercaptopurine and azathioprine), estrogens, 5-fluorouracil, cytarabine, interleukin-2, alkylating agents (chlorambucil, cyclophosphamide, cisplatin), and mitomycin are associated with cholestatic liver injury [29, 35].
Thiopurines cause a variety of DILI phenotypes that can be intrinsic or idiosyncratic with a mixed or cholestatic form of hepatic injury [47]. Intrahepatic cholestasis is the most frequent type of injury in patients undergoing treatment with 6-mercaptopurine (frequently when the daily dose exceeds 2 mg/kg). Azathioprine may produce hepatic injury, but less frequently than 6-mercaptopurine, and this one has been related to a mild form of liver toxicity; however, long-term use can cause cholestatic liver disease [35].
Significant hepatotoxicity has been linked to fluorodeoxyuridine, a metabolite of fluorouracil that was previously administered through the hepatic artery to patients with hepatic metastases from colorectal cancer. In several cases, the treatment has been linked to irreversible intrahepatic and extrahepatic biliary strictures. Monitoring of aminotransferases helps with identifying the right time for drug discontinuation when the liver is suffering [29].
Interleukin-2 therapy is used in melanoma and renal cell cancers, and a lot of patients undergoing this treatment can develop a deep and reversible intrahepatic cholestasis with increased serum levels of biochemical markers of cholestasis. Some potential physiopathological mechanisms may include chemical hepatitis and biliary sclerosis. Allopurinol can block xanthine oxidase involved in drug metabolism, which rises hepatotoxicity. Histologically features of this hepatic injury appear as cholestasis with variable hepatocellular necrosis. Laboratory tests show elevated levels of bilirubin, alkaline phosphatase, and aminotransferases. Jaundice is the clinical feature that is associated with this type of hepatotoxicity [6]. In conclusion, cholestasis is induced by a multitude of antineoplastic drugs and withdrawal usually leads to recovery of the liver and jaundice disappearance [29].
2.8 Fibrosis and cirrhosis
Liver fibrosis and cirrhosis induced by chemotherapy are usually associated with alkylating agents, 6-thioguanine, and methotrexate.
Methotrexate is a folic acid antagonist that inhibits the proliferation of certain body cells, particularly those that are multiplying rapidly such as tumor cells, bone marrow cells, and skin cells. Long-term methotrexate treatment, commonly used to treat severe psoriasis or rheumatoid arthritis, can induce hepatic fibrosis, which leads to cirrhosis without producing significant symptoms [48]. The use of methotrexate as maintenance therapy in children with acute leukemia was related to fibrosis and cirrhosis development in multiple cases [49, 50]. Furthermore, cirrhosis induced by methotrexate has led to the transplantation of the liver in an important number of patients. Hepatic stellate cells have a central role in the physiopathological mechanism. The hepatic test may be normal or ALT can be temporarily increased. In rare cases, a liver biopsy may be necessary to confirm the diagnosis [29].
Patients who receive treatment with methotrexate need rigorous monitoring, especially those who have both obesity and diabetes [51]. It has been demonstrated that folic acid may reduce hepatic injury [29].
2.9 Sinusal obstructive syndrome
Previously named veno-occlusive disease, sinusoidal obstruction syndrome is the last step of hepatic sinusoidal injury evolution. The most exposed are patients who receive cytoreductive chemotherapy combined with radiotherapy or are in the setting of bone marrow transplantation [52].
Cyclophosphamide, oxaliplatin, irinotecan, 5-fluorouracil, 6-mercaptopurine, dacarbazine, vincristine, mitomycin-C, cytarabine, busulfan are chemotherapy agents involved in hepatic sinusoidal injury [53, 54, 55, 56, 57, 58]. Usually, sinusoidal obstruction syndrome occurs 5 weeks or later after administration of the aforementioned agents [23].
Direct injury of endothelial cells that lined the hepatic sinusoids is the mechanism of this type of disease. Endothelial injury promotes erythrocyte extravasation and aggregation into space of Disse, which impairs venous outflow. This leads to sinusoidal congestion. The next step is a fibrotic reaction due to hepatic stellate cell activation, which leads to presinusoidal collagen deposit and central venules obstruction with sinusoidal obstruction syndrome development and centrilobular necrosis. Increased activity of matrix metalloproteinase 2 and 9 may facilitate this process [59, 60].
No direct hepatocellular function alteration was observed for this entity [61, 62]. Histological findings vary from hepatic sinusoidal dilatation to subendothelial fibrin deposits associated with centrilobular necrosis of hepatocytes and low grades of nodular regenerative changes. The macroscopic liver had a bluish marbled appearance. Due to the area affected, sinusoidal obstruction syndrome can be classified into mild, moderate, or severe if less than 1/3, 1/3–2/3, or more than 2/3 of the lobule was affected [7, 63]. There are three phases of sinusoidal obstruction syndrome: acute, subacute, and chronic. Patients may present painful hepatomegaly, short periods of jaundice, weight gain, and encephalopathy. Some patients have splenomegaly and ascites due to portal hypertension. Transient elevation of transaminases and bilirubin can be revealed on blood tests [64, 65].
Transabdominal ultrasound revealed hepatosplenomegaly, decreased flow in portal vein on Doppler mode, ascites, and gallbladder wall thickening. In the hepatobiliary phase of gadoxetic-acid-enhanced MRI, sinusoidal obstruction syndrome can present a diffuse heterogenous reticular pattern. CT and MRI findings also include narrowing of main hepatic veins [66, 67].
Viral hepatitis, Budd-Chiari syndrome, or other forms of DILI must be excluded before sinusoidal obstruction syndrome diagnosis. The evolution of persistent sinusoidal obstruction syndrome is represented by progression to regenerative nodular hyperplasia followed by fibrosis and cirrhosis development. Also, sinusoidal obstruction syndrome can impair chemotherapy response and liver regeneration after resection, which worsens prognosis. Patients with hepatitis C infection, stem cell transplant recipients, and those treated for Hodgkin lymphoma are more susceptible to developing sinusoidal obstruction syndrome after specific chemotherapeutic regimens. In addition, patients with colorectal cancer with hepatic metastasis are more susceptible to sinusoidal obstruction syndrome development if the oxaliplatin or irinotecan treatment is combined with 5-fluorouracil [57, 58, 68].
Sinusoidal obstruction syndrome changes can be reversible after cessation of chemotherapy. Supportive therapy and administration of bevacizumab or defibrotide sodium can reduce liver injury and may improve the efficacy of systemic treatment. Delaying surgery for patients with suspected sinusoidal obstruction syndrome can be an option [69].
Except for the patterns discussed above, other chemotherapy-induced liver disease exists, with a low frequency. For example, estrogens, which are used for advanced prostate cancer, are associated with a high risk of peliosis hepatitis, hepatic adenoma, or hepatocellular carcinoma development [70].
Despite the pattern of liver disease induced by oncologic agents administration, a correct diagnosis and management may reduce the hepatic damage and improve the prognosis of these patients.
Acknowledgments
This work was supported by a grant of the Romanian Ministry of Education and Research, CNCS—UEFISCDI, project number PN-III-P1-1.1-TE-2019-1474, within PNCDI III.
\n',keywords:"oncological therapy, immunotherapy, hepatic toxicity, adverse effects, chemotherapy-induced liver injuries",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/83031.pdf",chapterXML:"https://mts.intechopen.com/source/xml/83031.xml",downloadPdfUrl:"/chapter/pdf-download/83031",previewPdfUrl:"/chapter/pdf-preview/83031",totalDownloads:1,totalViews:0,totalCrossrefCites:0,dateSubmitted:"May 19th 2022",dateReviewed:"June 30th 2022",datePrePublished:"August 9th 2022",datePublished:null,dateFinished:"August 9th 2022",readingETA:"0",abstract:"Drug-induced liver injury (DILI) represents a large group of hepatic disease caused by various treatments, including oncological agents. The liver is an important organ with a role in drug metabolization and excretion and may be affected when oncologic treatment is initiated. The most common liver disease patterns induced by oncologic therapy are steatosis and steatohepatitis, focal nodular hyperplasia, pseudocirrhosis, acute hepatitis, hepatic necrosis, immune-mediated hepatitis, cholestasis, fibrosis and cirrhosis, sinusal obstructive syndrome. In rare cases, chemotherapy treatment is associated with a high-risk hepatic adenoma or hepatocellular carcinoma development. It was demonstrated that the majority of chemotherapy classes can induce these effects on the liver, for example, alkylating agents, antimetabolites, and antitumor antibiotics, but also immunotherapy agents can be involved. The majority of patients that receive oncological treatment who developed liver injury as adverse reactions are identified by symptoms and/or blood test abnormalities. Imaging techniques may be helpful in the diagnosis of oncological-therapy-associated liver injuries, for example, focal nodular hyperplasia, pseudocirrhosis, and sinusal obstructive syndrome. If liver disease occurs as an adverse effect of these agents, the recommendation to stop or continue the administration of oncologic treatment with close monitoring relies upon the risk and benefits of this medication.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/83031",risUrl:"/chapter/ris/83031",signatures:"Victor-Mihai Sacerdoțianu, Costin-Teodor Streba, Ion Rogoveanu, Liliana Streba and Cristin Constantin Vere",book:{id:"11265",type:"book",title:"Hepatotoxicity",subtitle:null,fullTitle:"Hepatotoxicity",slug:null,publishedDate:null,bookSignature:"Dr. Costin Teodor Streba, Dr. Ion Rogoveanu and Dr. Cristin Constantin Vere",coverURL:"https://cdn.intechopen.com/books/images_new/11265.jpg",licenceType:"CC BY 3.0",editedByType:null,isbn:"978-1-80355-781-6",printIsbn:"978-1-80355-780-9",pdfIsbn:"978-1-80355-782-3",isAvailableForWebshopOrdering:!0,editors:[{id:"55546",title:"Dr.",name:"Costin",middleName:"Teodor",surname:"Streba",slug:"costin-streba",fullName:"Costin Streba"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:null,sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Patterns of oncological-therapy-related liver injury",level:"1"},{id:"sec_2_2",title:"2.1 Steatosis and steatohepatitis",level:"2"},{id:"sec_3_2",title:"2.2 Focal nodular hyperplasia",level:"2"},{id:"sec_4_2",title:"2.3 Pseudocirrhosis",level:"2"},{id:"sec_5_2",title:"2.4 Acute hepatitis",level:"2"},{id:"sec_6_2",title:"2.5 Hepatic necrosis",level:"2"},{id:"sec_7_2",title:"2.6 Immune-mediated hepatitis",level:"2"},{id:"sec_8_2",title:"2.7 Cholestasis",level:"2"},{id:"sec_9_2",title:"2.8 Fibrosis and cirrhosis",level:"2"},{id:"sec_10_2",title:"2.9 Sinusal obstructive syndrome",level:"2"},{id:"sec_12",title:"Acknowledgments",level:"1"}],chapterReferences:[{id:"B1",body:'Roth RA, Ganey PE. Intrinsic versus idiosyncratic drug-induced hepatotoxicity—Two villains or one? The Journal of Pharmacology and Experimental Therapeutics. 2010;332(3):692-697. 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Journal of Clinical Oncology. 2015;33(18):2092-2099. DOI: 10.1200/jco.2014.60.0379'},{id:"B69",body:'Gangi A, Lu SC. Chemotherapy-associated liver injury in colorectal cancer. Therapeutic Advances in Gastroenterology. 2020;13:1756284820924194. DOI: 10.1177/1756284820924194'},{id:"B70",body:'Langley RE, Gilbert DC, Duong T, Clarke NW, Nankivell M, Rosen SD, et al. Transdermal oestradiol for androgen suppression in prostate cancer: Long-term cardiovascular outcomes from the randomised prostate adenocarcinoma transcutaneous hormone (PATCH) trial programme. Lancet. 2021;397(10274):581-591. DOI: 10.1016/s0140-6736(21)00100-8'}],footnotes:[],contributors:[{corresp:null,contributorFullName:"Victor-Mihai Sacerdoțianu",address:null,affiliation:'
Department of Gastroenterology, University of Medicine and Pharmacy of Craiova, Romania
Department of Oncology, University of Medicine and Pharmacy of Craiova, Romania
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Department of Gastroenterology, University of Medicine and Pharmacy of Craiova, Romania
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Küden and Ali Küden",coverURL:"https://cdn.intechopen.com/books/images_new/10900.jpg",editedByType:"Edited by",editors:[{id:"200365",title:"Prof.",name:"Ayzin B.",middleName:"B.",surname:"Küden",slug:"ayzin-b.-kuden",fullName:"Ayzin B. Küden"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"5179",title:"Organic Fertilizers",subtitle:"From Basic Concepts to Applied Outcomes",isOpenForSubmission:!1,hash:"93748f3bd6a9c0240d71ffd350d624b1",slug:"organic-fertilizers-from-basic-concepts-to-applied-outcomes",bookSignature:"Marcelo L. Larramendy and Sonia Soloneski",coverURL:"https://cdn.intechopen.com/books/images_new/5179.jpg",editedByType:"Edited by",editors:[{id:"14764",title:"Dr.",name:"Marcelo L.",middleName:null,surname:"Larramendy",slug:"marcelo-l.-larramendy",fullName:"Marcelo L. Larramendy"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],booksByTopicTotal:3,seriesByTopicCollection:[],seriesByTopicTotal:0,mostCitedChapters:[{id:"50478",doi:"10.5772/62473",title:"Bio-Organo-Phos: A Sustainable Approach for Managing Phosphorus Deficiency in Agricultural Soils",slug:"bio-organo-phos-a-sustainable-approach-for-managing-phosphorus-deficiency-in-agricultural-soils",totalDownloads:2092,totalCrossrefCites:8,totalDimensionsCites:18,abstract:"Sustainable agriculture is essential for a positive relationship between supply and demand of food for the growing world population. This relationship was found to be affected by many environmental factors, including biotic and abiotic. From the point of view of crop nutrition, sustainability in the supply of essential nutrients particularly phosphorus is vital. Due to the energy crisis, the fluctuation in the prices of chemical fertilizers, environmental concerns, and cessation in the supply of high quality rock phosphate (RP) are hindering the use of chemical phosphatic fertilizers for sustainable crop production. Therefore, there is great need for a sustainable solution to this problem. It could be solved by employing a strategy to use native low quality RP. It is only possible by composting of organic material in the presence of RP and phosphate solubilizing microorganisms. During composting, most of organic P is mineralized. Due to release of organic acids, P availability to crop plants increases. In this chapter, the importance of economical and sustainable sources of P and comparative efficacy of the use of organic fertilizer containing RP for legumes is critically reviewed.",book:{id:"5179",slug:"organic-fertilizers-from-basic-concepts-to-applied-outcomes",title:"Organic Fertilizers",fullTitle:"Organic Fertilizers - From Basic Concepts to Applied Outcomes"},signatures:"Allah Ditta and Azeem Khalid",authors:[{id:"149636",title:"Dr.",name:"Allah",middleName:null,surname:"Ditta",slug:"allah-ditta",fullName:"Allah Ditta"}]},{id:"50720",doi:"10.5772/62529",title:"Use of Organic Fertilizers to Enhance Soil Fertility, Plant Growth, and Yield in a Tropical Environment",slug:"use-of-organic-fertilizers-to-enhance-soil-fertility-plant-growth-and-yield-in-a-tropical-environmen",totalDownloads:5106,totalCrossrefCites:11,totalDimensionsCites:18,abstract:"Soils rarely have sufficient nutrient for crops to reach their potential yield. Applying organic fertilizers without prior knowledge of their properties may cause yield decline under low application or pollute the environment with excessive application. Understanding the nutrient variability and release pattern of organic fertilizers is crucial to supply plants with sufficient nutrients to achieve optimum productivity, while also rebuilding soil fertility and ensuring protection of environmental and natural resources. This chapter presents the authors’ experiences with different organic amendments under Hawaii's tropical conditions, rather than an intensive literature review. For meat and bone meal by‐products (tankage), batch‐to‐batch variability, nutrient content/release pattern and quality, and plant growth response to the liquid fertilizer produced from tankage were evaluated. For animal livestock, dairy manure (DM) and chicken manure (CM) quality, changes in soil properties, and crop biomass production and root distributions were evaluated. For seaweed, an established bio‐security protocol, nutrient, especially potassium (K) variability, and plant growth and yield response were evaluated in different tropical soils.",book:{id:"5179",slug:"organic-fertilizers-from-basic-concepts-to-applied-outcomes",title:"Organic Fertilizers",fullTitle:"Organic Fertilizers - From Basic Concepts to Applied Outcomes"},signatures:"Amjad A. Ahmad, Theodore J.K. Radovich, Hue V. Nguyen, Jensen\nUyeda, Alton Arakaki, Jeana Cadby, Robert Paull, Jari Sugano and\nGlenn Teves",authors:[{id:"178933",title:"Dr.",name:"Amjad",middleName:"A.",surname:"Ahmad",slug:"amjad-ahmad",fullName:"Amjad Ahmad"},{id:"184973",title:"Dr.",name:"Theodore",middleName:null,surname:"Radovich",slug:"theodore-radovich",fullName:"Theodore Radovich"},{id:"184974",title:"Prof.",name:"Hue",middleName:null,surname:"Nguyen",slug:"hue-nguyen",fullName:"Hue Nguyen"},{id:"184975",title:"MSc.",name:"Jensen",middleName:null,surname:"Uyeda",slug:"jensen-uyeda",fullName:"Jensen Uyeda"},{id:"184976",title:"MSc.",name:"Alton",middleName:null,surname:"Arakaki",slug:"alton-arakaki",fullName:"Alton Arakaki"},{id:"184977",title:"Mr.",name:"Glenn",middleName:null,surname:"Teves",slug:"glenn-teves",fullName:"Glenn Teves"},{id:"184978",title:"MSc.",name:"Jeana",middleName:null,surname:"Cadby",slug:"jeana-cadby",fullName:"Jeana Cadby"},{id:"184979",title:"Prof.",name:"Robert",middleName:null,surname:"Paull",slug:"robert-paull",fullName:"Robert Paull"},{id:"184980",title:"MSc.",name:"Jari",middleName:null,surname:"Sugano",slug:"jari-sugano",fullName:"Jari Sugano"}]},{id:"51059",doi:"10.5772/64195",title:"Organic Fertilizers: Public Health Intricacies",slug:"organic-fertilizers-public-health-intricacies",totalDownloads:2744,totalCrossrefCites:10,totalDimensionsCites:16,abstract:"Organic fertilizers are an essential source for plant nutrients and a soil conditioner in agriculture. Due to its sources and the composition of the organic inputs as well as the type, functionality and failures of the applied treatment process, the organic fertilizer may contain various amounts of infectious agents and toxic chemicals, especially the antibiotics that can be introduced to the subsequent food chain. A range of human and animal pathogens of bacterial, viral and parasitic origin have been the cause of food-borne epidemics due to unintended contamination from organic fertilizers. The use of antibiotics by humans and in animal feeds will also end up in the organic fertilizers. These antibiotics and other chemicals, depending on the sources of the organics, will enhance the likelihood of occurrence of resistant and multi-resistant strains of microorganisms in society and have been reported to cause ecotoxicological environmental effects and disruption of the ecological balance. Exposure of microorganisms to sublethal concentration of antibiotics in the organic products induces antibiotic resistance. WHO guidelines for the reuse of excreta and other organic matters identify the risk for the exposed groups to the reuse of the excreta and are applicable in the use of organic fertilizers in agriculture.",book:{id:"5179",slug:"organic-fertilizers-from-basic-concepts-to-applied-outcomes",title:"Organic Fertilizers",fullTitle:"Organic Fertilizers - From Basic Concepts to Applied Outcomes"},signatures:"Anthony A. Adegoke, Oluyemi O. Awolusi and Thor A. Stenström",authors:[{id:"175730",title:"Dr.",name:"Anthony Ayodeji",middleName:null,surname:"Adegoke",slug:"anthony-ayodeji-adegoke",fullName:"Anthony Ayodeji Adegoke"},{id:"180623",title:"Dr.",name:"Oluyemi Olatunji",middleName:null,surname:"Awolusi",slug:"oluyemi-olatunji-awolusi",fullName:"Oluyemi Olatunji Awolusi"},{id:"186321",title:"Prof.",name:"Thor Axel",middleName:null,surname:"Stenstrom",slug:"thor-axel-stenstrom",fullName:"Thor Axel Stenstrom"}]},{id:"50516",doi:"10.5772/63047",title:"Soil Amendments for Agricultural Production",slug:"soil-amendments-for-agricultural-production",totalDownloads:2384,totalCrossrefCites:5,totalDimensionsCites:10,abstract:"The word organic, applied to fertilizers, indicates that the nutrients are derived from the remains or by‐products of a once‐living organism. Farmers are continually searching for alternatives to synthetic inorganic fertilizers to alleviate the escalating production costs associated with the increasing costs of energy and fertilizers and the problems of soil and surface water deterioration associated with intensive use and release of inorganic fertilizers such as N and P fertilizers. One of the advantages of organic fertilizers is that they provide their nutrients especially the principal nutrients (NPK) to growing plants over a long period of time in a slow release process. The soil has to be moist and warm enough to allow soil microorganisms to decompose and breakdown the complex forms of organic fertilizers. Generally, the application of organic amendments to agricultural soils makes good use of natural resources and reduces the need of synthetic inorganic fertilizers. Soil structure, nutrient composition, and microbiological activity of soil are usually increased following the application of organic amendments. This is because of the presence of sugars and amino acids as simple molecules in organic amendments that contribute to microbiological activity and fertility and elevated levels of enzymes secreted by soil microbes. To investigate the soil microbiological activity after the addition of soil amendments, three enzymes that control the C, N, and P cycles should be monitored in the plant rhizosphere zone, which is defined as the zone of increased microbial and enzyme activity where soil and root make contact. An increase of organic waste originated from different humans and productive activities is a continuous concern. Waste application (i.e., municipal sewage sludge, chicken manure, horse manure, and cow manure) to soil is proposed as a solution to disposal problem. This practice is popular in the agricultural fields because of the value of this waste as organic fertilizer. At KSU, numerous studies have been conducted on organic soil amendments and their impact on crop yield and quality, soil erosion and nutrient availability, soil enzymes activity, and bioremediation of heavy metals in organic amendments.",book:{id:"5179",slug:"organic-fertilizers-from-basic-concepts-to-applied-outcomes",title:"Organic Fertilizers",fullTitle:"Organic Fertilizers - From Basic Concepts to Applied Outcomes"},signatures:"George F. Antonious",authors:[{id:"174916",title:"Dr.",name:"George",middleName:"Fouad",surname:"Antonious",slug:"george-antonious",fullName:"George Antonious"}]},{id:"50233",doi:"10.5772/62388",title:"Integrated Use of Phosphorus, Animal Manures and Biofertilizers Improve Maize Productivity under Semiarid Condition",slug:"integrated-use-of-phosphorus-animal-manures-and-biofertilizers-improve-maize-productivity-under-semi",totalDownloads:2477,totalCrossrefCites:9,totalDimensionsCites:10,abstract:"Phosphorus unavailability and lack of organic matter in the soils under semiarid condition are the major reasons for low crop productivity. Field trial was conducted to investigate the impact of different animal manures (poultry, cattle, and sheep manures) and phosphorus levels (40, 80, 120, and 160 kg P2O5 ha−1) on yield and yield components of hybrid maize (CS-200) with (+) and without (−) phosphate-solubilizing bacteria (PSB) seed treatment at the Agronomy Research Farm of The University of Agriculture Peshawar, during summer 2014. Our results confirmed that the application of poultry manure significantly (P ≤ 0.05) increased yield and yield components of maize. Phosphorus applied at the rate of 120 kg P2O5 ha−1 increased ear length, grains ear−1, and shelling percentage, while the highest rate of 160 kg P ha−1 increased grains weight, grain yield, and harvest index. Maize seeds treated with PSB (+) before sowing had produced higher yield and yield components than untreated seeds (−). We concluded from this study that combined application of 160 kg P2O5 ha−1 + poultry manure and seed treatment with PSB (+) could improve crop productivity and profitability under semiarid condition.",book:{id:"5179",slug:"organic-fertilizers-from-basic-concepts-to-applied-outcomes",title:"Organic Fertilizers",fullTitle:"Organic Fertilizers - From Basic Concepts to Applied Outcomes"},signatures:"Dr. Amanullah and Shah Khalid",authors:[{id:"178825",title:"Dr.",name:"Dr.",middleName:null,surname:"Amanullah",slug:"dr.-amanullah",fullName:"Dr. Amanullah"}]}],mostDownloadedChaptersLast30Days:[{id:"50720",title:"Use of Organic Fertilizers to Enhance Soil Fertility, Plant Growth, and Yield in a Tropical Environment",slug:"use-of-organic-fertilizers-to-enhance-soil-fertility-plant-growth-and-yield-in-a-tropical-environmen",totalDownloads:5116,totalCrossrefCites:11,totalDimensionsCites:18,abstract:"Soils rarely have sufficient nutrient for crops to reach their potential yield. Applying organic fertilizers without prior knowledge of their properties may cause yield decline under low application or pollute the environment with excessive application. Understanding the nutrient variability and release pattern of organic fertilizers is crucial to supply plants with sufficient nutrients to achieve optimum productivity, while also rebuilding soil fertility and ensuring protection of environmental and natural resources. This chapter presents the authors’ experiences with different organic amendments under Hawaii's tropical conditions, rather than an intensive literature review. For meat and bone meal by‐products (tankage), batch‐to‐batch variability, nutrient content/release pattern and quality, and plant growth response to the liquid fertilizer produced from tankage were evaluated. For animal livestock, dairy manure (DM) and chicken manure (CM) quality, changes in soil properties, and crop biomass production and root distributions were evaluated. For seaweed, an established bio‐security protocol, nutrient, especially potassium (K) variability, and plant growth and yield response were evaluated in different tropical soils.",book:{id:"5179",slug:"organic-fertilizers-from-basic-concepts-to-applied-outcomes",title:"Organic Fertilizers",fullTitle:"Organic Fertilizers - From Basic Concepts to Applied Outcomes"},signatures:"Amjad A. Ahmad, Theodore J.K. Radovich, Hue V. Nguyen, Jensen\nUyeda, Alton Arakaki, Jeana Cadby, Robert Paull, Jari Sugano and\nGlenn Teves",authors:[{id:"178933",title:"Dr.",name:"Amjad",middleName:"A.",surname:"Ahmad",slug:"amjad-ahmad",fullName:"Amjad Ahmad"},{id:"184973",title:"Dr.",name:"Theodore",middleName:null,surname:"Radovich",slug:"theodore-radovich",fullName:"Theodore Radovich"},{id:"184974",title:"Prof.",name:"Hue",middleName:null,surname:"Nguyen",slug:"hue-nguyen",fullName:"Hue Nguyen"},{id:"184975",title:"MSc.",name:"Jensen",middleName:null,surname:"Uyeda",slug:"jensen-uyeda",fullName:"Jensen Uyeda"},{id:"184976",title:"MSc.",name:"Alton",middleName:null,surname:"Arakaki",slug:"alton-arakaki",fullName:"Alton Arakaki"},{id:"184977",title:"Mr.",name:"Glenn",middleName:null,surname:"Teves",slug:"glenn-teves",fullName:"Glenn Teves"},{id:"184978",title:"MSc.",name:"Jeana",middleName:null,surname:"Cadby",slug:"jeana-cadby",fullName:"Jeana Cadby"},{id:"184979",title:"Prof.",name:"Robert",middleName:null,surname:"Paull",slug:"robert-paull",fullName:"Robert Paull"},{id:"184980",title:"MSc.",name:"Jari",middleName:null,surname:"Sugano",slug:"jari-sugano",fullName:"Jari Sugano"}]},{id:"51059",title:"Organic Fertilizers: Public Health Intricacies",slug:"organic-fertilizers-public-health-intricacies",totalDownloads:2749,totalCrossrefCites:10,totalDimensionsCites:16,abstract:"Organic fertilizers are an essential source for plant nutrients and a soil conditioner in agriculture. Due to its sources and the composition of the organic inputs as well as the type, functionality and failures of the applied treatment process, the organic fertilizer may contain various amounts of infectious agents and toxic chemicals, especially the antibiotics that can be introduced to the subsequent food chain. A range of human and animal pathogens of bacterial, viral and parasitic origin have been the cause of food-borne epidemics due to unintended contamination from organic fertilizers. The use of antibiotics by humans and in animal feeds will also end up in the organic fertilizers. These antibiotics and other chemicals, depending on the sources of the organics, will enhance the likelihood of occurrence of resistant and multi-resistant strains of microorganisms in society and have been reported to cause ecotoxicological environmental effects and disruption of the ecological balance. Exposure of microorganisms to sublethal concentration of antibiotics in the organic products induces antibiotic resistance. WHO guidelines for the reuse of excreta and other organic matters identify the risk for the exposed groups to the reuse of the excreta and are applicable in the use of organic fertilizers in agriculture.",book:{id:"5179",slug:"organic-fertilizers-from-basic-concepts-to-applied-outcomes",title:"Organic Fertilizers",fullTitle:"Organic Fertilizers - From Basic Concepts to Applied Outcomes"},signatures:"Anthony A. Adegoke, Oluyemi O. Awolusi and Thor A. Stenström",authors:[{id:"175730",title:"Dr.",name:"Anthony Ayodeji",middleName:null,surname:"Adegoke",slug:"anthony-ayodeji-adegoke",fullName:"Anthony Ayodeji Adegoke"},{id:"180623",title:"Dr.",name:"Oluyemi Olatunji",middleName:null,surname:"Awolusi",slug:"oluyemi-olatunji-awolusi",fullName:"Oluyemi Olatunji Awolusi"},{id:"186321",title:"Prof.",name:"Thor Axel",middleName:null,surname:"Stenstrom",slug:"thor-axel-stenstrom",fullName:"Thor Axel Stenstrom"}]},{id:"50612",title:"Green Manures and Crop Residues as Source of Nutrients in Tropical Environment",slug:"green-manures-and-crop-residues-as-source-of-nutrients-in-tropical-environment",totalDownloads:2608,totalCrossrefCites:4,totalDimensionsCites:8,abstract:"Tropical areas have prevalence of soils with low fertility, which makes the management of soil fertility a necessary practice to maintain a farming system economically and environmentally sustainable. The purpose of this chapter is to demonstrate the importance of green manure and the use of crop residues as management for soil fertility. We highlight the potential of these practices to increase/sustain productivity by providing nutrients. First, we made a short review on the main factors influencing the decomposition and mineralization processes. Subsequently, we discuss green manure techniques, presenting the main green manures, criteria for choosing, managements, potential for nutrient accumulation, and advantages and disadvantages of this practice. Finally, we use some examples to demonstrate the potential nutrient supply of crop residues from the main crops grown in the tropics. The difficulties and limitations involved are also discussed.",book:{id:"5179",slug:"organic-fertilizers-from-basic-concepts-to-applied-outcomes",title:"Organic Fertilizers",fullTitle:"Organic Fertilizers - From Basic Concepts to Applied Outcomes"},signatures:"Rafael Vasconcelos Valadares, Lucas de Ávila‐Silva, Rafael da Silva Teixeira, Rodrigo Nogueira de Sousa and Leonardus Vergütz",authors:[{id:"179932",title:"M.Sc.",name:"Rafael",middleName:null,surname:"Vasconcelos Valadares",slug:"rafael-vasconcelos-valadares",fullName:"Rafael Vasconcelos Valadares"},{id:"183947",title:"MSc.",name:"Lucas",middleName:null,surname:"De Avila-Silva",slug:"lucas-de-avila-silva",fullName:"Lucas De Avila-Silva"},{id:"183948",title:"MSc.",name:"Rafael",middleName:null,surname:"Da Silva Teixeira",slug:"rafael-da-silva-teixeira",fullName:"Rafael Da Silva Teixeira"},{id:"183949",title:"Mr.",name:"Rodrigo",middleName:null,surname:"Nogueira De Sousa",slug:"rodrigo-nogueira-de-sousa",fullName:"Rodrigo Nogueira De Sousa"},{id:"184785",title:"Prof.",name:"Leonardus",middleName:null,surname:"Vergutz",slug:"leonardus-vergutz",fullName:"Leonardus Vergutz"}]},{id:"50167",title:"On-Farm-Produced Organic Amendments on Maintaining and Enhancing Soil Fertility and Nitrogen Availability in Organic or Low Input Agriculture",slug:"on-farm-produced-organic-amendments-on-maintaining-and-enhancing-soil-fertility-and-nitrogen-availab",totalDownloads:1631,totalCrossrefCites:2,totalDimensionsCites:3,abstract:"Maintaining and enhancing soil fertility are key issues for sustainability in an agricultural system with organic or low input methods. On-farm–produced green manure as a source of soil organic matter (SOM) plays a critical role in long-term productivity. But producing green manure requires land and water; thus, increasing biodiversity, such as by intercropping with green manure crops, could be an approach to enhance the efficiency of renewable resources especially in developing countries. This article discusses soil fertility and its maintenance and enhancement with leguminous intercropping from four points of view: soil fertility and organic matter function, leguminous green manure, intercropping principles, and soil conservation. Important contributions of leguminous intercropping include SOM enhancement and fertility building, biological nitrogen (N) and other plant nutrition availability. Under a well-designed and managed system, competition between the target and intercropping crops can be reduced. The plant uptake efficiency of biologically fixed N is estimated to be double that of industrial N fertilizers. After N-rich plant residues are incorporated into soil, the carbon (C):nitrogen ratio of added straw decreases. Another high mitigation potential of legume intercropping lies in soil conservation by preventing soil and water erosion. Many opportunities exist to introduce legumes in short-term rotation, intercropping, living mulch, and cover crops in an organically managed farm system. Worldwide, long-term soil fertility enhancement remains a challenge due to the current world population and agricultural practices. Cropping system including legumes is a step in the right direction to meeting the needs of food security and sustainability.",book:{id:"5179",slug:"organic-fertilizers-from-basic-concepts-to-applied-outcomes",title:"Organic Fertilizers",fullTitle:"Organic Fertilizers - From Basic Concepts to Applied Outcomes"},signatures:"Yani Nin, Pinchun Diao, Qian Wang, Qingzhong Zhang, Ziliang\nZhao and Zhifang Li",authors:[{id:"178869",title:"Dr.",name:"Zhifang",middleName:null,surname:"Li",slug:"zhifang-li",fullName:"Zhifang Li"},{id:"180022",title:"BSc.",name:"Yani",middleName:null,surname:"Ning",slug:"yani-ning",fullName:"Yani Ning"},{id:"184348",title:"MSc.",name:"Pinchun",middleName:null,surname:"Diao",slug:"pinchun-diao",fullName:"Pinchun Diao"},{id:"184349",title:"Prof.",name:"Qian",middleName:null,surname:"Wang",slug:"qian-wang",fullName:"Qian Wang"},{id:"184350",title:"Prof.",name:"Qingzhong",middleName:null,surname:"Zhang",slug:"qingzhong-zhang",fullName:"Qingzhong Zhang"},{id:"184351",title:"MSc.",name:"Ziliang",middleName:null,surname:"Zhao",slug:"ziliang-zhao",fullName:"Ziliang Zhao"}]},{id:"50244",title:"An Overview of the Studies on Biochar Fertilizer Carried Out at the Beginning of the Twentieth Century in Japan",slug:"an-overview-of-the-studies-on-biochar-fertilizer-carried-out-at-the-beginning-of-the-twentieth-centu",totalDownloads:2062,totalCrossrefCites:1,totalDimensionsCites:2,abstract:"Biochar is a recently coined term for charred organic matter used as a soil amendment. Although the term is relatively new, the substance has been used for a long time throughout the world, including Japan. After we read a Japanese book entitled Nibai Shukaku Tenri Nouhou (How to Double Crop Yield by Almighty Farming System) originally published in 1912, we found that there were conflicting opinions between the author (Mr. Katsugoro Oyaizu) and soil scientists of the time (Dr. Gintaro Daikuhara and others) on the benefits of the use of biochar fertilizer. Previous publications on this topic have been written in Japanese from a sociological viewpoint. By referring to the literature published at the beginning of the twentieth century in Japan, we attempt to shed light on the conflict between traditional knowledge of biochar fertilizer and new concepts of soil science imported from the Western countries. We also describe briefly the socioeconomic impacts on the use of biochar fertilizer in the later generations.",book:{id:"5179",slug:"organic-fertilizers-from-basic-concepts-to-applied-outcomes",title:"Organic Fertilizers",fullTitle:"Organic Fertilizers - From Basic Concepts to Applied Outcomes"},signatures:"Naoki Moritsuka and Kaori Matsuoka",authors:[{id:"179714",title:"Dr.",name:"Naoki",middleName:null,surname:"Moritsuka",slug:"naoki-moritsuka",fullName:"Naoki Moritsuka"}]}],onlineFirstChaptersFilter:{topicId:"338",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:107,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:139,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:122,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:21,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:10,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:"11",title:"Biochemistry",doi:"10.5772/intechopen.72877",issn:"2632-0983",scope:"Biochemistry, the study of chemical transformations occurring within living organisms, impacts all areas of life sciences, from molecular crystallography and genetics to ecology, medicine, and population biology. Biochemistry examines macromolecules - proteins, nucleic acids, carbohydrates, and lipids – and their building blocks, structures, functions, and interactions. Much of biochemistry is devoted to enzymes, proteins that catalyze chemical reactions, enzyme structures, mechanisms of action and their roles within cells. Biochemistry also studies small signaling molecules, coenzymes, inhibitors, vitamins, and hormones, which play roles in life processes. Biochemical experimentation, besides coopting classical chemistry methods, e.g., chromatography, adopted new techniques, e.g., X-ray diffraction, electron microscopy, NMR, radioisotopes, and developed sophisticated microbial genetic tools, e.g., auxotroph mutants and their revertants, fermentation, etc. More recently, biochemistry embraced the ‘big data’ omics systems. Initial biochemical studies have been exclusively analytic: dissecting, purifying, and examining individual components of a biological system; in the apt words of Efraim Racker (1913 –1991), “Don’t waste clean thinking on dirty enzymes.” Today, however, biochemistry is becoming more agglomerative and comprehensive, setting out to integrate and describe entirely particular biological systems. The ‘big data’ metabolomics can define the complement of small molecules, e.g., in a soil or biofilm sample; proteomics can distinguish all the comprising proteins, e.g., serum; metagenomics can identify all the genes in a complex environment, e.g., the bovine rumen. This Biochemistry Series will address the current research on biomolecules and the emerging trends with great promise.",coverUrl:"https://cdn.intechopen.com/series/covers/11.jpg",latestPublicationDate:"August 2nd, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:33,editor:{id:"31610",title:"Dr.",name:"Miroslav",middleName:null,surname:"Blumenberg",slug:"miroslav-blumenberg",fullName:"Miroslav Blumenberg",profilePictureURL:"https://mts.intechopen.com/storage/users/31610/images/system/31610.jpg",biography:"Miroslav Blumenberg, Ph.D., was born in Subotica and received his BSc in Belgrade, Yugoslavia. He completed his Ph.D. at MIT in Organic Chemistry; he followed up his Ph.D. with two postdoctoral study periods at Stanford University. Since 1983, he has been a faculty member of the RO Perelman Department of Dermatology, NYU School of Medicine, where he is codirector of a training grant in cutaneous biology. Dr. Blumenberg’s research is focused on the epidermis, expression of keratin genes, transcription profiling, keratinocyte differentiation, inflammatory diseases and cancers, and most recently the effects of the microbiome on the skin. He has published more than 100 peer-reviewed research articles and graduated numerous Ph.D. and postdoctoral students.",institutionString:null,institution:{name:"New York University Langone Medical Center",institutionURL:null,country:{name:"United States of America"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:4,paginationItems:[{id:"14",title:"Cell and Molecular Biology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/14.jpg",isOpenForSubmission:!0,editor:{id:"165627",title:"Dr.",name:"Rosa María",middleName:null,surname:"Martínez-Espinosa",slug:"rosa-maria-martinez-espinosa",fullName:"Rosa María Martínez-Espinosa",profilePictureURL:"https://mts.intechopen.com/storage/users/165627/images/system/165627.jpeg",biography:"Dr. Rosa María Martínez-Espinosa has been a Spanish Full Professor since 2020 (Biochemistry and Molecular Biology) and is currently Vice-President of International Relations and Cooperation development and leader of the research group 'Applied Biochemistry” (University of Alicante, Spain). Other positions she has held at the university include Vice-Dean of Master Programs, Vice-Dean of the Degree in Biology and Vice-Dean for Mobility and Enterprise and Engagement at the Faculty of Science (University of Alicante). She received her Bachelor in Biology in 1998 (University of Alicante) and her PhD in 2003 (Biochemistry, University of Alicante). She undertook post-doctoral research at the University of East Anglia (Norwich, U.K. 2004-2005; 2007-2008).\nHer multidisciplinary research focuses on investigating archaea and their potential applications in biotechnology. She has an H-index of 21. She has authored one patent and has published more than 70 indexed papers and around 60 book chapters.\nShe has contributed to more than 150 national and international meetings during the last 15 years. Her research interests include archaea metabolism, enzymes purification and characterization, gene regulation, carotenoids and bioplastics production, antioxidant\ncompounds, waste water treatments, and brines bioremediation.\nRosa María’s other roles include editorial board member for several journals related\nto biochemistry, reviewer for more than 60 journals (biochemistry, molecular biology, biotechnology, chemistry and microbiology) and president of several organizing committees in international meetings related to the N-cycle or respiratory processes.",institutionString:null,institution:{name:"University of Alicante",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null},{id:"15",title:"Chemical Biology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/15.jpg",isOpenForSubmission:!0,editor:{id:"441442",title:"Dr.",name:"Şükrü",middleName:null,surname:"Beydemir",slug:"sukru-beydemir",fullName:"Şükrü Beydemir",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003GsUoIQAV/Profile_Picture_1634557147521",biography:"Dr. Şükrü Beydemir obtained a BSc in Chemistry in 1995 from Yüzüncü Yıl University, MSc in Biochemistry in 1998, and PhD in Biochemistry in 2002 from Atatürk University, Turkey. He performed post-doctoral studies at Max-Planck Institute, Germany, and University of Florence, Italy in addition to making several scientific visits abroad. He currently works as a Full Professor of Biochemistry in the Faculty of Pharmacy, Anadolu University, Turkey. Dr. Beydemir has published over a hundred scientific papers spanning protein biochemistry, enzymology and medicinal chemistry, reviews, book chapters and presented several conferences to scientists worldwide. He has received numerous publication awards from various international scientific councils. He serves in the Editorial Board of several international journals. Dr. Beydemir is also Rector of Bilecik Şeyh Edebali University, Turkey.",institutionString:null,institution:{name:"Anadolu University",institutionURL:null,country:{name:"Turkey"}}},editorTwo:{id:"13652",title:"Prof.",name:"Deniz",middleName:null,surname:"Ekinci",slug:"deniz-ekinci",fullName:"Deniz Ekinci",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYLT1QAO/Profile_Picture_1634557223079",biography:"Dr. Deniz Ekinci obtained a BSc in Chemistry in 2004, MSc in Biochemistry in 2006, and PhD in Biochemistry in 2009 from Atatürk University, Turkey. He studied at Stetson University, USA, in 2007-2008 and at the Max Planck Institute of Molecular Cell Biology and Genetics, Germany, in 2009-2010. Dr. Ekinci currently works as a Full Professor of Biochemistry in the Faculty of Agriculture and is the Head of the Enzyme and Microbial Biotechnology Division, Ondokuz Mayıs University, Turkey. He is a member of the Turkish Biochemical Society, American Chemical Society, and German Genetics society. Dr. Ekinci published around ninety scientific papers, reviews and book chapters, and presented several conferences to scientists. He has received numerous publication awards from several scientific councils. Dr. Ekinci serves as the Editor in Chief of four international books and is involved in the Editorial Board of several international journals.",institutionString:null,institution:{name:"Ondokuz Mayıs University",institutionURL:null,country:{name:"Turkey"}}},editorThree:null},{id:"17",title:"Metabolism",coverUrl:"https://cdn.intechopen.com/series_topics/covers/17.jpg",isOpenForSubmission:!0,editor:{id:"138626",title:"Dr.",name:"Yannis",middleName:null,surname:"Karamanos",slug:"yannis-karamanos",fullName:"Yannis Karamanos",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002g6Jv2QAE/Profile_Picture_1629356660984",biography:"Yannis Karamanos, born in Greece in 1953, completed his pre-graduate studies at the Université Pierre et Marie Curie, Paris, then his Masters and Doctoral degree at the Université de Lille (1983). He was associate professor at the University of Limoges (1987) before becoming full professor of biochemistry at the Université d’Artois (1996). He worked on the structure-function relationships of glycoconjugates and his main project was the investigations on the biological roles of the de-N-glycosylation enzymes (Endo-N-acetyl-β-D-glucosaminidase and peptide-N4-(N-acetyl-β-glucosaminyl) asparagine amidase). From 2002 he contributes to the understanding of the Blood-brain barrier functioning using proteomics approaches. He has published more than 70 papers. His teaching areas are energy metabolism and regulation, integration and organ specialization and metabolic adaptation.",institutionString:null,institution:{name:"Artois University",institutionURL:null,country:{name:"France"}}},editorTwo:null,editorThree:null},{id:"18",title:"Proteomics",coverUrl:"https://cdn.intechopen.com/series_topics/covers/18.jpg",isOpenForSubmission:!0,editor:{id:"200689",title:"Prof.",name:"Paolo",middleName:null,surname:"Iadarola",slug:"paolo-iadarola",fullName:"Paolo Iadarola",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSCl8QAG/Profile_Picture_1623568118342",biography:"Paolo Iadarola graduated with a degree in Chemistry from the University of Pavia (Italy) in July 1972. He then worked as an Assistant Professor at the Faculty of Science of the same University until 1984. In 1985, Prof. Iadarola became Associate Professor at the Department of Biology and Biotechnologies of the University of Pavia and retired in October 2017. Since then, he has been working as an Adjunct Professor in the same Department at the University of Pavia. His research activity during the first years was primarily focused on the purification and structural characterization of enzymes from animal and plant sources. During this period, Prof. Iadarola familiarized himself with the conventional techniques used in column chromatography, spectrophotometry, manual Edman degradation, and electrophoresis). Since 1995, he has been working on: i) the determination in biological fluids (serum, urine, bronchoalveolar lavage, sputum) of proteolytic activities involved in the degradation processes of connective tissue matrix, and ii) on the identification of biological markers of lung diseases. In this context, he has developed and validated new methodologies (e.g., Capillary Electrophoresis coupled to Laser-Induced Fluorescence, CE-LIF) whose application enabled him to determine both the amounts of biochemical markers (Desmosines) in urine/serum of patients affected by Chronic Obstructive Pulmonary Disease (COPD) and the activity of proteolytic enzymes (Human Neutrophil Elastase, Cathepsin G, Pseudomonas aeruginosa elastase) in sputa of these patients. More recently, Prof. Iadarola was involved in developing techniques such as two-dimensional electrophoresis coupled to liquid chromatography/mass spectrometry (2DE-LC/MS) for the proteomic analysis of biological fluids aimed at the identification of potential biomarkers of different lung diseases. He is the author of about 150 publications (According to Scopus: H-Index: 23; Total citations: 1568- According to WOS: H-Index: 20; Total Citations: 1296) of peer-reviewed international journals. He is a Consultant Reviewer for several journals, including the Journal of Chromatography A, Journal of Chromatography B, Plos ONE, Proteomes, International Journal of Molecular Science, Biotech, Electrophoresis, and others. He is also Associate Editor of Biotech.",institutionString:null,institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorTwo:{id:"201414",title:"Dr.",name:"Simona",middleName:null,surname:"Viglio",slug:"simona-viglio",fullName:"Simona Viglio",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRKDHQA4/Profile_Picture_1630402531487",biography:"Simona Viglio is an Associate Professor of Biochemistry at the Department of Molecular Medicine at the University of Pavia. She has been working since 1995 on the determination of proteolytic enzymes involved in the degradation process of connective tissue matrix and on the identification of biological markers of lung diseases. She gained considerable experience in developing and validating new methodologies whose applications allowed her to determine both the amount of biomarkers (Desmosine and Isodesmosine) in the urine of patients affected by COPD, and the activity of proteolytic enzymes (HNE, Cathepsin G, Pseudomonas aeruginosa elastase) in the sputa of these patients. Simona Viglio was also involved in research dealing with the supplementation of amino acids in patients with brain injury and chronic heart failure. She is presently engaged in the development of 2-DE and LC-MS techniques for the study of proteomics in biological fluids. The aim of this research is the identification of potential biomarkers of lung diseases. She is an author of about 90 publications (According to Scopus: H-Index: 23; According to WOS: H-Index: 20) on peer-reviewed journals, a member of the “Società Italiana di Biochimica e Biologia Molecolare,“ and a Consultant Reviewer for International Journal of Molecular Science, Journal of Chromatography A, COPD, Plos ONE and Nutritional Neuroscience.",institutionString:null,institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorThree:null}]},overviewPageOFChapters:{paginationCount:42,paginationItems:[{id:"82914",title:"Glance on the Critical Role of IL-23 Receptor Gene Variations in Inflammation-Induced Carcinogenesis",doi:"10.5772/intechopen.105049",signatures:"Mohammed El-Gedamy",slug:"glance-on-the-critical-role-of-il-23-receptor-gene-variations-in-inflammation-induced-carcinogenesis",totalDownloads:8,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Chemokines Updates",coverURL:"https://cdn.intechopen.com/books/images_new/11672.jpg",subseries:{id:"18",title:"Proteomics"}}},{id:"82875",title:"Lipidomics as a Tool in the Diagnosis and Clinical Therapy",doi:"10.5772/intechopen.105857",signatures:"María Elizbeth Alvarez Sánchez, Erick Nolasco Ontiveros, Rodrigo Arreola, Adriana Montserrat Espinosa González, Ana María García Bores, Roberto Eduardo López Urrutia, Ignacio Peñalosa Castro, María del Socorro Sánchez Correa and Edgar Antonio Estrella Parra",slug:"lipidomics-as-a-tool-in-the-diagnosis-and-clinical-therapy",totalDownloads:7,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Fatty Acids - Recent Advances",coverURL:"https://cdn.intechopen.com/books/images_new/11669.jpg",subseries:{id:"17",title:"Metabolism"}}},{id:"82440",title:"Lipid Metabolism and Associated Molecular Signaling Events in Autoimmune Disease",doi:"10.5772/intechopen.105746",signatures:"Mohan Vanditha, Sonu Das and Mathew John",slug:"lipid-metabolism-and-associated-molecular-signaling-events-in-autoimmune-disease",totalDownloads:17,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Fatty Acids - Recent Advances",coverURL:"https://cdn.intechopen.com/books/images_new/11669.jpg",subseries:{id:"17",title:"Metabolism"}}},{id:"82483",title:"Oxidative Stress in Cardiovascular Diseases",doi:"10.5772/intechopen.105891",signatures:"Laura Mourino-Alvarez, Tamara Sastre-Oliva, Nerea Corbacho-Alonso and Maria G. Barderas",slug:"oxidative-stress-in-cardiovascular-diseases",totalDownloads:10,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Importance of Oxidative Stress and Antioxidant System in Health and Disease",coverURL:"https://cdn.intechopen.com/books/images_new/11671.jpg",subseries:{id:"15",title:"Chemical Biology"}}}]},overviewPagePublishedBooks:{paginationCount:33,paginationItems:[{type:"book",id:"7006",title:"Biochemistry and Health Benefits of Fatty Acids",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7006.jpg",slug:"biochemistry-and-health-benefits-of-fatty-acids",publishedDate:"December 19th 2018",editedByType:"Edited by",bookSignature:"Viduranga Waisundara",hash:"c93a00abd68b5eba67e5e719f67fd20b",volumeInSeries:1,fullTitle:"Biochemistry and Health Benefits of Fatty Acids",editors:[{id:"194281",title:"Dr.",name:"Viduranga Y.",middleName:null,surname:"Waisundara",slug:"viduranga-y.-waisundara",fullName:"Viduranga Y. Waisundara",profilePictureURL:"https://mts.intechopen.com/storage/users/194281/images/system/194281.jpg",biography:"Dr. Viduranga Waisundara obtained her Ph.D. in Food Science\nand Technology from the Department of Chemistry, National\nUniversity of Singapore, in 2010. She was a lecturer at Temasek Polytechnic, Singapore from July 2009 to March 2013.\nShe relocated to her motherland of Sri Lanka and spearheaded the Functional Food Product Development Project at the\nNational Institute of Fundamental Studies from April 2013 to\nOctober 2016. She was a senior lecturer on a temporary basis at the Department of\nFood Technology, Faculty of Technology, Rajarata University of Sri Lanka. She is\ncurrently Deputy Principal of the Australian College of Business and Technology –\nKandy Campus, Sri Lanka. She is also the Global Harmonization Initiative (GHI)",institutionString:"Australian College of Business & Technology",institution:{name:"Kobe College",institutionURL:null,country:{name:"Japan"}}}]},{type:"book",id:"6820",title:"Keratin",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/6820.jpg",slug:"keratin",publishedDate:"December 19th 2018",editedByType:"Edited by",bookSignature:"Miroslav Blumenberg",hash:"6def75cd4b6b5324a02b6dc0359896d0",volumeInSeries:2,fullTitle:"Keratin",editors:[{id:"31610",title:"Dr.",name:"Miroslav",middleName:null,surname:"Blumenberg",slug:"miroslav-blumenberg",fullName:"Miroslav Blumenberg",profilePictureURL:"https://mts.intechopen.com/storage/users/31610/images/system/31610.jpg",biography:"Miroslav Blumenberg, Ph.D., was born in Subotica and received his BSc in Belgrade, Yugoslavia. He completed his Ph.D. at MIT in Organic Chemistry; he followed up his Ph.D. with two postdoctoral study periods at Stanford University. Since 1983, he has been a faculty member of the RO Perelman Department of Dermatology, NYU School of Medicine, where he is codirector of a training grant in cutaneous biology. Dr. Blumenberg’s research is focused on the epidermis, expression of keratin genes, transcription profiling, keratinocyte differentiation, inflammatory diseases and cancers, and most recently the effects of the microbiome on the skin. He has published more than 100 peer-reviewed research articles and graduated numerous Ph.D. and postdoctoral students.",institutionString:null,institution:{name:"New York University Langone Medical Center",institutionURL:null,country:{name:"United States of America"}}}]},{type:"book",id:"7978",title:"Vitamin A",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7978.jpg",slug:"vitamin-a",publishedDate:"May 15th 2019",editedByType:"Edited by",bookSignature:"Leila Queiroz Zepka, Veridiana Vera de Rosso and Eduardo Jacob-Lopes",hash:"dad04a658ab9e3d851d23705980a688b",volumeInSeries:3,fullTitle:"Vitamin A",editors:[{id:"261969",title:"Dr.",name:"Leila",middleName:null,surname:"Queiroz Zepka",slug:"leila-queiroz-zepka",fullName:"Leila Queiroz Zepka",profilePictureURL:"https://mts.intechopen.com/storage/users/261969/images/system/261969.png",biography:"Prof. Dr. Leila Queiroz Zepka is currently an associate professor in the Department of Food Technology and Science, Federal University of Santa Maria, Brazil. She has more than fifteen years of teaching and research experience. She has published more than 550 scientific publications/communications, including 15 books, 50 book chapters, 100 original research papers, 380 research communications in national and international conferences, and 12 patents. She is a member of the editorial board of five journals and acts as a reviewer for several national and international journals. 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Presently he is working as a associate professor in the Dept of Prosthodontics, Rural Dental College, Loni and maintains a successful private practice specialising in Implantology at Rahata.\n\nEmail: drdeepak_mvikhe@yahoo.com..................",institutionString:null,institution:{name:"Pravara Institute of Medical Sciences",country:{name:"India"}}},{id:"204110",title:"Dr.",name:"Ahmed A.",middleName:null,surname:"Madfa",slug:"ahmed-a.-madfa",fullName:"Ahmed A. Madfa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204110/images/system/204110.jpg",biography:"Dr. Madfa is currently Associate Professor of Endodontics at Thamar University and a visiting lecturer at Sana'a University and University of Sciences and Technology. He has more than 6 years of experience in teaching. His research interests include root canal morphology, functionally graded concept, dental biomaterials, epidemiology and dental education, biomimetic restoration, finite element analysis and endodontic regeneration. Dr. Madfa has numerous international publications, full articles, two patents, a book and a book chapter. Furthermore, he won 14 international scientific awards. Furthermore, he is involved in many academic activities ranging from editorial board member, reviewer for many international journals and postgraduate students' supervisor. Besides, I deliver many courses and training workshops at various scientific events. Dr. Madfa also regularly attends international conferences and holds administrative positions (Deputy Dean of the Faculty for Students’ & Academic Affairs and Deputy Head of Research Unit).",institutionString:"Thamar University",institution:null},{id:"210472",title:"Dr.",name:"Nermin",middleName:"Mohammed Ahmed",surname:"Yussif",slug:"nermin-yussif",fullName:"Nermin Yussif",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/210472/images/system/210472.jpg",biography:"Dr. Nermin Mohammed Ahmed Yussif is working at the Faculty of dentistry, University for October university for modern sciences and arts (MSA). Her areas of expertise include: periodontology, dental laserology, oral implantology, periodontal plastic surgeries, oral mesotherapy, nutrition, dental pharmacology. She is an editor and reviewer in numerous international journals.",institutionString:"MSA University",institution:null},{id:"204606",title:"Dr.",name:"Serdar",middleName:null,surname:"Gözler",slug:"serdar-gozler",fullName:"Serdar Gözler",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204606/images/system/204606.jpeg",biography:"Dr. Serdar Gözler has completed his undergraduate studies at the Marmara University Faculty of Dentistry in 1978, followed by an assistantship in the Prosthesis Department of Dicle University Faculty of Dentistry. Starting his PhD work on non-resilient overdentures with Assoc. Prof. Hüsnü Yavuzyılmaz, he continued his studies with Prof. Dr. Gürbüz Öztürk of Istanbul University Faculty of Dentistry Department of Prosthodontics, this time on Gnatology. He attended training programs on occlusion, neurology, neurophysiology, EMG, radiology and biostatistics. In 1982, he presented his PhD thesis \\Gerber and Lauritzen Occlusion Analysis Techniques: Diagnosis Values,\\ at Istanbul University School of Dentistry, Department of Prosthodontics. As he was also working with Prof. Senih Çalıkkocaoğlu on The Physiology of Chewing at the same time, Gözler has written a chapter in Çalıkkocaoğlu\\'s book \\Complete Prostheses\\ entitled \\The Place of Neuromuscular Mechanism in Prosthetic Dentistry.\\ The book was published five times since by the Istanbul University Publications. Having presented in various conferences about occlusion analysis until 1998, Dr. Gözler has also decided to use the T-Scan II occlusion analysis method. Having been personally trained by Dr. Robert Kerstein on this method, Dr. Gözler has been lecturing on the T-Scan Occlusion Analysis Method in conferences both in Turkey and abroad. Dr. Gözler has various articles and presentations on Digital Occlusion Analysis methods. He is now Head of the TMD Clinic at Prosthodontic Department of Faculty of Dentistry , Istanbul Aydın University , Turkey.",institutionString:"Istanbul Aydin University",institution:{name:"Istanbul Aydın University",country:{name:"Turkey"}}},{id:"256417",title:"Associate Prof.",name:"Sanaz",middleName:null,surname:"Sadry",slug:"sanaz-sadry",fullName:"Sanaz Sadry",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/256417/images/8106_n.jpg",biography:null,institutionString:null,institution:{name:"Istanbul Aydın University",country:{name:"Turkey"}}},{id:"240870",title:"Ph.D.",name:"Alaa Eddin Omar",middleName:null,surname:"Al Ostwani",slug:"alaa-eddin-omar-al-ostwani",fullName:"Alaa Eddin Omar Al Ostwani",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/240870/images/system/240870.jpeg",biography:"Dr. Al Ostwani Alaa Eddin Omar received his Master in dentistry from Damascus University in 2010, and his Ph.D. in Pediatric Dentistry from Damascus University in 2014. Dr. Al Ostwani is an assistant professor and faculty member at IUST University since 2014. \nDuring his academic experience, he has received several awards including the scientific research award from the Union of Arab Universities, the Syrian gold medal and the international gold medal for invention and creativity. Dr. Al Ostwani is a Member of the International Association of Dental Traumatology and the Syrian Society for Research and Preventive Dentistry since 2017. He is also a Member of the Reviewer Board of International Journal of Dental Medicine (IJDM), and the Indian Journal of Conservative and Endodontics since 2016.",institutionString:"International University for Science and Technology.",institution:{name:"Islamic University of Science and Technology",country:{name:"India"}}},{id:"42847",title:"Dr.",name:"Belma",middleName:null,surname:"Işik Aslan",slug:"belma-isik-aslan",fullName:"Belma Işik Aslan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/42847/images/system/42847.jpg",biography:"Dr. Belma IşIk Aslan was born in 1976 in Ankara-TURKEY. After graduating from TED Ankara College in 1994, she attended to Gazi University, Faculty of Dentistry in Ankara. She completed her PhD in orthodontic education at Gazi University between 1999-2005. Dr. Işık Aslan stayed at the Providence Hospital Craniofacial Institude and Reconstructive Surgery in Michigan, USA for three months as an observer. She worked as a specialist doctor at Gazi University, Dentistry Faculty, Department of Orthodontics between 2005-2014. She was appointed as associate professor in January, 2014 and as professor in 2021. Dr. Işık Aslan still works as an instructor at the same faculty. She has published a total of 35 articles, 10 book chapters, 39 conference proceedings both internationally and nationally. Also she was the academic editor of the international book 'Current Advances in Orthodontics'. She is a member of the Turkish Orthodontic Society and Turkish Cleft Lip and Palate Society. She is married and has 2 children. Her knowledge of English is at an advanced level.",institutionString:"Gazi University Dentistry Faculty Department of Orthodontics",institution:null},{id:"202198",title:"Dr.",name:"Buket",middleName:null,surname:"Aybar",slug:"buket-aybar",fullName:"Buket Aybar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/202198/images/6955_n.jpg",biography:"Buket Aybar, DDS, PhD, was born in 1971. She graduated from Istanbul University, Faculty of Dentistry, in 1992 and completed her PhD degree on Oral and Maxillofacial Surgery in Istanbul University in 1997.\r\nDr. Aybar is currently a full-time professor in Istanbul University, Faculty of Dentistry Department of Oral and Maxillofacial Surgery. She has teaching responsibilities in graduate and postgraduate programs. Her clinical practice includes mainly dentoalveolar surgery.\r\nHer topics of interest are biomaterials science and cell culture studies. She has many articles in international and national scientific journals and chapters in books; she also has participated in several scientific projects supported by Istanbul University Research fund.",institutionString:null,institution:{name:"Marmara University",country:{name:"Turkey"}}},{id:"178412",title:"Associate Prof.",name:"Guhan",middleName:null,surname:"Dergin",slug:"guhan-dergin",fullName:"Guhan Dergin",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178412/images/6954_n.jpg",biography:"Assoc. Prof. Dr. Gühan Dergin was born in 1973 in Izmit. He graduated from Marmara University Faculty of Dentistry in 1999. He completed his specialty of OMFS surgery in Marmara University Faculty of Dentistry and obtained his PhD degree in 2006. In 2005, he was invited as a visiting doctor in the Oral and Maxillofacial Surgery Department of the University of North Carolina, USA, where he went on a scholarship. Dr. Dergin still continues his academic career as an associate professor in Marmara University Faculty of Dentistry. He has many articles in international and national scientific journals and chapters in books.",institutionString:null,institution:{name:"Marmara University",country:{name:"Turkey"}}},{id:"178414",title:"Prof.",name:"Yusuf",middleName:null,surname:"Emes",slug:"yusuf-emes",fullName:"Yusuf Emes",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178414/images/6953_n.jpg",biography:"Born in Istanbul in 1974, Dr. Emes graduated from Istanbul University Faculty of Dentistry in 1997 and completed his PhD degree in Istanbul University faculty of Dentistry Department of Oral and Maxillofacial Surgery in 2005. He has papers published in international and national scientific journals, including research articles on implantology, oroantral fistulas, odontogenic cysts, and temporomandibular disorders. Dr. Emes is currently working as a full-time academic staff in Istanbul University faculty of Dentistry Department of Oral and Maxillofacial Surgery.",institutionString:null,institution:{name:"Istanbul University",country:{name:"Turkey"}}},{id:"192229",title:"Ph.D.",name:"Ana Luiza",middleName:null,surname:"De Carvalho Felippini",slug:"ana-luiza-de-carvalho-felippini",fullName:"Ana Luiza De Carvalho Felippini",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/192229/images/system/192229.jpg",biography:null,institutionString:"University of São Paulo",institution:{name:"University of Sao Paulo",country:{name:"Brazil"}}},{id:"256851",title:"Prof.",name:"Ayşe",middleName:null,surname:"Gülşen",slug:"ayse-gulsen",fullName:"Ayşe Gülşen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/256851/images/9696_n.jpg",biography:"Dr. Ayşe Gülşen graduated in 1990 from Faculty of Dentistry, University of Ankara and did a postgraduate program at University of Gazi. \nShe worked as an observer and research assistant in Craniofacial Surgery Departments in New York, Providence Hospital in Michigan and Chang Gung Memorial Hospital in Taiwan. \nShe works as Craniofacial Orthodontist in Department of Aesthetic, Plastic and Reconstructive Surgery, Faculty of Medicine, University of Gazi, Ankara Turkey since 2004.",institutionString:"Orthodontist, Assoc Prof in the Department of Aesthetic, Plastic and Reconstructive Surgery, Faculty of Medicine, University of Gazi",institution:null},{id:"255366",title:"Prof.",name:"Tosun",middleName:null,surname:"Tosun",slug:"tosun-tosun",fullName:"Tosun Tosun",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255366/images/7347_n.jpg",biography:"Graduated at the Faculty of Dentistry, University of Istanbul, Turkey in 1989;\nVisitor Assistant at the University of Padua, Italy and Branemark Osseointegration Center of Treviso, Italy between 1993-94;\nPhD thesis on oral implantology in University of Istanbul and was awarded the academic title “Dr.med.dent.”, 1997;\nHe was awarded the academic title “Doç.Dr.” (Associated Professor) in 2003;\nProficiency in Botulinum Toxin Applications, Reading-UK in 2009;\nMastership, RWTH Certificate in Laser Therapy in Dentistry, AALZ-Aachen University, Germany 2009-11;\nMaster of Science (MSc) in Laser Dentistry, University of Genoa, Italy 2013-14.\n\nDr.Tosun worked as Research Assistant in the Department of Oral Implantology, Faculty of Dentistry, University of Istanbul between 1990-2002. \nHe worked part-time as Consultant surgeon in Harvard Medical International Hospitals and John Hopkins Medicine, Istanbul between years 2007-09.\u2028He was contract Professor in the Department of Surgical and Diagnostic Sciences (DI.S.C.), Medical School, University of Genova, Italy between years 2011-16. \nSince 2015 he is visiting Professor at Medical School, University of Plovdiv, Bulgaria. \nCurrently he is Associated Prof.Dr. at the Dental School, Oral Surgery Dept., Istanbul Aydin University and since 2003 he works in his own private clinic in Istanbul, Turkey.\u2028\nDr.Tosun is reviewer in journal ‘Laser in Medical Sciences’, reviewer in journal ‘Folia Medica\\', a Fellow of the International Team for Implantology, Clinical Lecturer of DGZI German Association of Oral Implantology, Expert Lecturer of Laser&Health Academy, Country Representative of World Federation for Laser Dentistry, member of European Federation of Periodontology, member of Academy of Laser Dentistry. Dr.Tosun presents papers in international and national congresses and has scientific publications in international and national journals. He speaks english, spanish, italian and french.",institutionString:null,institution:{name:"Istanbul Aydın University",country:{name:"Turkey"}}},{id:"260116",title:"Dr.",name:"Mehmet",middleName:null,surname:"Yaltirik",slug:"mehmet-yaltirik",fullName:"Mehmet Yaltirik",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/260116/images/7413_n.jpg",biography:"Birth Date 25.09.1965\r\nBirth Place Adana- Turkey\r\nSex Male\r\nMarrial Status Bachelor\r\nDriving License Acquired\r\nMother Tongue Turkish\r\n\r\nAddress:\r\nWork:University of Istanbul,Faculty of Dentistry, Department of Oral Surgery and Oral Medicine 34093 Capa,Istanbul- TURKIYE",institutionString:null,institution:{name:"Istanbul University",country:{name:"Turkey"}}},{id:"171887",title:"Prof.",name:"Zühre",middleName:null,surname:"Akarslan",slug:"zuhre-akarslan",fullName:"Zühre Akarslan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/171887/images/system/171887.jpg",biography:"Zühre Akarslan was born in 1977 in Cyprus. She graduated from Gazi University Faculty of Dentistry, Ankara, Turkey in 2000. \r\nLater she received her Ph.D. degree from the Oral Diagnosis and Radiology Department; which was recently renamed as Oral and Dentomaxillofacial Radiology, from the same university. \r\nShe is working as a full-time Associate Professor and is a lecturer and an academic researcher. \r\nHer expertise areas are dental caries, cancer, dental fear and anxiety, gag reflex in dentistry, oral medicine, and dentomaxillofacial radiology.",institutionString:"Gazi University",institution:{name:"Gazi University",country:{name:"Turkey"}}},{id:"272237",title:"Dr.",name:"Pinar",middleName:"Kiymet",surname:"Karataban",slug:"pinar-karataban",fullName:"Pinar Karataban",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/272237/images/8911_n.png",biography:"Assist.Prof.Dr.Pınar Kıymet Karataban, DDS PhD \n\nDr.Pınar Kıymet Karataban was born in Istanbul in 1975. After her graduation from Marmara University Faculty of Dentistry in 1998 she started her PhD in Paediatric Dentistry focused on children with special needs; mainly children with Cerebral Palsy. She finished her pHD thesis entitled \\'Investigation of occlusion via cast analysis and evaluation of dental caries prevalance, periodontal status and muscle dysfunctions in children with cerebral palsy” in 2008. She got her Assist. Proffessor degree in Istanbul Aydın University Paediatric Dentistry Department in 2015-2018. ın 2019 she started her new career in Bahcesehir University, Istanbul as Head of Department of Pediatric Dentistry. In 2020 she was accepted to BAU International University, Batumi as Professor of Pediatric Dentistry. She’s a lecturer in the same university meanwhile working part-time in private practice in Ege Dental Studio (https://www.egedisklinigi.com/) a multidisciplinary dental clinic in Istanbul. Her main interests are paleodontology, ancient and contemporary dentistry, oral microbiology, cerebral palsy and special care dentistry. She has national and international publications, scientific reports and is a member of IAPO (International Association for Paleodontology), IADH (International Association of Disability and Oral Health) and EAPD (European Association of Pediatric Dentistry).",institutionString:null,institution:null},{id:"172009",title:"Dr.",name:"Fatma Deniz",middleName:null,surname:"Uzuner",slug:"fatma-deniz-uzuner",fullName:"Fatma Deniz Uzuner",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/172009/images/7122_n.jpg",biography:"Dr. Deniz Uzuner was born in 1969 in Kocaeli-TURKEY. After graduating from TED Ankara College in 1986, she attended the Hacettepe University, Faculty of Dentistry in Ankara. \nIn 1993 she attended the Gazi University, Faculty of Dentistry, Department of Orthodontics for her PhD education. After finishing the PhD education, she worked as orthodontist in Ankara Dental Hospital under the Turkish Government, Ministry of Health and in a special Orthodontic Clinic till 2011. Between 2011 and 2016, Dr. Deniz Uzuner worked as a specialist in the Department of Orthodontics, Faculty of Dentistry, Gazi University in Ankara/Turkey. In 2016, she was appointed associate professor. Dr. Deniz Uzuner has authored 23 Journal Papers, 3 Book Chapters and has had 39 oral/poster presentations. She is a member of the Turkish Orthodontic Society. Her knowledge of English is at an advanced level.",institutionString:null,institution:null},{id:"332914",title:"Dr.",name:"Muhammad Saad",middleName:null,surname:"Shaikh",slug:"muhammad-saad-shaikh",fullName:"Muhammad Saad Shaikh",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Jinnah Sindh Medical University",country:{name:"Pakistan"}}},{id:"315775",title:"Dr.",name:"Feng",middleName:null,surname:"Luo",slug:"feng-luo",fullName:"Feng Luo",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Sichuan University",country:{name:"China"}}},{id:"344229",title:"Dr.",name:"Sankeshan",middleName:null,surname:"Padayachee",slug:"sankeshan-padayachee",fullName:"Sankeshan Padayachee",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of the Witwatersrand",country:{name:"South Africa"}}},{id:"315727",title:"Ms.",name:"Kelebogile A.",middleName:null,surname:"Mothupi",slug:"kelebogile-a.-mothupi",fullName:"Kelebogile A. Mothupi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of the Witwatersrand",country:{name:"South Africa"}}},{id:"423519",title:"Dr.",name:"Sizakele",middleName:null,surname:"Ngwenya",slug:"sizakele-ngwenya",fullName:"Sizakele Ngwenya",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of the Witwatersrand",country:{name:"South Africa"}}},{id:"337613",title:"Mrs.",name:"Tshakane",middleName:null,surname:"R.M.D. Ralephenya",slug:"tshakane-r.m.d.-ralephenya",fullName:"Tshakane R.M.D. Ralephenya",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of the Witwatersrand",country:{name:"South Africa"}}},{id:"419270",title:"Dr.",name:"Ann",middleName:null,surname:"Chianchitlert",slug:"ann-chianchitlert",fullName:"Ann Chianchitlert",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Walailak University",country:{name:"Thailand"}}},{id:"419271",title:"Dr.",name:"Diane",middleName:null,surname:"Selvido",slug:"diane-selvido",fullName:"Diane Selvido",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Walailak University",country:{name:"Thailand"}}},{id:"419272",title:"Dr.",name:"Irin",middleName:null,surname:"Sirisoontorn",slug:"irin-sirisoontorn",fullName:"Irin Sirisoontorn",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Walailak University",country:{name:"Thailand"}}}]}},subseries:{item:{id:"23",type:"subseries",title:"Computational Neuroscience",keywords:"Single-Neuron Modeling, Sensory Processing, Motor Control, Memory and Synaptic Pasticity, Attention, Identification, Categorization, Discrimination, Learning, Development, Axonal Patterning and Guidance, Neural Architecture, Behaviours and Dynamics of Networks, Cognition and the Neuroscientific Basis of Consciousness",scope:"Computational neuroscience focuses on biologically realistic abstractions and models validated and solved through computational simulations to understand principles for the development, structure, physiology, and ability of the nervous system. 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Particularly interesting are models of various types of more compound functions and abilities, various and more general fundamental principles (e.g., regarding architecture, organization, learning, development, etc.) found at various spatial and temporal levels.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/23.jpg",hasOnlineFirst:!1,hasPublishedBooks:!0,annualVolume:11419,editor:{id:"14004",title:"Dr.",name:"Magnus",middleName:null,surname:"Johnsson",slug:"magnus-johnsson",fullName:"Magnus Johnsson",profilePictureURL:"https://mts.intechopen.com/storage/users/14004/images/system/14004.png",biography:"Dr Magnus Johnsson is a cross-disciplinary scientist, lecturer, scientific editor and AI/machine learning consultant from Sweden. \n\nHe is currently at Malmö University in Sweden, but also held positions at Lund University in Sweden and at Moscow Engineering Physics Institute. \nHe holds editorial positions at several international scientific journals and has served as a scientific editor for books and special journal issues. \nHis research interests are wide and include, but are not limited to, autonomous systems, computer modeling, artificial neural networks, artificial intelligence, cognitive neuroscience, cognitive robotics, cognitive architectures, cognitive aids and the philosophy of mind. \n\nDr. Johnsson has experience from working in the industry and he has a keen interest in the application of neural networks and artificial intelligence to fields like industry, finance, and medicine. \n\nWeb page: www.magnusjohnsson.se",institutionString:null,institution:{name:"Malmö University",institutionURL:null,country:{name:"Sweden"}}},editorTwo:null,editorThree:null,series:{id:"14",title:"Artificial Intelligence",doi:"10.5772/intechopen.79920",issn:"2633-1403"},editorialBoard:[{id:"13818",title:"Dr.",name:"Asim",middleName:null,surname:"Bhatti",slug:"asim-bhatti",fullName:"Asim Bhatti",profilePictureURL:"https://mts.intechopen.com/storage/users/13818/images/system/13818.jpg",institutionString:null,institution:{name:"Deakin University",institutionURL:null,country:{name:"Australia"}}},{id:"151889",title:"Dr.",name:"Joao Luis Garcia",middleName:null,surname:"Rosa",slug:"joao-luis-garcia-rosa",fullName:"Joao Luis Garcia Rosa",profilePictureURL:"https://mts.intechopen.com/storage/users/151889/images/4861_n.jpg",institutionString:null,institution:{name:"University of Sao Paulo",institutionURL:null,country:{name:"Brazil"}}},{id:"103779",title:"Prof.",name:"Yalcin",middleName:null,surname:"Isler",slug:"yalcin-isler",fullName:"Yalcin Isler",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRyQ8QAK/Profile_Picture_1628834958734",institutionString:null,institution:{name:"Izmir Kâtip Çelebi University",institutionURL:null,country:{name:"Turkey"}}}]},onlineFirstChapters:{paginationCount:7,paginationItems:[{id:"82777",title:"Sustainability and Social Investment: Community Microhydropower Systems in the Dominican Republic",doi:"10.5772/intechopen.105995",signatures:"Michela Izzo, Alberto Sánchez and Rafael Fonseca",slug:"sustainability-and-social-investment-community-microhydropower-systems-in-the-dominican-republic",totalDownloads:4,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Globalization and Sustainability - Recent Advances, New Perspectives and Emerging Issues",coverURL:"https://cdn.intechopen.com/books/images_new/11476.jpg",subseries:{id:"91",title:"Sustainable Economy and Fair Society"}}},{id:"82387",title:"Kept Promises? 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