",isbn:"978-1-80356-357-2",printIsbn:"978-1-80356-356-5",pdfIsbn:"978-1-80356-358-9",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,isSalesforceBook:!1,isNomenclature:!1,hash:"3aba1eb3600a8c9ff880c628f70b3298",bookSignature:"Ph.D. Delfín Ortega-Sánchez",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11481.jpg",keywords:"Integrated Curriculum, Transdisciplinarity, Integrated Active Learning, Educational Programs, Contemporary Social Problems, Critical Thinking, Creative Thinking, Social Thinking, Agenda 2030, Sustainable Development Goals, Educational Paradigm, Social Reality",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"February 18th 2022",dateEndSecondStepPublish:"March 18th 2022",dateEndThirdStepPublish:"May 17th 2022",dateEndFourthStepPublish:"August 5th 2022",dateEndFifthStepPublish:"October 4th 2022",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"2 months",secondStepPassed:!0,areRegistrationsClosed:!0,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,biosketch:"Internationally recognized researcher in the field of historical and social science education. Author of more than 100 publications, awarded three Doctorate degrees and the National End of Degree Award, granted by the Ministry of Education to the best academic records of Bachelor's degrees in Spain. Dr. Ortega-Sánchez has been Vice-Rector for Social Responsibility, Culture, and Sports at the University of Burgos since 2021.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"302925",title:"Ph.D.",name:"Delfín",middleName:null,surname:"Ortega-Sánchez",slug:"delfin-ortega-sanchez",fullName:"Delfín Ortega-Sánchez",profilePictureURL:"https://mts.intechopen.com/storage/users/302925/images/system/302925.jpg",biography:"I hold a PhD in Didactics of Social Sciences from the Autonomous University of Barcelona, a PhD in Educational Sciences from the University of Burgos, and a PhD in History from the University of Extremadura. My research interests focus on the construction of identities in the History and Geography teaching, gender mainstreaming in initial education and training for teachers, the didactic treatment of relevant social problems and controversial issues in the teaching of the social and human sciences, and the application of educational technology in the specific field of social sciences. 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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
The BRAF mutant (MT) colorectal cancer (CRC) population is a small and unique subgroup noted for its association with poor prognosis and survival. BRAF mutation occurs in approximately 10% (range, 5–22%) [1, 2] of the unselected CRC population and consistently has inferior median survival outcomes ranging from 8 to 14 months [3, 4]. Failure to achieve good survival outcomes through standard doublet chemotherapy agents in this population has ignited efforts to combine multiple target therapies, aiming for breakthroughs. In this chapter, the BRAF gene and its signalling pathway are explored in detail. BRAF gene mutation frequency and its impact on clinical presentation as well as its prognostic and predictive significance are also discussed. Updates on the current and latest management strategies as well as novel investigational treatments in this subgroup are also presented.
\n
\n
\n
2. BRAF and the RAS/RAF/MEK/ERK signalling pathway
\n
V-raf murine sarcoma viral oncogene homologue (RAF) is one of the most intensively researched mammalian effectors of RAS in the RAS/RAF/MEK/ERK signalling pathway (Figure 1) [5, 6]. The RAF protein itself is made up of three conserved regions: CR1, CR2, and CR3. CR1 and CR2 are situated in the N terminus. CR1 acts as the main binding domain for RAS. CR2 is the regulatory domain. CR3 is situated at the C terminus and functions as the catalytic kinase domain [7].
\n
When GTP bound, RAS recruits RAF protein to the cell membrane and binds to it. This binding process activates RAF kinase by the phosphorylation of two amino acids (T599 and S602 of BRAF) situated in the activation segment of the kinase domain. RAF then phosphorylates its downstream effectors MEK1, MEK2, ERK1, and ERK2, leading to the activation of cellular proliferation, differentiation, and transcriptional regulation (Figure 1) [7].
\n
Figure 1.
RAS and PIK3CA signalling pathways.
\n
B-RAF (BRAF) together with A-RAF and C-RAF are the members of the RAF kinase family [8]. These three RAF isoforms are homologous in sequence and substrate specificity but do differ in their biological functions and regulations. Of these, BRAF remains the most potent activator of MEK [9].
\n
The BRAF gene is a proto-oncogene located on chromosome arm 7q34, composed of 18 exons. There are more than 30 different BRAF mutations [10]. The most common activating mutation, BRAF V600E (p.Val600Glu/c.1799T>A), accounts for 90% of all activating BRAF mutations and is found in exon 15 at nucleotide position 1799 [11]. The thymine-to-adenine transversion within codon 600 leads to the substitution of valine by glutamate at the amino acid level. This mutation occurs in the activating segment of the kinase domain, resulting in increased basal kinase activity. Compared to wild-type (WT) BRAF, BRAF V600E demonstrates an almost 500-fold increase in endogenous kinase activity [10, 12].
\n
In solid tumours, the highest incidence of BRAF mutations is in malignant melanoma (27–70%), CRC (5–22%), and serous ovarian cancer (~30%) and less (1–3%) in non-small cell lung carcinoma (NSCLC) [13–15]. In colonic cell lines, the oncogenic effects of BRAF V600E include cell proliferation and inhibition of apoptosis [16]. Although dependent on continued BRAF activity for tumourigenic growth, BRAF MT cells did not require an upstream RAS function for proliferation [17].
\n
\n
2.1. BRAF mutation detection methods
\n
CRC BRAF mutations can be identified using first- and second-generation direct sequencing, immunohistochemistry (IHC), and, potentially, circulating tumour cells (CTC).
\n
Sanger sequencing is the earliest form of first-generation direct sequencing. Sanger sequencing was developed in 1975 and relies on the chain-termination sequencing of amplified DNA by polymerase chain reaction (PCR) and detection through electrophoresis. It requires approximately 18 to 19 h to process and is also 10 times less sensitive than pyrosequencing. Sanger sequencing method also cannot detect the changes in chromosomal copy number and translocations [18].
\n
Next-generation sequencing (NGS) differs in technology using a specific reagent wash of nucleotide triphosphates with synchronised optical detection and includes pyrosequencing, allele-specific (AS) PCR, mass spectrometry, and real-time qPCR with melt-curve analysis [19]. NGS is the new gold standard test in BRAF mutation detection given its superior detection and speed.
\n
Pyrosequencing is referred to as sequencing by synthesis and relies on the release of pyrophosphate (PPi) by DNA polymerase. The test detects light emitted when nucleotides are added to the target DNA template by DNA polymerase releasing PPi via a chemiluminescence reaction. It is a more rapid and sensitive test in detecting BRAF V600E mutations in addition to other variants such as V600D, V600K, V600R, and K601E. It can provide the percentage of DNA that harbours the BRAF V600E mutations. However, this method is limited by the length of DNA template and is prone to error readings in homopolymer sequences (TTTTTTTT) [18].
\n
AS-PCR enriches known mutations in samples to increase the sensitivity of detection and is particularly useful in tissue with low tumour content. Mass spectrometry-based sequencing relies on the analysis of matrix-assisted laser desorption/ionisation time-of-flight (MALDI-TOF). This process is facilitated by the addition of mass-modified bases A, C, T, and G to the primed and amplified mutational hotspots. It is this flight time difference of the generated mass-modified complex that is measured by the mass spectrometer. Mass spectrometry-based sequencing is an even more sensitive test compared to pyrosequencing, with a detection ratio of 1:10 and 1:8, respectively [18].
\n
Melt-curve analysis involves detecting the melting temperature for WT BRAF at 61°C and the V600E MT melting at 53°C. PCR methods, on the contrary, can perform as well and has advantages in terms of reduced labour (1.25 vs 16 min), faster turnaround (4 min vs 10 h), and lower cost ($2.6 vs $10.4). The sensitivity and specificity of real-time qPCR is reported to be 100% [19]. Table 1 details the comparisons among some of the available NGS techniques.
\n
\n\n\n
\n
Method
\n
Sensitivity
\n
Accuracy
\n
Time
\n
Cost/1 mill bases (USD)
\n
Advantages/disadvantages
\n
\n\n\n
\n
Chain termination (Sanger)
\n
Low
\n
99.9%
\n
20 min–3 h
\n
2400
\n
Requires the time-consuming step of PCR of plasmid cloning; impractical for larger sequencing projects
\n
\n
\n
Pyrosequencing (454)
\n
Medium
\n
99.9%
\n
24 h
\n
10
\n
Homopolymer errors
\n
\n
\n
Sequencing by synthesis (Illumina)
\n
High
\n
99.9%
\n
1–11 days
\n
0.05–0.15
\n
Expensive equipment; requires high DNA concentrations
\n
\n
\n
Sequencing by ligation
\n
High
\n
99.9%
\n
1–2 weeks
\n
0.13
\n
Slower; issues sequencing palindromic sequences
\n
\n
\n
Ion semi conductor
\n
High
\n
98%
\n
2 h
\n
1
\n
Homopolymer errors
\n
\n
\n
Single-molecule real-time sequencing
\n
High
\n
87%
\n
30 min–4 h
\n
0.13–0.60
\n
Expensive equipment; moderate throughput
\n
\n\n
Table 1.
Available NGS techniques in detecting BRAF V600E mutation [20, 21].
\n
The IHC detection of BRAF V600E with a mutation-specific antibody (clone VE1) was first described in metastatic melanoma and papillary thyroid carcinoma and is currently commercially available [22]. The advantage of IHC lies in the minimal amount of tissue needed and the availability of this technique in most pathological laboratories. Most studies have reported high sensitivities and specificities (98.8–100%) compared to PCR-based methods or sequencing [23–25]. However, there is one study that has reported sensitivity and specificity of only 71% and 74%, respectively [26]. The choice of positive control tissue and the amplification protocol is regarded to be crucial in the successful detection of BRAF mutation by IHC [27].
\n
Recently, examination of CTC in peripheral blood has been explored as a new non-invasive means for detecting BRAF mutation in CRC [28]. Blood collected from 44 patients was enriched for CTC using a size-based microsieve technology. By incorporating the high-resolution melt-curve analysis technique, the concordance rates between CTC and tumour mutations were observed to be 90.9% (p=0.174) for BRAF mutation genotype status and 84.1% (p=0.000129) for KRAS mutation genotype status.
\n
\n
\n
2.2. BRAF mutation and its frequency in CRC
\n
A meta-analysis of 10 studies reported BRAF mutations in 4.8% to 20.8% of CRC [74]. Table 2 further details the BRAF mutation rates and the corresponding detection methods in some notable metastatic CRC (mCRC) trials.
BRAF mutation detection methods and reported frequencies in notable CRC trials.
\n
Figure 2.
Somatic mutation frequencies in CRC.
\n
Importantly, BRAF MT CRC is reported to be mutually exclusive to KRAS mutation [36]. BRAF mutation coexists with PIK3CA mutations in 13% and PTEN mutations in 22% of CRC [37]. Figure 2 depicts the frequency of the different somatic mutations discovered in CRC patients.Chan, E. My Cancer Genome. Molecular Profiling of Colorectal Cancer [Internet]. January 26, 2016 [Updated:January 26, 2016]. Available from: https://www.mycancergenome.org/content/disease/colorectal-cancer/ [Accessed: January 26, 2016].
\n
\n
\n
\n
3. BRAF mutation and its clinical significance in CRC
\n
\n
3.1. CRC tumourigenesis pathways
\n
The two main separate pathways observed in CRC development and progression are the chromosomal instability pathway (CIN), which accounts for 75% of the cases, and the microsatellite instability (MSI) pathway in 25% of the cases. Two processes are observed to contribute towards the MSI pathway: (1) germ-line mutations from Lynch syndrome and (2) sporadic MLH1 methylation from the serrated methylated pathway (Figure 3) [38] [100].
\n
Figure 3.
CRC tumourigenesis pathways.
\n
The CIN pathway involves a defect in replication, mitosis, or DNA repair leading to genetic abnormalities, both structural and numeric, which are acquired sequentially. As a result, oncogenes are activated or tumour suppressor gene function is lost, which contributes towards malignant growth. This pathway is also often associated with aneuploidy by karyotyping. The genetic changes found in CRC arising via the CIN pathway include APC mutations (90%), KRAS mutation (50%), TP53 mutations (70%), and allelic loss of 18q (80%) [39]. The CIN pathway has been traditionally associated with CRC arising in adenomatous polyps.
\n
The MSI pathway is a result of defective mismatch repair (MMR) and occurs in a subset of CRC that arise from either adenomas or serrated polyps. It contributes towards tumour progression via the accumulation of tiny insertions and deletions in the repetitive sequences of microsatellites in coding genes, thereby retaining a near-diploid karyotype. This mechanism of tumourigenesis is readily recognized through a test for MSI, which categorises each tumour as MSI-high (MSI-H), MSI-low (MSI-L), or microsatellite stable (MSS), based on the proportion of microsatellites mutated. MSI-H cases usually imply an acquired or inherited defect in DNA repair.
\n
In inherited cases of MSI-H CRC, germ-line mutation in one of the four genes that encode proteins responsible for MMR (MLH1, MSH2, PMS2, and MSH6) is responsible for a familial predisposition to cancer. This familial predisposition to CRC is known as Lynch syndrome [40], and the CRC that arise in this condition develop in adenomas.
\n
In sporadic cases of MSI-H CRC, the serrated methylated pathway is increasingly implicated. Serrated polyps, not driven by CIN but by BRAF mutations, are observed to replace adenomas as precursor lesions in CRC. MSI-H CRC occur due to the epigenetic inactivation of MLH1 by promoter methylation, which prevents MLH1 protein expression, resulting in defective MMR and producing MSI. This pathway is also closely associated with the widespread methylation of CpG islands, causing the transcriptional silencing of tumour suppressor genes, known as the CpG island methylator phenotype (CIMP) [38, 39].
\n
\n
\n
3.2. BRAF testing to distinguish between sporadic versus germ-line MSI-H cases (Lynch syndrome)
\n
Approximately 12% of MSI-H cases are sporadic in nature and BRAF mutation is implicated in nearly all (91%) of these cases [41, 42]. The methylation of MLH1 is found only in 1.6% of germ-line Lynch syndrome cases [43], whereas it is typically found in sporadic tumour lacking MLH1 expression [44]. Hence, BRAF mutation testing is recommended in MSI-H CRC as a triage for Lynch syndrome. Only those lacking the BRAF mutation proceed with further workup for Lynch syndrome, as CRC harbouring the BRAF mutation are, with few exceptions, unlikely to have this condition.
\n
MLH1 methylation testing is an alternative assay to distinguish sporadic from familial cases of CRC. However, given that methylation testing is more technically challenging than BRAF mutation testing, most would advocate BRAF testing as the more cost-effective assay to distinguish sporadic from familial MSI-H CRC [44].
\n
\n
\n
3.3. Clinicopathological and molecular features of BRAF MT CRC
\n
\nBRAF mutation has been reported in multiple studies to be associated with several clinicopathological parameters in CRC patients. BRAF V600E mutation is reported to increase from 10% in unselected patients to 37% in females ages >70 years [45]. BRAF mutations in the Western population tend to be more common in females and to have a more proximal location in the colorectum [27, 46–52]. BRAF mutations are rarely found in the left-sided colon (4%) and rectal cancers (2%) compared to the right-sided colon (22%; p<0.0001) [53]. BRAF mutation also varies by pathology. Approximately 60% of BRAF MT tumours are poorly differentiated and only up to 36% of them are well to moderately differentiated. Mucinous cancers tend to have a higher rate of BRAF mutation (22–67%) compared to non-mucinous cancers (6–21%) [39, 54, 55].
\n
The relationship between BRAF mutation and these clinicopathological features was confirmed in a meta-analysis reported in 2014 [36]. Twenty-five studies of 11,955 CRC patients were included in this analysis. The mutation rate was seen to vary with the highest reported at 21.8% [2], the lowest being 5.0% [1], and the overall rate being 10.8%. Nine of the 25 studies have shown that BRAF mutation was associated with advanced tumor-node-metastasis (TNM) stage at diagnosis [11.6% in stage III/IV CRC vs 8.0% in stage I/II CRC; odds ratio (OR)=1.59; 95% confidence interval (CI)=1.16–2.17]. Thirteen of these studies showed that BRAF MT CRC was more prevalent in poorly differentiated tumours than well to moderately differentiated tumours. Of 766 patients with poorly differentiated tumours, 25.6% were BRAF MT, whereas only 8% of 4257 patients with well to moderately differentiated tumours were BRAF MT (OR=3.89; 95% CI=2.94–5.17). Six studies have also shown that more BRAF MT were detected in the mucinous subgroup than in the non-mucinous subgroup (19.4% vs 8.1%; OR=2.99; 95% CI=2.20–4.07). Twenty studies have also significantly demonstrated that proximal cancers (21.6%) harbour more BRAF mutations than distal cancers (4.8%; OR=4.85; 95% CI=3.59–6.56) [36].
\n
Another study [56] reported a significantly increased rate of peritoneal (46% vs 24%; p<0.001) and distant lymph node metastases (53% vs 38%; p=0.001) and a lower rate of lung metastases (35% vs 49%; p=0.049) in BRAF MT CRC compared to BRAF WT tumours that might help to explain their poor prognosis.
\n
\n\n
\n
Clinicopathological features of BRAF V600E MT CRC patients
\n
Molecular features of BRAF V600E MT CRC
\n
\n\n\n
\n
1. Age >70 years
\n
1. More prevalent in MSI-H>MSS CRC
\n
\n
\n
2. Female patients
\n
2. More CIMP
\n
\n
\n
3. Proximal right-sided tumours
\n
3. More MLH-1 methylation
\n
\n
\n
4. High-grade and poorly differentiated
\n
4. Mutually exclusive to KRAS mutation
\n
\n
\n
5. Mucinous>non-mucinous
\n
\n
\n
\n
6. More peritoneal and lymph node metastases
\n
\n
\n
\n
7. Less lung metastases
\n
\n
\n\n
Table 3.
Clinicopathological and molecular characteristics of BRAF V600E MT CRC
\n
Relationships between BRAF MT and some molecular characteristics were also reported [36]. BRAF MT were significantly more prevalent in MSI-H CRC (38.9%) than MSS CRC (9.3%; OR=8.18; 95% CI=5.08–13.17). As mentioned above, CIMP characterized by widespread aberrant DNA methylation at select CpG islands was implicated in a minority of CRC tumourigenecity cases. Two studies were analysed for CIMP status and demonstrated a positive relationship with BRAF MT CRC: 45.9% (CIMP) vs 9.1% (non-CIMP; (OR=16.44; 95% CI=6.72–40.21). The methylation of the MLH1 promoter region is an underlying cause of sporadic non-Lynch cases of MSI-H CRC. Three studies reported a relationship between BRAF MT and MLH1 methylation status; 62.5% of MLH1 methylated CRC had BRAF mutations compared to 9.2% of non-methylated CRC (OR=13.84; 95% CI=1.75–109.24). BRAF MT and KRAS MT were found to be mutually exclusive in this meta-analysis.
\n
Table 3 summarises the clinicopathological and molecular characteristics of BRAF MT CRC.
\n
\n
\n
\n
4. BRAF mutation and its prognostic and predictive significance
\n
\n
4.1. Prognostic role and nature of progression
\n
Multiple studies have reported poorer median overall survival (OS) in the BRAF MT mCRC subgroup. Regardless of treatment modality, median survival is generally reported to be between 10 and 16 months shorter than the overall population. For instance, the COIN trial, which studied 1630 patients for the effect of cetuximab and doublet chemotherapy FOLFOX in mCRC patients, had reported a median OS of 8.8 months in BRAF MT patients versus 20.1 months in patients with (BRAF and RAS) WT [34]. The PRIME study had reported a median OS of 10.5 months in the BRAF MT/RAS WT subgroup, contrasting to a median OS of 25.8 months in RAS WT group and 15.5 months in the RAS MT group. In this study, both (BRAF and RAS) WT patients also had the longest median OS of 28.3 months [29]. The pooled analysis of CRYSTAL and OPUS had also reported lower median OS in the BRAF MT group compared to the BRAF WT group (9.9 vs 21.1 months in the chemotherapy arm and 14.1 vs 24.8 months in the chemotherapy in combination with cetuximab arms) [57]. In 2013, the PLoS ONE meta-analysis analysed 21 mCRC trials of 5229 patients treated with monoclonal antibodies [58]. Fourteen of these trials were retrospective; two trials were prospective and five trials were randomised-controlled trials (RCTs). BRAF mutation was detected in 7.4%. Patients with BRAF WT showed decreased risks of progression and death with an improved progression-free survival [PFS; hazard ratio (HR)=0.38; 95% CI=0.29–0.51] and an improved OS (HR=0.35; 95% CI=0.29–0.42) compared to BRAF MT. Compared to BRAF WT patients, the updated prognostic analyses from the TRIBE study in 2014, which compared standard doublet chemotherapy to triplet chemotherapy, also reported significantly shorter PFS and OS, in the BRAF MT group in unresectable mCRC patients, independent of the treatment received [35]. Table 4 summarises the reported median OS in the BRAF MT CRC subgroup reported from various phase III trials. It is also noted here that the BRAF mutation rates decrease with lines of therapy, signifying the reducing likelihood of BRAF MT patients surviving long enough to receive further lines of treatment.
Second line: irinotecan vs irinotecan/panitumumab (IrPan)
\n
14.8%
\n
Favours irinotecan (HR=1.40; p=0.018)
\n
Favours irinotecan (HR=1.84; p=0.029)
\n
Favours IrPan (~6M) (HR=0.78; p=0.015)
\n
10.5 vs 10.4 (HR=1.01; p=0.91)
\n
\n
\n
181 Peeters M, Oliner KS, Price TJ, Cervantes A, Sobrero AF, Ducreux M, et al. Updated analysis of KRAS/NRAS and BRAF mutations in study 20050181 of panitumumab (pmab) + FOLFIRI for 2nd-line treatment (tx) of metastatic colorectal cancer (mCRC). J Clin Oncol 2014;32(Suppl.). Abstract 3568.
Poorer survival in BRAF MT CRC and mutation frequencies in subsequent lines of treatment
\n
The BRAF MT CRC patients of Eastern populations were also reported to share the same fate as those in Western populations. A retrospective study [60] reported a BRAF mutation rate of 4.2% in 212 Chinese CRC patients. This study, which did not specifically examine the lines of treatment administered, showed that BRAF MT was associated with advanced TNM (p<0.001), more distant metastases (p=0.025), and worse OS (3-year OS: 16.7% in the BRAF MT subgroup vs 73.2% in the BRAF WT subgroup; p<0.001). The BRAF mutation rate of 4.2% in the Chinese population was found similar to the rates (1–7%) reported for Taiwanese and Japanese populations [61–64].
\n
\nBRAF MT is also associated with poor prognosis in other stages of CRC. A review in 2013 [65] on seven studies that included stages I to IV CRC patients has concluded that BRAF mutation served as an independent prognostic factor for reduced OS, disease-free survival (DFS), and cancer-specific survival, especially in MSS CRC. One of the studies that included 911 stage II to IV CRC patients demonstrated BRAF mutation to be associated with a poor 5-year OS (BRAF MT vs WT, 47.5% vs 60.7%; p<0.01) [66]. Another study [47] looked at 1307 patients with stage II to III CRC and reported reduced OS in BRAF MT group (HR=2.2; 95% CI=1.4–3.4; p=0.0003).
\n
To further analyse the impact of MSI status in the BRAF MT CRC patients, Samowitz et al. [66] have shown that survival differs for stages II to IV CRC BRAF MT tumours with MSI compared to MSS tumours. Poor prognosis was only demonstrated in MSS tumours (5YS: BRAF MT vs WT, 16.7% vs 60.0%; log-rank p<0.01) from a multivariate analysis adjusted for age, stage, and tumour sites. MSI tumours were reported to have good prognosis regardless of BRAF MT status, with 5YS 76.2% (with BRAF mutation) vs 75.0% (without BRAF mutation). Interestingly, a recent retrospective Japanese study also studied the role of BRAF MT in MSI tumours [67]. They examined KRAS, BRAF, and MSI status in 813 patients with curatively resected, stage I to III CRC. After adjusting for relevant variables, including MSI status, they reported that BRAF MT were poor prognostic factors for DFS (HR=2.20; 95% CI=1.19–4.06) and OS (HR=2.30; 95% CI=1.15–4.71) independent of MSI status. This small study, which excludes stage IV patients, suggests that MSI-H tumours without BRAF mutation may have the best prognosis compared to MSI-H tumours with BRAF mutation. MSS tumours with BRAF mutation would have the worst prognosis.
\n
In accordance with their aggressive nature, BRAF MT cancers have also been reported to have poor PFS with sequential systemic treatments. A retrospective study on 1567 patients detected a BRAF mutation rate of 8%. These BRAF MT patients had received a median of two later lines of chemotherapy, with the median PFS for the first three lines of chemotherapy being 6.3, 2.5, and 2.6 months, respectively [68]. Another smaller study had reported even shorter median PFS (4.3 months) after first-line treatment in BRAF MT [69]. This observation highlights the importance of considering early intensified treatment given the propensity for these patients to not survive long enough for second- or third-line treatments.
\n
Recently, other rare (<1%) subtypes of BRAF MT, which harbour mutations in codon 594 or 596, were reported to have markedly longer OS compared to BRAF V600E MT (median OS=62.0 vs 12.6 months; HR=0.36; 95% CI=0.20–0.64; p=0.002). These subtypes are noted to be MSS and also differ in other molecular and clinical characteristics, being more frequently rectal in origin, non-mucinous, and with no peritoneal spread [70].
\n
\n
\n
4.2. Predictive role
\n
Given that RAS MT are negative predictors of anti-epidermal growth factor receptor (EGFR) therapies, the predictive role of BRAF MT for anti-EGFR agents has been of interest given the relationship with RAS in the EGFR/RAS/RAF/MEK/ERK pathway. BRAF MT and its associated resistance to anti-EGFR agents have been suggested by several retrospective analyses [71–73].
\n
To date, the predictive role of BRAF MT on anti-EGFR agents remains unclear, in light of differing conclusions from two separate meta-analyses [74, 75]. Pietrantonio et al. concluded that BRAF MT might be a negative predictor for anti-EGFR agents, supporting the meta-analysis by Yuan et al. [58]. This study included a pooled analysis of nine phase III trials and one phase II trial and shown that cetuximab- or panitumumab-based therapy did not increase the benefit of standard treatment versus best supportive care in RAS-WT/BRAF-MT CRC patients. Overall, the addition of cetuximab or panitumumab did not significantly improve the PFS (HR=0.88; p=0.33), OS (HR=0.91; p=0.63), and overall response rate [ORR; relative risk (RR)=1.31; p=0.25] in this subgroup population [74]. However, another recent meta-analysis reviewed seven RCTs for OS and eight RCTs for PFS and concluded on insufficient evidence to justify the exclusion of anti-EGFR agents in the BRAF MT population [75]. Nevertheless, these latest findings have supported the need for BRAF mutation assessment before the initiation of treatment to study and tailor the most effective strategies to the BRAF MT population.
\n
\n
\n
\n
5. Treatment strategies
\n
\n
5.1. Triplet chemotherapy effect
\n
\nBRAF MT has not been known to be a predictor of benefit from chemotherapy or anti-vascular endothelial growth factor (VEGF) agents. The Italian TRIBE study [35] compared anti-VEGF therapy, bevacizumab added to intensified triplet chemotherapy, fluorouracil, oxaliplatin, and irinotecan (FOLFOXIRI), to standard first-line doublet chemotherapy with fluorouracil and irinotecan (FOLFIRI) plus bevacizumab in 508 unresectable mCRC patients. The study reported a higher response rate of 65% vs 53% with the triplet FOLFOXIRI and bevacizumab arm. Reassuringly, there was no increase in fatal or serious adverse events.
\n
The updated analyses of the same study reported a BRAF mutation rate of 7.5%. In the BRAF MT group, there was a significant trend for better survival in the triplet arm compared to the doublet arm (19.1 vs 10.8 months; HR=0.55). Significantly, this is the only regimen to have resulted in a median OS of more than 15 months in the BRAF MT group compared to the more often reported median of 4.4 to 14 months in most studies [29, 57]. It was proposed that intensified triplet chemotherapy (FOLFOXIRI+bevaczicumab) is considered first line in the BRAF MT group, who usually have aggressive cancers with limited ability to undergo a more sequential approach to treat metastatic disease.
\n
\n
\n
5.2. Maintenance treatment
\n
A recent meta-analysis on five RCTs had failed to demonstrate a statistically significant OS benefit (HR=0.93; 95% CI=0.85–1.02; p=0.12; I2=5%) with administering maintenance chemotherapy versus complete treatment interruption after first-line therapy in unselected CRC [76]. The chemotherapy free interval in the group not using maintenance treatment was 3.9 months (3.6–4.3 months). Nevertheless, the author had emphasized the importance of predictive markers to guide the selection of patients who would benefit from the maintenance strategy. Although not formally tested in the BRAF MT subgroup population, the maintenance strategy might prove more favourable than the intermittent strategy given its known aggressive nature. This is especially relevant given that the median reported PFS in BRAF MT as indicated previously ranged from 4.3 to 6.3 months after first-line treatment [68, 69].
\n
In terms of the choice for maintenance treatment, there is no current recommended standard. However, practice trends could perhaps be extrapolated from the AIO KRK 0207 trial, which confirmed the prognostic impact of mutation status [77]. In all patients (irrespective of BRAF or RAS status), at a median follow-up of 27 months, the authors reported a time to failure of strategy of 3.6, 6.2, and 4.6 months among all patients receiving no treatment, fluoropyrimidine plus bevacizumab, or bevacizumab alone, respectively (p<0.001). However, in RAS/BRAF WT patients, bevacizumab monotherapy was as effective as combination treatment (fluoropyramidine/bevacizumab) for maintenance. In contrast, in the RAS or BRAF MT subgroup, the combination treatment was favoured, as single-agent bevacizumab was equivalent to no maintenance at all.
\n
\n
\n
\n
6. Investigated treatments targeting EGFR/RAF/MEK
\n
\n
6.1. BRAF/MEK inhibitors
\n
As mentioned above, RAS proteins normally activate BRAF along with A-RAF and C-RAF [78]. BRAF mutations lead to the constitutive activation of BRAF kinase activity, resulting in phosphorylation and activation of the MEK kinases (MEK1 and MEK2). Once activated, MEK kinases phosphorylate and activate ERK kinases, which phosphorylate a multitude of cellular substrates involved in cell proliferation and survival (Figure 1).
\n
RAF inhibitors, such as vemurafenib and dabrafenib, have produced response rates of 50 to 80% in melanomas that harbour the BRAF V600 mutations [79, 80]. This is disappointingly contrasting to the response rate of only 5%, and median PFS of 2.1 months achieved in BRAF MT CRC [81]. Previous observations have proposed that RAF inhibitor insensitivity in BRAF MT CRC was driven by the feedback reactivation of the RAS/RAF/MEK/ERK signalling cascade. In many BRAF MT CRC cell lines, EGFR-mediated activation of RAS and C-RAF was observed to be the culprit [82, 83]. Solit et al. had also demonstrated the critical dependency of BRAF MT colorectal cell lines and xenografts on MEK-ERK signalling, which renders them highly sensitive to pharmacological MEK inhibition. Pharmacological MEK inhibition completely abrogated tumour growth in BRAF MT xenografts, whereas RAS MT tumours were only partially inhibited [84].
\n
Many RAF inhibitor combinations were hence evaluated in clinical trials in recent years and have shown promising results. A phase I to II clinical trial of combined RAF/MEK inhibition with dabrafenib (150 mg BD) and trametenib (2 mg OD) in 43 BRAF MT CRC resistant to anti-EGFR therapy produced partial responses in 12% and complete response in 2%. One patient achieved a durable complete response exceeding 36 months. Additionally, 56% achieved stable disease as the best confirmed response [85].
\n
\n
\n
6.2. Dual and triplet targeting EGFR/BRAF/MEK inhibitors
\n
The observations above have also led to a number of studies assessing the combined blockade at other sites in the EGFR pathway in addition to RAF/MEK inhibition. It was observed that the dual inhibition of anti-EGFR therapy in combination with RAF inhibition in resistant cell lines might still produce a lower degree of mitogen-activated protein kinase (MAPK) pathway inhibition in BRAF MT CRC compared to single-agent RAF inhibitors in BRAF MT melanoma patients. Dabrafenib and panitumumab doublet was trialled with a response rate of (partial and complete response) 2/20 (10%) and stabilised disease in 16/20 (80%) as the best overall response [86]. Another study examined the combination of vemurafenib (BRAF-inhibitor) and panitumumab in 15 patients. Two (13%) patients reported partial responses lasting 40 and 24 weeks, respectively. Eight (53%) patients stable disease lasting more than 6 months [87]. A phase II study studied dual inhibition with encorafenib (BRAF inhibitor) and cetuximab with 26 patients. Encorafenib and cetuximab doublet was reported to produce an overall RR (complete and partial) of 23.1% with a median PFS of 3.7 months. The most common treatment-related grade 3/4 adverse events associated with this doublet regimen were fatigue and hypophosphatemia (8% each) [88].
\n
Encouragingly, the triplet combination of EGFR/RAF/MEK inhibition in BRAF MT CRC reported an improved response rate (26% complete and partial) in 35 patients compared to the doublet inhibition. The triplet regimen had also stabilised disease in 57%. The most common adverse events reported were diarrhoea (60% grade 1/2 and 9% grade 3) and dermatitis acneiform (47% grade 1/2 and 9% grade 3) [86].
\n
\n
\n
6.3. Acquired resistance to EGFR/RAF/MEK targeted therapies
\n
Although trials have demonstrated early efficacies of combination targeted therapies in these BRAF MT patients, attention was brought towards their eventual treatment resistance and disease progression. A group in Harvard recently compared pretreatment and postprogression BRAF MT CRC tumour biopsies by whole exome sequencing (WES) to examine the related changes that could explain treatment resistance in these cases [89]. They have identified four possible acquired molecular mechanisms that could lead to resistance to combination treatments with RAF/MEK and RAF/EGFR. These four mechanisms include (1) KRAS exon 2 mutation (G12D and G13D), (2) KRAS WT amplification [confirmed by fluorescence in situ hybridisation (FISH) to be ~25-fold overexpression], (3) BRAF MT allele amplification, and (4) MEK1 mutation. These alterations converge on the MAPK pathway reactivation and promote resistance.
\n
Interestingly, the group also discovered an ERK inhibitor that retained the ability to suppress MAPK signalling and overcome each of these mechanisms identified [89]. In conjunction with these findings, early-phase clinical trials are currently incorporating ERK inhibitors as potential future treatment strategies for BRAF MT CRC.
\n
\n
\n
6.4. Other possible EGFR/RAF targeted combination treatments
The phase I vemurafenib/irinotecan/cetuximab triplet study reported a RR of 35% (partial response) in 18 mCRC patients with a median PFS of 7.7 months. The most common adverse effects were fatigue (94%), diarrhoea (89%), nausea (83%), and rash (78%). Following this, a U.S. cooperative group randomised phase II trial (NCT01787500) of irinotecan and cetuximab±vemurafenib in BRAF-mutated mCRC (SWOG 1406) is now ongoing [90].
\n
\n
\n
\n
\n
7. Alternative target signalling pathways
\n
Although our increasing understanding of the complexity of the EGFR/RAF pathway has led to some advances in our understanding of possible mechanisms of resistance to BRAF inhibition, additional complex interactions with related pathways are likely to be involved, including the phosphatidylinositol 3-kinase (PI3K)/AKT pathway, mammalian target of rapamycin (mTOR), and Wnt signalling.
\n
\n
7.1. PI3K/AKT and mTOR pathway
\n
The PI3K/AKT pathway is an alternative resistance mechanism to BRAF inhibition in BRAF MT CRC. Approximately 40% of CRC have been shown to have alterations in one of eight PI3K pathway genes. These mutations are almost always mutually exclusive to each other [91]. In addition, BRAF mutation co-exists with PIK3CA mutations in 13% and PTEN mutations in 22% of CRC [37]. Compared to BRAF MT melanoma cell lines, BRAF MT CRC cell lines seemed to also display a higher rate of PI3K/AKT pathway activation. These cell lines were reported to be less sensitive to the BRAF inhibitor, vemurafenib [92].
\n
Based on the above observations, the combination triplet inhibition treatment was studied with encorafenib (BRAF inhibitor), cetuximab, and PI3K inhibitor (alpelisib) in 28 patients and reported an overall RR of 32.1% with a median PFS of 4.3 months. The most common grade 3/4 adverse events reported were hyperglycemia (11%) and increased lipase (7%) [88].
\n
Sustained PI3K/mTOR activity was demonstrated also by Corcoran et al. [82] in BRAF MT CRC cell lines upon BRAF inhibition. Pleasingly, a potent growth-inhibitory effect was recently observed in xenografts of BRAF MT CRC with the combined BRAF/PI3K/mTOR inhibition [93].
\n
\n
\n
7.2. Wnt/β-catenin pathway
\n
A study by Lemieux et al. demonstrated the Wnt/β-catenin pathway (Figure 3) as a potential novel target in MEK/ERK signalling involved in CRC tumourigenesis [94]. The Wnt/β-catenin pathway is activated via the binding of Wnt1 protein to the G-protein coupled receptor, Frizzled. After the activation by Wnt1, Dishevelled protein (Dsh) induces the dissociation of the destruction complex that usually degrades β-catenin. Without the destruction complex, β-catenin is accumulated in the cytoplasm and transported to the nucleus to act as a transcriptional coactivator of transcription factors as shown in Figure 4. The aforementioned destruction complex comprises Axin (A), adenomatous polyposis coli (APC), and glycogen synthase kinase 3 (GSK3β). In the absence of Wnt1 activation, the destruction complex phosphorylates the downstream ubiquinating process. Here, the β-transducin repeat containing protein (βTrCP) binds β-catenin, ubiquinating it and marks it for degradation by the proteasome. Although there is conflicting literature with regards to the role of MAPK signalling in activating Wnt/β-catenin pathway, this group found Wnt signalling induction in high-grade BRAF MT tumours. Their data also show that the oncogenic activation of KRAS/BRAF/MEK signalling stimulates the canonical Wnt/β-catenin pathway, which in turn promotes intestinal tumour growth and invasion. This has in turn sparked trial designs to incorporate Wnt signalling as a treatment strategy.
\n
Figure 4.
Wnt/β-catenin pathway.
\n
\n
\n
\n
8. Other possible therapeutic mechanisms
\n
Recently, a number of other early studies have reported additional potential mechanisms of targeted treatment, which had shown promise in BRAF MT CRC xenografts or cell line studies.
Dovitinib is a multi-target angiokinase inhibitor with activity against fibroblast growth factor receptors (FGFRs), platelet-derived growth factor receptors (PDGFRs), and VEGF receptors, which participate in tumour growth, survival, angiogenesis, and vascular development. Although not effective in vitro, in vivo studies have shown the inhibition of BRAF MT xenografts tumours with dovitinib. Lee et al. proposed that this observation is secondary to its angiogenesis-suppressing effect and could be a novel approach to improve the outcome of CRC patients in whom FGFR is overexpressed or amplified [95].
\n
\n
\n
8.2. Proteasome inhibitor (carfilzomib)
\n
A novel use of proteasome inhibitors (carfilzomib, bortezomib), known more for utility in haematological malignancy, has shown promising preclinical results in BRAF MT CRC [96]. Zecchin et al. have observed increased sensitivity of BRAF MT CRC to carfilzomib, whereas WT cells were significantly less affected (p<0.05). This response seemed to be independent of the phosphatase and tensin homologue (PTEN) or retinoblastoma protein (RB1) expression status in CRC. The mechanism of this activity was explained by the higher accumulation rate of ubiquitinated proteins in MT cells with respect to WT. It was speculated that this is secondary to the non-oncogenic addiction of BRAF MT cells to the protein degradation function of proteasome to counterbalance the proteotoxic stress induced by the MT protein. Interestingly, carfilzomib was also found to have antagonistic effects with the RAF inhibitor, vemurafenib, and was proposed as a possible alternative treatment to BRAF/MEK inhibition.
\n
\n
\n
8.3. microRNA (miR-145)
\n
miR-145, a short RNA molecule of microRNA gene, which was observed to have tumour suppressor function, was found to be down-regulated in vemurafenib-resistant BRAF MT CRC cell lines [97]. Peng et al. reported that the overexpression of miR-145 increased the sensitivity of BRAF MT CRC cell lines both in vitro and in vivo and could be used as a potential therapeutic target.
\n
\n
\n
8.4. In situ cancer vaccine (Allostim)
\n
AlloStim is an innovative design based on immunotherapy principles. It is derived from the blood of normal blood donors and is intentionally mismatched to the recipient. CD4+ T cells are initially separated from the blood and differentiated and expanded for 9 days in culture to make an intermediary called T-Stim. AlloStim is made by incubating T-Stim cells for 4 h with antibody-coated microbeads. The cells with the beads still attached are suspended in infusion media and loaded into syringes. The syringes are shipped refrigerated to the point-of-care. A phase I study was completed in May 2011 and a phase II/III study is due to recruit in 2016. It involves an in situ (in the body) cancer vaccine step that combines killing a single metastatic tumour (usually liver metastasis) lesion by the use of cryoablation to cause the release of tumour-specific markers to the immune system and then injecting bioengineered allogeneic immune cells (AlloStim) into the lesion as an adjuvant to modulate the immune response and educate the immune system to kill other tumour cells wherever they reside in the body [98].
Apoptosis regulator (BCL-2/BCL-XL) inhibitor (Navitoclax) was explored as a novel approach in sensitising BRAF MT CRC to mTOR inhibition. The results showed that this combination strategy leads to efficient apoptosis in specifically KRAS and BRAF MT but not WT CRC cells [99]. These data showed promising results with the combination strategy of apoptosis regulator inhibitors with mTOR inhibitors in BRAF MT CRC.
\n
\n
\n
\n
9. Ongoing trials for BRAF MT CRC
\n
Many phase I/II trials are currently ongoing for BRAF MT mCRC. Most of them focus on the RAS/RAF/MEK/ERK signalling pathway, trialling combination targeted treatments. Table 5 lists these available trials.
MEK inhibitor+FOLFOX: CRC failing standard treatment
\n
Recruiting
\n
\n
\n
NCT02380443
\n
IIB
\n
Allostim (in situ cancer vaccine): third-line treatment in KRAS/BRAF MT CRC
\n
Pending
\n
\n
\n
NCT02278133
\n
IB/II
\n
Wnt ligand inhibitor (WNT974), RAF inhibitor and cetuximab
\n
Recruiting
\n
\n
\n
NCT01351103
\n
I
\n
Wnt ligand inhibitor (LGK974)
\n
Recruiting
\n
\n\n
Table 5.
Ongoing trials in BRAF MT CRC
\n
\n
\n
10. Conclusion
\n
The BRAF V600E MT CRC typically presents with right-sided proximal high-grade mucinous tumours in older women and may arise from serrated polyps. Molecularly, they are associated with more MLH1 methylation, MSI, and CIMP. This small subset of CRC, which generally affects approximately 10% of CRC patients, remains a challenging group with poor response to both anti-EGFR and standard doublet chemotherapy. This CRC subgroup is typically aggressive, has short median PFS between sequential lines of treatments, and emphasises the need to use effective treatments early. New evidence suggests that triplet chemotherapy with FOLFOXIRI could be considered in suitable patients with or without bevacizumab as first-line treatment. Many trials are currently studying the effective combinations of targeted treatments involving BRAF and MEK inhibitors in this subgroup and ways to overcome resistance.
\n
\n\n',keywords:"BRAF, colorectal cancer, dabrafenib, trametenib, FOLFOXIRI",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/50550.pdf",chapterXML:"https://mts.intechopen.com/source/xml/50550.xml",downloadPdfUrl:"/chapter/pdf-download/50550",previewPdfUrl:"/chapter/pdf-preview/50550",totalDownloads:2440,totalViews:766,totalCrossrefCites:1,totalDimensionsCites:1,totalAltmetricsMentions:0,impactScore:1,impactScorePercentile:59,impactScoreQuartile:3,hasAltmetrics:0,dateSubmitted:"October 4th 2015",dateReviewed:"January 11th 2016",datePrePublished:null,datePublished:"September 7th 2016",dateFinished:"May 4th 2016",readingETA:"0",abstract:"The BRAF mutant colorectal cancer subgroup is a small population with unique clinicopathological and molecular features. This subgroup has been associated with particularly poor prognosis and advanced disease. The poor response of these patients to available treatments has driven much of the effort in trialling combination targeted treatments involving BRAF and MEK inhibitors. Most recently, an observed survival benefit with intensive triplet chemotherapy agents would encourage its use as first-line treatment in suitable candidates given that few of these patients proceed to second- or third-line treatments.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/50550",risUrl:"/chapter/ris/50550",book:{id:"5122",slug:"colorectal-cancer-from-pathogenesis-to-treatment"},signatures:"Louisa Lo, Timothy Price, Joanne Young and Amanda Townsend",authors:[{id:"178563",title:"Associate Prof.",name:"Timothy",middleName:"Jay",surname:"Price",fullName:"Timothy Price",slug:"timothy-price",email:"timothy.price@adelaide.edu.au",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"University of Adelaide",institutionURL:null,country:{name:"Australia"}}},{id:"178572",title:"Dr.",name:"Amanda",middleName:null,surname:"Townsend",fullName:"Amanda Townsend",slug:"amanda-townsend",email:"amanda.townsend@health.sa.gov.au",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"University of Adelaide",institutionURL:null,country:{name:"Australia"}}},{id:"178573",title:"Dr.",name:"Louisa",middleName:null,surname:"Lo",fullName:"Louisa Lo",slug:"louisa-lo",email:"Louisa.lo@health.sa.gov.au",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"178574",title:"Dr.",name:"Joanne",middleName:null,surname:"Young",fullName:"Joanne Young",slug:"joanne-young",email:"joanne.young@adelaide.edu.au",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. BRAF and the RAS/RAF/MEK/ERK signalling pathway",level:"1"},{id:"sec_2_2",title:"2.1. BRAF mutation detection methods",level:"2"},{id:"sec_3_2",title:"2.2. BRAF mutation and its frequency in CRC",level:"2"},{id:"sec_5",title:"3. BRAF mutation and its clinical significance in CRC",level:"1"},{id:"sec_5_2",title:"3.1. CRC tumourigenesis pathways",level:"2"},{id:"sec_6_2",title:"3.2. BRAF testing to distinguish between sporadic versus germ-line MSI-H cases (Lynch syndrome)",level:"2"},{id:"sec_7_2",title:"3.3. Clinicopathological and molecular features of BRAF MT CRC",level:"2"},{id:"sec_9",title:"4. BRAF mutation and its prognostic and predictive significance",level:"1"},{id:"sec_9_2",title:"4.1. Prognostic role and nature of progression",level:"2"},{id:"sec_10_2",title:"4.2. Predictive role",level:"2"},{id:"sec_12",title:"5. Treatment strategies",level:"1"},{id:"sec_12_2",title:"5.1. Triplet chemotherapy effect",level:"2"},{id:"sec_13_2",title:"5.2. Maintenance treatment",level:"2"},{id:"sec_15",title:"6. Investigated treatments targeting EGFR/RAF/MEK",level:"1"},{id:"sec_15_2",title:"6.1. BRAF/MEK inhibitors",level:"2"},{id:"sec_16_2",title:"6.2. Dual and triplet targeting EGFR/BRAF/MEK inhibitors",level:"2"},{id:"sec_17_2",title:"6.3. Acquired resistance to EGFR/RAF/MEK targeted therapies",level:"2"},{id:"sec_18_2",title:"6.4. Other possible EGFR/RAF targeted combination treatments",level:"2"},{id:"sec_18_3",title:"6.4.1. Vemurafenib/irinotecan/cetuximab combination",level:"3"},{id:"sec_21",title:"7. Alternative target signalling pathways",level:"1"},{id:"sec_21_2",title:"7.1. PI3K/AKT and mTOR pathway",level:"2"},{id:"sec_22_2",title:"7.2. Wnt/β-catenin pathway",level:"2"},{id:"sec_24",title:"8. Other possible therapeutic mechanisms",level:"1"},{id:"sec_24_2",title:"8.1. Multi-targeted angiokinase inhibitor (dovitinib)",level:"2"},{id:"sec_25_2",title:"8.2. Proteasome inhibitor (carfilzomib)",level:"2"},{id:"sec_26_2",title:"8.3. microRNA (miR-145)",level:"2"},{id:"sec_27_2",title:"8.4. In situ cancer vaccine (Allostim)",level:"2"},{id:"sec_28_2",title:"8.5. Apoptosis regulator (BCL-2/BCL-XL) inhibitor (Navitoclax)",level:"2"},{id:"sec_30",title:"9. Ongoing trials for BRAF MT CRC",level:"1"},{id:"sec_31",title:"10. Conclusion",level:"1"}],chapterReferences:[{id:"B1",body:'\nRozek LS, Herron CM, Greenson JK, Moreno V, Capella G, Rennert G, et al. Smoking, gender, and ethnicity predict somatic BRAF mutations in colorectal cancer. Cancer Epidemiol Biomarkers Prev. 2010;19(3):838–43. DOI: 10.1158/1055-9965.EPI-09-1112\n'},{id:"B2",body:'\nShaukat A, Arain M, Thaygarajan B, Bond JH, Sawhney M. Is BRAF mutation associated with interval colorectal cancers? Dig Dis Sci. 2010;55(8):2352–6. DOI: 10.1007/s10620-010-1182-9\n'},{id:"B3",body:'\nPrice TJ, Hardingham JE, Lee CK, Weickhardt A, Townsend AR, Wrin JW, et al. 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J Clin Oncol. 2010;28(15s):abstr 3534.\n'},{id:"B82",body:'\nCorcoran RB, Ebi H, Turke AB, Coffee EM, Nishino M, Cogdill AP, et al. EGFR-mediated re-activation of MAPK signaling contributes to insensitivity of BRAF mutant colorectal cancers to RAF inhibition with vemurafenib. Cancer Discov. 2012;2(3):227–35. DOI: 10.1158/2159-8290.CD-11-0341\n'},{id:"B83",body:'\nPrahallad A, Sun C, Huang S, Di Nicolantonio F, Salazar R, Zecchin D, et al. Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature. 2012;483(7387):100–3. DOI: 10.1038/nature10868\n'},{id:"B84",body:'\nSolit DB, Garraway LA, Pratilas CA, Sawai A, Getz G, Basso A, et al. BRAF mutation predicts sensitivity to MEK inhibition. Nature. 2006;439(7074):358–62.\n'},{id:"B85",body:'\nCorcoran RB, Atreya CE, Falchook GS, Kwak EL, Ryan DP, Bendell JC. Combined BRAF and MEK inhibition with dabrafenib and trametinib in BRAF V600-mutant colorectal cancer. J Clin Oncol. 2015;33(34):4023–31. DOI: 10.1200/JCO.2015.63.2471\n'},{id:"B86",body:'\nAtreya CE, Van Cutsem E, Bendell JC, Andre T, Schellens JHM, Gordon MS, et al. Updated efficacy of the MEK inhibitor trametinib (T), BRAF inhibitor dabrafenib (D), and anti-EGFR antibody panitumumab (P) in patients (pts) with BRAF V600E mutated (BRAFm) metastatic colorectal cancer (mCRC). J Clin Oncol. 2015;33:abstr 103.\n'},{id:"B87",body:'\nYaeger RD, Cercek A, O’Reilly EM, Reidy DL, Kemeny NE, Wolinsky T, et al. Pilot study of vemurafenib and panitumumab combination therapy in patients with BRAF V600E mutated metastatic colorectal cancer. J Clin Oncol. 2015;33(suppl 3):abstr 611.\n'},{id:"B88",body:'\nElez E, Schellens J, Van Geel R, Bendell JC, Spreafico A, Schuler M, et al. Results of a phase 1b study of the selective BRAF V600 inhibitor encorafenib in combination with cetuximab alone or cetuximab + alpelisib for treatment of patients with advanced BRAF-mutant metastatic colorectal cancer. Ann Oncol. 2015;26(suppl 4):117–22. DOI: 10.1093/annonc/mdv262.08\n'},{id:"B89",body:'\nAhronian LG, Sennott EM, Van Allen EM, Wagle N, Kwak EL, Faris JE, et al. Clinical acquired resistance to RAF inhibitor combinations in BRAF-mutant colorectal cancer through MAPK pathway alterations. Cancer Discov. 2015;5(4):358–67. DOI: 10.1158/2159-8290.CD-14-1518\n'},{id:"B90",body:'\nHong DS, Morris VK, El Osta BE, Fu S, Overman MJ, Piha-Paul SA, et al. Phase Ib study of vemurafenib in combination with irinotecan and cetuximab in patients with BRAF-mutated metastatic colorectal cancer and advanced cancers. J Clin Oncol. 2015;33(suppl 15):abstr 3511.\n'},{id:"B91",body:'\nParsons DW, Wang TL, Samuels Y, Bardelli A, Cummins JM, De Long L, et al. Colorectal cancer: mutations in a signalling pathway. Nature. 2005;436(7052):792.\n'},{id:"B92",body:'\nMao M, Tian F, Mariadason JM, Tsao CC, Lemos RJr, Dayyani F, et al. Resistance to BRAF inhibition in BRAF-mutant colon cancer can be overcome with PI3K inhibition or demethylating agents. Clin Cancer Res. 2013;19(3):657–67. DOI: 10.1158/1078-0432.CCR-11-1446\n'},{id:"B93",body:'\nCoffee EM, Faber AC, Roper J, Sinnamon MJ, Goel G, Keung L, et al. Concomitant BRAF and PI3K/m TOR blockade is required for effective treatment of BRAF(V600E) colorectal cancer. Clin Cancer Res. 2013;19(10):2688–98. DOI: 10.1158/1078-0432.CCR-12-2556\n'},{id:"B94",body:'\nLemieux E, Cagnol S, Beaudry K, Carrier J, Rivard N. Oncogenic KRAS signalling promotes the Wnt/β-catenin pathway through LRP6 in colorectal cancer. Oncogene. 2015;34(38):4914–27. DOI: 10.1038/onc.2014.416\n'},{id:"B95",body:'\nLee CK, Lee ME, Lee WS, Kim JM, Park KH, Kim TS, et al. Dovitinib (TKI258), a multi-target angiokinase inhibitor, is effective regardless of KRAS or BRAF mutation status in colorectal cancer. Am J Cancer Res. 2014;5(1):72–86.\n'},{id:"B96",body:'\nZecchin D, Boscaro V, Medico E, Barault L, Martini M, Arena S, et al. BRAF V600E is a determinant of sensitivity to proteasome inhibitors. Mol Cancer Ther. 2013;12(12):2950–61. DOI: 10.1158/1535-7163.MCT-13-0243\n'},{id:"B97",body:'\nPeng W, Hu J, Zhu XD, Liu X, Wang CC, Li WH, et al. Overexpression of mi R-145 increases the sensitivity of vemurafenib in drug-resistant colo205 cell line. Tumour Biol. 2014;35(4):2983–8. DOI: 10.1007/s13277-013-1383-x\n'},{id:"B98",body:'\nImmunovative Therapies Ltd. Increased Frequency of Allo Stim(TM) Dosing in Combination With Cryoablation in Metastatic Colorectal Cancer [Internet]. March 2, 2015 [Updated: December 7, 2015]. Available from: https://clinicaltrials.gov/ct2/show/record/NCT02380443 [Accessed: December 28, 2015].\n'},{id:"B99",body:'\nFaber AC, Coffee EM, Costa C, Dastur A, Ebi H, Hata AN, et al. m TOR inhibition specifically sensitizes colorectal cancers with KRAS or BRAF mutations to BCL-2/BCL-XL inhibition by suppressing MCL-1. Cancer Discov. 2014;4(1):42–52. DOI: 10.1158/2159-8290.CD-13-0315\n'},{id:"B100",body:'\nWorthley DL, Whitehall VL, Spring KJ, Leggett BA. Colorectal carcinogenesis: road maps to cancer. World J Gastroenterol. 2007;13(28):3784–91.\n'}],footnotes:[],contributors:[{corresp:null,contributorFullName:"Louisa Lo",address:null,affiliation:'
Medical Oncology Department, Queen Elizabeth Hospital, Birmingham, England
Medical Oncology Department, Queen Elizabeth Hospital, Birmingham, England
University of Adelaide, Adelaide, Australia
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1. Introduction
The capital return rate is the relative time change rate of value. We choose to write
rt=dκKtdtE1
where κ in the numerator considers value growth, operative expenses, interests and amortizations, but neglects investments and withdrawals. In other words, it is the change of capitalization on an economic profit/loss basis. K in the denominator gives capitalization on a balance sheet basis, being directly affected by any investment or withdrawal.
A significant finding in Eq. (1) is that the capital return rate r depends not only on the value change rate dκdt, but also on the current valuation Kt. Apparently, there is an intimate relationship between the capital return rate and the valuation. A fundamental question then is whether the valuation can be approached by inverting Eq. (1) as
Kt=dκrtdtE2
Obviously, Eq. (2) is mathematically correct. However, in comparison with Eq. (1), it may appear less intuitive. While Eq. (1) provides the definition of capital return rate as a function of observable valuation, does Eq. (2) provide the definition of valuation as a function of observable capital return rate? Or does it possibly provide the definition of valuation as a function of the required capital return rate? Any of these interpretations is possible.
The quantities appearing on the right-hand side of Eq. (1) are observable in a variety of ways, including profit-loss—statement, balance sheet, and market valuation. As the right-hand side has been determined, the left-hand side is naturally known. However, this results in a circular definition in Eq. (2). Alternatively, the capital return rate appearing on the right-hand side of Eq. (2) can be determined from comparable reference investments.
The momentary definitions appearing in Eqs. (1) and (2) provide a highly simplified description of valuation and capital return rate. In reality, there is variability due to a number of factors. Enterprises often contain businesses distributed to a variety of production lines, geographic areas, and markets. In addition, quantities appearing in Eqs. (1) and (2) are not necessarily completely known but may contain probabilistic scatter. Correspondingly, the expected values of capital return rate and valuation can be written as
where pi corresponds to the probability density of quantity i. It is found that while the capital return rate and the capitalization are simply invertible in the absence of any variation (Eqs. (1) and (2)), the same is not the case in the presence of variation, either deterministic or probabilistic (Eqs. (3) and (4)). Here, it is worth noting that the capital return rate in the denominator of Eq. (4) obviously tends to a “reference” capital return rate, rather than a directly observed one.
In the remaining part of this chapter, we will first discuss the practical implementation of the determination of capital return rate and firm value using Eqs. (3) and (4) in the case of a real estate firm benefiting from the growth of multiannual plant stands of varying age. Then, we will discuss the determination of the values of the quantities appearing in Eqs. (3) and (4), as well as factors contributing to them. Finally, a few applications are discussed, as well as interpolation techniques.
2. Application to stands of multiannual plants
In this section, the determination of capital return rate and enterprise value is discussed in the case of a real estate firm benefiting from the growth of multiannual plant stands of varying ages. Conducting a change of variables in Eqs. (3) and (4) results as
rt=∫patdκdtatda∫patKatda=∫patratKatda∫patKatdaE5
and
Kt=∫patKatda=∫patdκdtatratdaE6
where a refers to stand age. Again, the capital return rate in the denominator of Eq. (6) rather refers to a reference rate than a directly observed one.
It is found from Eqs. (5) and (6) that the probability density of stand age is a function of time, and correspondingly, the capital return rate, as well as the estate value, evolves in time. A significant simplification would appear if the probability densities appearing on the right-hand side of Eqs. (5) and (6) would not change along with time. Within forestry, such a situation would be denoted “normal forest principle.” corresponding to evenly distributed stand age determining relevant stand properties [1].
rt=∫dκdtada∫Kada=∫raKada∫KadaE7
and
Kt=pa∫Katda=pa∫dκdtatratdaE8
The “normal forest principle” is rather useful when considering silvicultural practices, but seldom applies to the valuation of real-life real estate firms, with generally non-uniform stand age distribution. However, it has recently been shown [2] that the principle is not necessary for the simplification of Eqs. (5) and (6) into (7) and (8). This happens by focusing on a single stand, instead of an entire estate or enterprise, and considering that time proceeds linearly. Then, the probability density function p(a) is constant within an interval [0, τ]. Correspondingly, it has vanished from Eq. (7) and appeared outside of the integral in Eq. (8).
The topic of this chapter, however, is firm valuation. As the relatively simple Eqs. (7) and (8) are useful in the design of silvicultural practices, firm valuation typically happens at a specific instant of time, and the probability density p(a) generally is non-uniform. Correspondingly, Eqs. (5) and (6) must be applied. Fortunately, p(a) usually is known for any property where recent inventory results are available. It is further fortunate that Eqs. (4), (6), and (8) contain simple summations, unlike Eqs. (3), (5), and (7).
3. Determination of stand capitalization
There is a variety of methods to determine the value K appearing in Eqs. (3)–(6). In the case of an incorporated company or a firm with equivalent reporting, the value can be found from the balance sheet. Such an outcome does depend on applied accounting practices. On the other hand, the value can be determined as a market value. The latter is straightforward in the case of publicly listed companies, or other companies with the established share trading records. A third alternative for firm value determination is the computation of an “intrinsic value,” considering the prognosticated future development of the firm [3, 4, 5].
In the case of a real estate firm benefiting from the growth of multiannual plants of varying age, the value K within any stand may be approached as the sum of the value of the plants on the stand, the value of bare land, and the value of non-amortized investments. Such computation is problematic if non-mature plants do not have any immediate sale value. In such a case, it is not uncommon to determine stand value by discounting expected future revenues [6, 7, 8, 9]. The discount rate is sometimes taken arbitrarily, but often it can be determined as an internal rate of return [10].
We here provide a few examples of the determination of the value of forest stands by interpolation. It is not uncommon that planted seedlings may require several years to mature to young trees of commercial value. However, during those years, expected revenues become closer in time. Correspondingly, it would be unrealistic to assume the growth of saplings would not add value. The capitalization, including such an additional expected value, could be approximated by some kind of a smoothing function. One possibility could be
ka=1τ−a∫aτKtexprt∗a−tdtE9
where r(t) is the capital return rate at stand age t. A simpler version would be
ka=1τ−a∫aτKtexpr∗a−tdtE10
Both of the above equations converge to terminal capitalization kτ=Kτ, regardless of the capital return rate r(t) or r. However, there is no guarantee of any definite convergence in a newly established stand. Such convergence kinitial=Kinitial could be approached by fitting an internal rate of return i, which provides convergence. That would correspond to assuming that the bare land value includes any additional expectation value for a newly established stand, resulting as
ka=1τ−a∫aτKtexpi∗a−tdtE11
It might be possible to determine capitalization indirectly by discounting revenue. This would result as
ka=BL+∫aτRtexpj∗a−tdtE12
where BL denotes bare land value, and R(t) net revenue at time t. Again, the discount rate j shall be fitted for convergence kinitial=Kinitial.
The functionality of Eqs. (11) and (12) are investigated in Figure 1, in the case of a spruce stand established with 1800 saplings/ha, and a wooded stand observed at the age of 35 years. The former initial condition is based on the early application of a growth model on saplings stands [11, 12], the latter on the observations of the wooded stand [12, 13]. The former shows a positive additional expectation value of trees for young stands and after thinnings. If such additional values would be considered, microeconomically optimal rotation ages would be affected. However, Eq. (11) results as the additional value being negative before the first thinning. It is not known how the negative additional expectation value should be considered in management. Within the wooded stand observed at 35 years of age, the additional expectation value of trees of young stands according to Eq. (11) would be negative, being slightly positive only after thinning. Eq. (12) would indicate zero additional value before thinning and somewhat negative after thinning. An explanation for the latter is that regeneration expenses are carried in the balance sheet until the end of the rotation. This results in the capitalization at mature age being greater than the sum of discounted terminal revenue and bare land value.
Figure 1.
Capitalization, as appearing in Eq. (1), as well as smoothed capitalization according to Eqs. (11) and (12), in the case of the two example stands. (a) (above) shows a spruce stand established with 1800 saplings/hectare. (b) (below) shows a spruce stand first observed at the age of 35 years.
Figure 1a indicates that in the case of the early application of the growth model, internal rate of return-based interpolation could be useful in the determination of young stand capitalization. In the absence of such adjustment, there would be a negligible value increment for a period of two decades. Eq. (12) can be straightforwardly applied by substituting k(a) from in place of K(a) in Eqs. (5), (6), (7), or (8). However, interpolation is possible only after an initial treatment schedule has been designed using Eqs. (5) or (7). Correspondingly, Eq. (12) must be used iteratively with the other equations.
On the other hand, in the case of Figure 1b, interpolation of capitalization appears irrelevant. A natural reason is that the stand has been first observed at the age of 35 years. The capitalization from the stand establishment to the time of observation already has been approximated by exponential interpolation. Correspondingly, results based on the observations of wooded stands do not appear to be in the need of any further interpolation.
4. Determination of a reference capital return rate
In money market theory, increased duration of commitments tends to increase the risk experienced by the borrower [14, 15, 16]. However, in Figure 1, the discount rates do not depend on the delay time of revenues. This could be corrected by introducing a delay-dependent discount rate. One possibility is a spot discount rate
j=lnu+dsE13
where d is time to maturity, and u and s are constants. Now, the constants u and s can be adjusted to gain the correspondence kinitial=Kinitial in Eq. (12). On the other hand, it is only the constant u that determines the discount rate at maturity and that can be determined through matching terminal discount rate to terminal capital return rate, determined as the ratio of terminal value increment rate to terminal capitalization. The outcome, in terms of stand capitalization, is shown in Figure 2. At intermediate stand ages, the capitalization becomes higher when Eq. (13) is applied. This is because the revenue is less severely discounted close to maturity. Greater discount rate close to the stand establishment then ensures the correspondence kinitial=Kinitial.
Figure 2.
Capitalization, as appearing in Eq. (1), as well as smoothed capitalization according to Eq. (12) with constant discount rate and (12) together with (13), in the case of the two example stands. (a) (above) shows a spruce stand established with 1800 saplings/hectare. (b) (below) shows a spruce stand first observed at the age of 35 years.
5. Determination of stand value increment rate
There is a variety of methods to determine the value increment rate dκdt appearing in Eqs. (1)–(8). In the case of an incorporated company, or a firm with equivalent reporting, the value increment rate can be found from a(n annual, quarterly, or prognosticated) profit/loss—statement. The outcome does depend on applied accounting practices.
In the case of a real estate firm benefiting from the growth of multiannual plants of varying age, the value increment rate within any stand may be approached by the value increment rate of the plants on the stand, possibly complemented with the increment rate of bare land value. The value increment rate generally is constituted on volumetric increment on the one hand and increment of volumetrically specific value on the other hand [17]. Again, such computation is problematic if non-mature plants do not have any immediate sales value.
Figure 3 shows the annual value increment rate per hectare, determined using three different methods. Firstly, the annual value increment is determined directly using the growth model, as often applied in Eq. (1). With the initial condition based on the early application of a growth model on saplings stands (Figure 3a), the initial value increment rate is small, increasing rapidly later. Value increment rate based on discounting of revenue with the constant discount rate (Eq. (12)) is smoother, even if not monotonic. Incorporating the delay-dependent discount rate (Eq. (13)) increases the value increment rate at a young age and reduces it at a mature age (Figure 3). Similar trends are observable in the case of the example stand first observed at the age of 35 years, except for early stand development according to Eq. (1) is similar to the discounting result with the constant discount rate (Eq. (12) (Figure 3b).
Figure 3.
Annual monetary value increment rate, as appearing in Eq. (1), as well as Eq. (12) with constant discount rate and (12) together with (13), in the case of the two example stands. Fig. 3a (above) shows a spruce stand established with 1800 saplings/hectare. Fig. 3b (below) shows a spruce stand first observed at the age of 35 years.
The relative annual value increment rate can be readily found by normalizing the monetary increment rate of Figure 3 with the capitalization appearing in Figure 2. The outcome is in Figure 4. With the initial condition based on the early application of a growth model on saplings stands (Figure 4a), direct application of the growth model induces a volatile relative value increment rate. On the contrary, capitalization determined by discounting revenue yields stationary value increment rates, except for increases after thinnings. Again, delay-dependent discount rate (Eq. (13)) induces larger value increments at a young age and lower at a mature age. The latter effect is more pronounced in the case of the example stand observed at the wooded state (Figure 4b).
Figure 4.
Annual relative value increment rate, as appearing in Eq. (1), as well as Eq. (12) with constant discount rate and (12) together with (13), in the case of the two example stands. (a) (above) shows a spruce stand established with 1800 saplings/hectare. (b) (below) shows a spruce stand first observed at the age of 35 years.
6. Further valuation attempts
It is of interest whether Eqs. (4) and (13) can be combined for the valuation of an individual stand. A possibility is
Ka=∫aτdκdtexpjt−a∗a−tdtτ−a∗raE14
where reference capital return rate r(a) comprises a numerical solution of Eqs. (12) and (13), appearing in Figure 4. The result is shown in Figure 5. The reference capital return rate according to Eq. (13) increasing with increasing time to maturity, it is found that mature stands show greater value than the reference curves, whereas juvenile stands show lower value. Eq. (14), however, has an obvious deficiency: The value estimate does match the known terminal value but not the initial value.
Figure 5.
Capitalization, as appearing in Eq. (1), as well as Eq. (12) with constant discount rate and (12) together with (13), in the case of the two example stands.
The obvious deficiency in Eq. (14) can be simply corrected. The reference capital return rate r(a) can be modified, however possibly retaining the simple form of Eq. (13). Eq. (14) can possibly be further simplified by using the same reference rate in the discounting of the value increments. The outcome would be
Ka=∫aτdκdtexplt−a∗a−tdtτ−a∗laE15
However, there is another deficiency in Eq. (14) and in Figure 5. The approximated stand value before the first thinning appears lower than the immediate sales value of the trees. This deficiency does not become corrected by Eq. (15). Correspondingly, Eqs. (14) and (15) cannot be considered appropriate.
7. Discussion
The capital return rate and firm valuation have been discussed as inverse problems. The invertibility is obvious in the absence of probabilistic or deterministic scatter. In the presence of scatter, the invertibility is less straightforward. However, the firm valuation corresponds to a simple sum of units or compartments according to Eqs. (4), (6), and (8).
A real estate firm benefiting from the growth of multiannual plant stands of varying age was discussed as a practical example. Again, the total value is a simple sum of the values of compartments, which transfers the focus to the valuation of individual stands. Young stands with small immediate sales value, or other stands expected to increase in value rapidly in the future, appear to be a problem in stand valuation. Attempts in discounting future capitalization appear to be unsuccessful but attempts in discounting revenue successful. Such discounting appears necessary if the value of the plants is determined through high-resolution observation or computation. Observation of more mature stands, along with interpolation to more juvenile stands, takes care of such interpolation in value (Figures 1,2, and 5).
Discounting of revenue with constant discount rate, however, appears to be unsatisfactory since it produces stand values slightly lower than the immediate sales value (Figures 1,2, and 5). This can be corrected by introducing a discount rate that considers the duration effect (or time-to-maturity), according to Eq. (13). Such discount rate slightly increases stand value estimates (Figure 2). It increases value increment rate at a young age and reduces it at a mature age (Figures 3 and 4).
This chapter, after introducing generic expressions for valuation and capital return as inverse problems, has discussed the valuation of two example cases in a restricted manner. In other words, the initial value and the terminal value are taken as known quantities, and value evolution between these extremes has been interpolated. Such a restricted treatment has some definite benefits: Internal consistency of the results can be relatively easily verified. An important tool in the verification is the non-interpolated sum of value components generally used in Eq. (1). In the case of a forestry firm, that might become
Ka=bare land value+value of trees+value of non‐amortized investmentsE16
The last term in Eq. (16) depends on investment intensity, as well as the amortization schedule. For the purposes of an internal consistency criterion, we define a reduced current capitalization as
K’a=bare land value+value of treesE17
Approximations of capitalization established in Eqs. (9) to (12) are designed to include expectations of forthcoming value increment. Consequently, one can take for granted
ka≥K\'aE18
The brief examination above revealed that Eqs. (9), (10), (11), and (14) generally do not satisfy this internal consistency criterion and must thus be rejected. Eq. (12), applied with or without Eq. (13), often does satisfy the consistency criterion. However, this does not happen in all circumstances. Particularly, Eq. (12) with a constant discount rate fails to comply with Eq. (18) with large rotation ages, where the value increment rate becomes essentially non-exponential.
Other kinds of problems relate to Eq. (13). First, there are circumstances where the parameter s turns negative. In particular, this happens in the case of young, productive stands with growth only slightly differing from exponential. Consequently, increased duration of commitments tends to decrease the discount rate or, in other words, invert the yield curve.
Another issue related to Eq. (13) is that it is sensitive to short-range disturbances close to maturity. In particular, recent thinning typically increases the relative value increment rate. Consequently, parameter u in Eq. (13) increases. The estimated capitalization then decreases, and the expected value of capital return rate according to Eqs. (3), (5), or (7) increases. This suggests terminal clear-cutting soon after thinning—a result which obviously is a computational artifact. Instead, Eq. (12) with a constant discount rate appears to remain a valid estimate, provided the internal consistency criterion of Eq. (18) is satisfied.
As mentioned, this chapter has discussed the valuation of two example cases in a restricted manner. A less restricted treatment might open further avenues. A particular possibility might be the introduction of a variety of reference capital return rates in the denominator of Eqs. (2), (4), (6), and (8). Linking the reference rate to alternative investments like interest instruments or shares of listed companies would significantly change valuations—not only intermediate valuations but also the initial and terminal values. The initial value would likely be more affected since the proportion of the bare land value is greater than in the terminal value, the latter including the terminal sales value of mature timber.
Acknowledgments
This work was partially supported by Niemi Foundation. Prof. Dr. Lauri Mehtätalo is gratefully acknowledged for fruitful discussions.
\n',keywords:"capitalization, capital return rate, value increment rate, expected value",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/80138.pdf",chapterXML:"https://mts.intechopen.com/source/xml/80138.xml",downloadPdfUrl:"/chapter/pdf-download/80138",previewPdfUrl:"/chapter/pdf-preview/80138",totalDownloads:63,totalViews:0,totalCrossrefCites:0,dateSubmitted:"September 14th 2021",dateReviewed:"December 8th 2021",datePrePublished:"January 20th 2022",datePublished:null,dateFinished:"January 20th 2022",readingETA:"0",abstract:"The capital return rate is the relative time change rate of value. Correspondingly, the current value can be produced in terms of value change rate divided by capital return rate. There is a variety of ways to approximate the expected capital return rate. These are briefly discussed. The approximation of the value change rate is still more variant, depending on the type of businesses discussed. A variety of businesses may appear within a firm, in which case the value change rates must be integrated. An example is provided of a real estate firm benefiting from the growth of multiannual plants of varying age. It is found that the application of a duration-dependent reference capital return rate increases the value increment rate of juvenile stands and decreases that of mature stands, however increasing the valuation result of both.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/80138",risUrl:"/chapter/ris/80138",signatures:"Petri P. Kärenlampi",book:{id:"11258",type:"book",title:"Innovation, Research and Development and Capital Evaluation",subtitle:null,fullTitle:"Innovation, Research and Development and Capital Evaluation",slug:null,publishedDate:null,bookSignature:"Prof. Luigi Aldieri",coverURL:"https://cdn.intechopen.com/books/images_new/11258.jpg",licenceType:"CC BY 3.0",editedByType:null,isbn:"978-1-80355-505-8",printIsbn:"978-1-80355-504-1",pdfIsbn:"978-1-80355-506-5",isAvailableForWebshopOrdering:!0,editors:[{id:"246585",title:"Prof.",name:"Luigi",middleName:null,surname:"Aldieri",slug:"luigi-aldieri",fullName:"Luigi Aldieri"}],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. Application to stands of multiannual plants",level:"1"},{id:"sec_3",title:"3. Determination of stand capitalization",level:"1"},{id:"sec_4",title:"4. Determination of a reference capital return rate",level:"1"},{id:"sec_5",title:"5. Determination of stand value increment rate",level:"1"},{id:"sec_6",title:"6. Further valuation attempts",level:"1"},{id:"sec_7",title:"7. Discussion",level:"1"},{id:"sec_8",title:"Acknowledgments",level:"1"}],chapterReferences:[{id:"B1",body:'Leslie AJ. A review of the concept of the normal forest. Australian Forestry. 1966;30:139-147. DOI: 10.1080/00049158.1966.10675407'},{id:"B2",body:'Kärenlampi PP. Two Sets of Initial Conditions on Boreal Forest Carbon Storage Economics. Accepted to PLOS Climate. 2021'},{id:"B3",body:'Tiwari R. Intrinsic value estimates and its accuracy: Evidence from Indian manufacturing industry. Future Business Journal. 2016;2(2):138-151. DOI: 10.1016/j.fbj.2016.10.001'},{id:"B4",body:'Tanjung G. The applications of discount cash flow, abnormal earning, and relative valuation approach. In: (Firm Intrinsic Value Analysis Pada Perusahaan BUMN) Conference: Seminar Nasional Kewirausahaan dan Inovasi Bisnis IVAt: Universitas, Tarumanegara. Bandung, Indonesia: Universitas Widyatama; 2014'},{id:"B5",body:'Carlin S. How To Calculate Intrinsic Value (Formula – Excel template & AMZN Example). Available from: https://svencarlin.com/how-to-calculate-intrinsic-value-formula/ [Accessed September 14, 2021]'},{id:"B6",body:'Kilkki P, Väisänen U. Determination of the optimum cutting policy for the forest stand by means of dynamic programming. Acta Forestalia Fennica. 1969;102:1-29'},{id:"B7",body:'Haight RG, Monserud RA. Optimizing any-aged management of mixed-species stands. II: Effects of decision criteria. Forest Science. 1990;36:125-144'},{id:"B8",body:'Pukkala T, Lähde E, Laiho O. Optimizing the structure and management of uneven-sized stands in Finland. Forestry. 2010;83:129-142'},{id:"B9",body:'Tahvonen O. Optimal structure and development of uneven-aged Norway spruce forests. Canadian Journal of Forest Research. 2011;41:2389-2402'},{id:"B10",body:'Kärenlampi PP. Wealth accumulation in rotation forestry–Failure of the net present value optimization? PLoS One. 2019;14:e0222918. DOI: 10.1371/journal.pone.0222918'},{id:"B11",body:'Kärenlampi PP. Capital return rate and carbon storage on forest estates of three boreal tree species. Sustainability. 2021;13(12):6675. DOI: 10.3390/su13126675'},{id:"B12",body:'Kärenlampi PP. Two sets of initial conditions on boreal forest carbon storage economics. Preprint. 2021:2021070439. DOI: 10.20944/preprints202107.0439.v2'},{id:"B13",body:'Kärenlampi PP. Diversity of carbon storage economics in fertile boreal spruce (Picea Abies) estates. Sustainability. 2021;13:560. Available from: https://www.mdpi.com/2071-1050/13/2/560'},{id:"B14",body:'Bouchaud J-P, Potters M. Théorie des Risques Financiers (Saclay: Aléa). In: (Engl. transl. 2000) Theory of Financial Risks. Cambridge: Cambridge University Press; 1997. Available from: http://web.math.ku.dk/∼rolf/Klaus/bouchaud-book.ps.pdf'},{id:"B15",body:'Brealey RA, Myers SC, Allen F. Principles of Corporate Finance. Tenth ed. New York, NY: McGraw-Hill Irwin; 2011'},{id:"B16",body:'Fabozzi FJ. Capital Markets: Institutions, Instruments, and Risk Management. Cambridge, Massachusetts: MIT Press; 2015'},{id:"B17",body:'Kärenlampi PP. The effect of empirical log yield observations on carbon storage economics. Forests. 2020;11:1312'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Petri P. Kärenlampi",address:"petri.karenlampi@professori.fi",affiliation:'
Lehtoi Research, Finland
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Corresponding authors will receive a 25% discount on their Open Access Publication Fees (OAPF) for Open Access book chapters. A 20% discount for publishing a long-form monographs, 25% for compacts and 23% for short-form monographs.
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CSIC affiliated authors can also take advantage of a central Open Access fund (amounting to 10,000 EUR) to cover up to 50% of the rest of the OAPF until it expires. Effective for chapters accepted from January 1, 2020.
Corresponding authors will receive a 25% discount on their Open Access Publication Fees (OAPF) for Open Access book chapters. A 20% discount for publishing a long-form monographs, 25% for compacts and 23% for short-form monographs.
Corresponding authors will receive a 25% discount on their Open Access Publication Fees (OAPF) for Open Access book chapters. A 20% discount for publishing a long-form monographs, 25% for compacts and 23% for short-form monographs.
Corresponding authors will receive a 25% discount on their Open Access Publication Fees (OAPF) for Open Access book chapters. A 20% discount for publishing a long-form monographs, 25% for compacts and 23% for short-form monographs.
The Claremont Colleges are pledging funds via the Knowledge Unlatched program to ensure academics can publish Open Access content more easily.
\\n\\n
Corresponding authors will receive a 15% discount on their Open Access Publication Fees (OAPF) for Open Access book chapters or monograph publications. To use the discount you will need to verify your institutional email address. These discounts are valid from 2020 to 2022.
The University of Massachusetts, Amherst is pledging funds via the Knowledge Unlatched program to ensure academics can publish Open Access content more easily.
\\n\\n
Corresponding authors will receive a 10% discount on their Open Access Publication Fees (OAPF) for Open Access book chapters or monograph publications. To use the discount you will need to verify your institutional email address. These discounts are valid from 2020 to 2022.
The University of Surrey is pledging funds via the Knowledge Unlatched program to ensure academics can publish Open Access content more easily.
\\n\\n
Corresponding authors will receive a 10% discount on their Open Access Publication Fees (OAPF) for Open Access book chapters or monograph publications. To use the discount you will need to verify your institutional email address. These discounts are valid from 2020 to 2022.
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\\n\\t
Virginia Polytechnic Institute and State University
Corresponding authors will receive a 25% discount on their Open Access Publication Fees (OAPF) for Open Access book chapters. A 20% discount for publishing a long-form monographs, 25% for compacts and 23% for short-form monographs.
\n\n
CSIC affiliated authors can also take advantage of a central Open Access fund (amounting to 10,000 EUR) to cover up to 50% of the rest of the OAPF until it expires. Effective for chapters accepted from January 1, 2020.
Corresponding authors will receive a 25% discount on their Open Access Publication Fees (OAPF) for Open Access book chapters. A 20% discount for publishing a long-form monographs, 25% for compacts and 23% for short-form monographs.
Corresponding authors will receive a 25% discount on their Open Access Publication Fees (OAPF) for Open Access book chapters. A 20% discount for publishing a long-form monographs, 25% for compacts and 23% for short-form monographs.
Corresponding authors will receive a 25% discount on their Open Access Publication Fees (OAPF) for Open Access book chapters. A 20% discount for publishing a long-form monographs, 25% for compacts and 23% for short-form monographs.
The Claremont Colleges are pledging funds via the Knowledge Unlatched program to ensure academics can publish Open Access content more easily.
\n\n
Corresponding authors will receive a 15% discount on their Open Access Publication Fees (OAPF) for Open Access book chapters or monograph publications. To use the discount you will need to verify your institutional email address. These discounts are valid from 2020 to 2022.
The University of Massachusetts, Amherst is pledging funds via the Knowledge Unlatched program to ensure academics can publish Open Access content more easily.
\n\n
Corresponding authors will receive a 10% discount on their Open Access Publication Fees (OAPF) for Open Access book chapters or monograph publications. To use the discount you will need to verify your institutional email address. These discounts are valid from 2020 to 2022.
The University of Surrey is pledging funds via the Knowledge Unlatched program to ensure academics can publish Open Access content more easily.
\n\n
Corresponding authors will receive a 10% discount on their Open Access Publication Fees (OAPF) for Open Access book chapters or monograph publications. To use the discount you will need to verify your institutional email address. These discounts are valid from 2020 to 2022.
\n\n
\n\t
Virginia Polytechnic Institute and State University
Important: You must be a member or grantee of the above listed institutions in order to apply for their Open Access publication funds.
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Variable outcomes and challenges of AMF application are also discussed for practical use in crop production under water scarcity.",book:{id:"8489",slug:"drought-detection-and-solutions",title:"Drought",fullTitle:"Drought - Detection and Solutions"},signatures:"Katalin Posta and Nguyen Hong Duc",authors:[{id:"290749",title:"Prof.",name:"Katalin",middleName:null,surname:"Posta",slug:"katalin-posta",fullName:"Katalin Posta"},{id:"298768",title:"Dr.",name:"Nguyen",middleName:null,surname:"Hong Duc",slug:"nguyen-hong-duc",fullName:"Nguyen Hong Duc"}]},{id:"34120",doi:"10.5772/29710",title:"Irrigation: Types, Sources and Problems in Malaysia",slug:"irrigation-types-sources-and-problems-in-malaysia",totalDownloads:4734,totalCrossrefCites:3,totalDimensionsCites:10,abstract:null,book:{id:"713",slug:"irrigation-systems-and-practices-in-challenging-environments",title:"Irrigation Systems and Practices in Challenging Environments",fullTitle:"Irrigation Systems and Practices in Challenging Environments"},signatures:"M. E. Toriman and M. Mokhtar",authors:[{id:"79054",title:"Dr.",name:"Mohd Ekhwan",middleName:null,surname:"Toriman",slug:"mohd-ekhwan-toriman",fullName:"Mohd Ekhwan Toriman"},{id:"129566",title:"Prof.",name:"Mazlin",middleName:null,surname:"Mokhtar",slug:"mazlin-mokhtar",fullName:"Mazlin Mokhtar"}]}],mostDownloadedChaptersLast30Days:[{id:"73179",title:"A Revisit of Rainfall Simulator as a Potential Tool for Hydrological Research",slug:"a-revisit-of-rainfall-simulator-as-a-potential-tool-for-hydrological-research",totalDownloads:527,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Different means of hydrological data collection have developed and used. However, they are constraint in one way or other. This paper therefore revisited the rainfall simulator as potential tool for hydrological research. The research disclosed that there are three different types of rainfall simulators; drop former simulator, pressure nozzle simulator and hybrid simulator. It can further be classified as indoor model and outdoor. The research also showed that precipitation is the driving force in hydrological studies. Consequently, in the design of rainfall simulator, the following should be taken into consideration: nozzle spacing, pump size, nozzle size, nozzle type, nozzle spacing, plot size and pressure. Meanwhile, intensity, distribution uniformity, kinetic energy, rainfall drop size and rainfall terminal velocity should be noted in its evaluation. Factoring-in the aforementioned design considerations, data collection is made easy without necessarily waiting for the natural rainfall. Since the rainfall can be controlled, the erratic and unpredictable changeability of natural rainfall is eliminated. Emanating from the findings, pressurized rainfall simulator produces rainfall characteristics similar to natural rainfall, which is therefore recommended for laboratory use if natural rainfall-like characteristics is the main target.",book:{id:"9643",slug:"agrometeorology",title:"Agrometeorology",fullTitle:"Agrometeorology"},signatures:"Felix Gemlack Ngasoh, Constantine Crown Mbajiorgu, Matthew Boniface Kamai and Gideon Onyekachi Okoro",authors:[{id:"276617",title:"Ph.D. Student",name:"Felix Gemlack",middleName:"Gemlack",surname:"Ngasoh",slug:"felix-gemlack-ngasoh",fullName:"Felix Gemlack Ngasoh"},{id:"327056",title:"Prof.",name:"Constantine C.",middleName:null,surname:"Mbajiorgu",slug:"constantine-c.-mbajiorgu",fullName:"Constantine C. Mbajiorgu"},{id:"327059",title:"MSc.",name:"Matthew B.",middleName:null,surname:"Kamai",slug:"matthew-b.-kamai",fullName:"Matthew B. Kamai"}]},{id:"66827",title:"Climate Risk and Early Warning Systems (CREWS) for Papua New Guinea",slug:"climate-risk-and-early-warning-systems-crews-for-papua-new-guinea",totalDownloads:1088,totalCrossrefCites:6,totalDimensionsCites:7,abstract:"Developing and least developed countries are particularly vulnerable to the impact of climate change and climate extremes, including drought. In Papua New Guinea (PNG), severe drought caused by the strong El Niño in 2015–2016 affected about 40% of the population, with almost half a million people impacted by food shortages. Recognizing the urgency of enhancing early warning systems to assist vulnerable countries with climate change adaptation, the Climate Risk and Early Warning Systems (CREWS) international initiative has been established. In this chapter, the CREWS-PNG project is described. The CREWS-PNG project aims to develop an improved drought monitoring and early warning system, running operationally through a collaboration between PNG National Weather Services (NWS), the Australian Bureau of Meteorology and the World Meteorological Organization that will enable better strategic decision-making for agriculture, water management, health and other climate-sensitive sectors. It is shown that current dynamical climate models can provide skillful predictions of regional rainfall at least 3 months in advance. Dynamical climate model-based forecast products are disseminated through a range of Web-based information tools. It is demonstrated that seasonal climate prediction is an effective solution to assist governments and local communities with informed decision-making in adaptation to climate variability and change.",book:{id:"8489",slug:"drought-detection-and-solutions",title:"Drought",fullTitle:"Drought - Detection and Solutions"},signatures:"Yuriy Kuleshov, Kasis Inape, Andrew B. Watkins, Adele Bear-Crozier, Zhi-Weng Chua, Pingping Xie, Takuji Kubota, Tomoko Tashima, Robert Stefanski and Toshiyuki Kurino",authors:[{id:"102903",title:"Prof.",name:"Yuriy",middleName:null,surname:"Kuleshov",slug:"yuriy-kuleshov",fullName:"Yuriy Kuleshov"}]},{id:"67399",title:"Benefits of Arbuscular Mycorrhizal Fungi Application to Crop Production under Water Scarcity",slug:"benefits-of-arbuscular-mycorrhizal-fungi-application-to-crop-production-under-water-scarcity",totalDownloads:1905,totalCrossrefCites:8,totalDimensionsCites:12,abstract:"Water deficit is one of the most severe abiotic stresses threatening crop growth and production on the globe. Water stress causes a series of morphological, biochemical, physiological, and molecular alterations that negatively influence plant productivity. However, in nature, plants are often associated with microbes that can modulate plant responses to water scarcity. Among beneficial microbes, arbuscular mycorrhizal fungi (AMF) are one of the most widespread symbiotic fungi colonizing the majority of agricultural plants. Besides an enhancement in plant nutrition, AMF have been reported to improve plant performance under water restrictions. In this chapter, we emphasize the benefits of AMF inoculation to crop production under water deficit based on related laboratory and field experiments. Variable outcomes and challenges of AMF application are also discussed for practical use in crop production under water scarcity.",book:{id:"8489",slug:"drought-detection-and-solutions",title:"Drought",fullTitle:"Drought - Detection and Solutions"},signatures:"Katalin Posta and Nguyen Hong Duc",authors:[{id:"290749",title:"Prof.",name:"Katalin",middleName:null,surname:"Posta",slug:"katalin-posta",fullName:"Katalin Posta"},{id:"298768",title:"Dr.",name:"Nguyen",middleName:null,surname:"Hong Duc",slug:"nguyen-hong-duc",fullName:"Nguyen Hong Duc"}]},{id:"34117",title:"Sustainable Irrigation Practices in India",slug:"sustainable-irrigation-practices-in-india",totalDownloads:7648,totalCrossrefCites:0,totalDimensionsCites:1,abstract:null,book:{id:"713",slug:"irrigation-systems-and-practices-in-challenging-environments",title:"Irrigation Systems and Practices in Challenging Environments",fullTitle:"Irrigation Systems and Practices in Challenging Environments"},signatures:"Rajapure V. A. and Kothari R. M.",authors:[{id:"84331",title:"Dr.",name:"Ramanlal",middleName:null,surname:"Kothari",slug:"ramanlal-kothari",fullName:"Ramanlal Kothari"},{id:"115872",title:"Dr.",name:"Vikram Ashok",middleName:null,surname:"Rajapure",slug:"vikram-ashok-rajapure",fullName:"Vikram Ashok Rajapure"}]},{id:"34118",title:"Irrigation in Mediterranean Fruit Tree Orchards",slug:"irrigation-in-mediterranean-fruit-tree-orchards",totalDownloads:3784,totalCrossrefCites:4,totalDimensionsCites:8,abstract:null,book:{id:"713",slug:"irrigation-systems-and-practices-in-challenging-environments",title:"Irrigation Systems and Practices in Challenging Environments",fullTitle:"Irrigation Systems and Practices in Challenging Environments"},signatures:"Cristos Xiloyannis, Giuseppe Montanaro and Bartolomeo Dichio",authors:[{id:"42991",title:"Dr.",name:"Giuseppe",middleName:null,surname:"Montanaro",slug:"giuseppe-montanaro",fullName:"Giuseppe Montanaro"},{id:"42996",title:"Prof.",name:"Bartolomeo",middleName:null,surname:"Dichio",slug:"bartolomeo-dichio",fullName:"Bartolomeo Dichio"},{id:"42997",title:"Prof.",name:"Cristos",middleName:null,surname:"Xiloyannis",slug:"cristos-xiloyannis",fullName:"Cristos Xiloyannis"}]}],onlineFirstChaptersFilter:{topicId:"308",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:0,limit:8,total:null},allSeries:{pteSeriesList:[],lsSeriesList:[],hsSeriesList:[],sshSeriesList:[],testimonialsList:[]},series:{item:{id:"25",title:"Environmental Sciences",doi:"10.5772/intechopen.100362",issn:"2754-6713",scope:"
\r\n\tScientists have long researched to understand the environment and man’s place in it. The search for this knowledge grows in importance as rapid increases in population and economic development intensify humans’ stresses on ecosystems. Fortunately, rapid increases in multiple scientific areas are advancing our understanding of environmental sciences. Breakthroughs in computing, molecular biology, ecology, and sustainability science are enhancing our ability to utilize environmental sciences to address real-world problems. \r\n\tThe four topics of this book series - Pollution; Environmental Resilience and Management; Ecosystems and Biodiversity; and Water Science - will address important areas of advancement in the environmental sciences. They will represent an excellent initial grouping of published works on these critical topics.
",coverUrl:"https://cdn.intechopen.com/series/covers/25.jpg",latestPublicationDate:"April 13th, 2022",hasOnlineFirst:!1,numberOfPublishedBooks:1,editor:{id:"197485",title:"Dr.",name:"J. Kevin",middleName:null,surname:"Summers",slug:"j.-kevin-summers",fullName:"J. Kevin Summers",profilePictureURL:"https://mts.intechopen.com/storage/users/197485/images/system/197485.jpg",biography:"J. Kevin Summers is a Senior Research Ecologist at the Environmental Protection Agency’s (EPA) Gulf Ecosystem Measurement and Modeling Division. He is currently working with colleagues in the Sustainable and Healthy Communities Program to develop an index of community resilience to natural hazards, an index of human well-being that can be linked to changes in the ecosystem, social and economic services, and a community sustainability tool for communities with populations under 40,000. He leads research efforts for indicator and indices development. Dr. Summers is a systems ecologist and began his career at the EPA in 1989 and has worked in various programs and capacities. This includes leading the National Coastal Assessment in collaboration with the Office of Water which culminated in the award-winning National Coastal Condition Report series (four volumes between 2001 and 2012), and which integrates water quality, sediment quality, habitat, and biological data to assess the ecosystem condition of the United States estuaries. He was acting National Program Director for Ecology for the EPA between 2004 and 2006. He has authored approximately 150 peer-reviewed journal articles, book chapters, and reports and has received many awards for technical accomplishments from the EPA and from outside of the agency. Dr. Summers holds a BA in Zoology and Psychology, an MA in Ecology, and Ph.D. in Systems Ecology/Biology.",institutionString:null,institution:{name:"Environmental Protection Agency",institutionURL:null,country:{name:"United States of America"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:4,paginationItems:[{id:"38",title:"Pollution",coverUrl:"https://cdn.intechopen.com/series_topics/covers/38.jpg",isOpenForSubmission:!0,annualVolume:11966,editor:{id:"110740",title:"Dr.",name:"Ismail M.M.",middleName:null,surname:"Rahman",slug:"ismail-m.m.-rahman",fullName:"Ismail M.M. Rahman",profilePictureURL:"https://mts.intechopen.com/storage/users/110740/images/2319_n.jpg",biography:"Ismail Md. Mofizur Rahman (Ismail M. M. Rahman) assumed his current responsibilities as an Associate Professor at the Institute of Environmental Radioactivity, Fukushima University, Japan, in Oct 2015. He also has an honorary appointment to serve as a Collaborative Professor at Kanazawa University, Japan, from Mar 2015 to the present. \nFormerly, Dr. Rahman was a faculty member of the University of Chittagong, Bangladesh, affiliated with the Department of Chemistry (Oct 2002 to Mar 2012) and the Department of Applied Chemistry and Chemical Engineering (Mar 2012 to Sep 2015). Dr. Rahman was also adjunctly attached with Kanazawa University, Japan (Visiting Research Professor, Dec 2014 to Mar 2015; JSPS Postdoctoral Research Fellow, Apr 2012 to Mar 2014), and Tokyo Institute of Technology, Japan (TokyoTech-UNESCO Research Fellow, Oct 2004–Sep 2005). \nHe received his Ph.D. degree in Environmental Analytical Chemistry from Kanazawa University, Japan (2011). He also achieved a Diploma in Environment from the Tokyo Institute of Technology, Japan (2005). Besides, he has an M.Sc. degree in Applied Chemistry and a B.Sc. degree in Chemistry, all from the University of Chittagong, Bangladesh. \nDr. Rahman’s research interest includes the study of the fate and behavior of environmental pollutants in the biosphere; design of low energy and low burden environmental improvement (remediation) technology; implementation of sustainable waste management practices for treatment, handling, reuse, and ultimate residual disposition of solid wastes; nature and type of interactions in organic liquid mixtures for process engineering design applications.",institutionString:null,institution:{name:"Fukushima University",institutionURL:null,country:{name:"Japan"}}},editorTwo:{id:"201020",title:"Dr.",name:"Zinnat Ara",middleName:null,surname:"Begum",slug:"zinnat-ara-begum",fullName:"Zinnat Ara Begum",profilePictureURL:"https://mts.intechopen.com/storage/users/201020/images/system/201020.jpeg",biography:"Zinnat A. Begum received her Ph.D. in Environmental Analytical Chemistry from Kanazawa University in 2012. She achieved her Master of Science (M.Sc.) degree with a major in Applied Chemistry and a Bachelor of Science (B.Sc.) in Chemistry, all from the University of Chittagong, Bangladesh. Her work affiliations include Fukushima University, Japan (Visiting Research Fellow, Institute of Environmental Radioactivity: Mar 2016 to present), Southern University Bangladesh (Assistant Professor, Department of Civil Engineering: Jan 2015 to present), and Kanazawa University, Japan (Postdoctoral Fellow, Institute of Science and Engineering: Oct 2012 to Mar 2014; Research fellow, Venture Business Laboratory, Advanced Science and Social Co-Creation Promotion Organization: Apr 2018 to Mar 2021). The research focus of Dr. Zinnat includes the effect of the relative stability of metal-chelator complexes in the environmental remediation process designs and the development of eco-friendly soil washing techniques using biodegradable chelators.",institutionString:null,institution:{name:"Fukushima University",institutionURL:null,country:{name:"Japan"}}},editorThree:null},{id:"39",title:"Environmental Resilience and Management",coverUrl:"https://cdn.intechopen.com/series_topics/covers/39.jpg",isOpenForSubmission:!0,annualVolume:11967,editor:{id:"137040",title:"Prof.",name:"Jose",middleName:null,surname:"Navarro-Pedreño",slug:"jose-navarro-pedreno",fullName:"Jose Navarro-Pedreño",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRAXrQAO/Profile_Picture_2022-03-09T15:50:19.jpg",biography:"Full professor at University Miguel Hernández of Elche, Spain, previously working at the University of Alicante, Autonomous University of Madrid and Polytechnic University of Valencia. Graduate in Sciences (Chemist), graduate in Geography and History (Geography), master in Water Management, Treatment, master in Fertilizers and Environment and master in Environmental Management; Ph.D. in Environmental Sciences. His research is focused on soil-water and waste-environment relations, mainly on soil-water and soil-waste interactions under different management and waste reuse. His work is reflected in more than 230 communications presented in national and international conferences and congresses, 29 invited lectures from universities, associations and government agencies. Prof. Navarro-Pedreño is also a director of the Ph.D. Program Environment and Sustainability (2012-present) and a member of several societies among which are the Spanish Society of Soil Science, International Union of Soil Sciences, European Society for Soil Conservation, DessertNet and the Spanish Royal Society of Chemistry.",institutionString:"Miguel Hernández University of Elche, Spain",institution:null},editorTwo:null,editorThree:null},{id:"40",title:"Ecosystems and Biodiversity",coverUrl:"https://cdn.intechopen.com/series_topics/covers/40.jpg",isOpenForSubmission:!0,annualVolume:11968,editor:{id:"209149",title:"Prof.",name:"Salustiano",middleName:null,surname:"Mato",slug:"salustiano-mato",fullName:"Salustiano Mato",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRLREQA4/Profile_Picture_2022-03-31T10:23:50.png",biography:"Salustiano Mato de la Iglesia (Santiago de Compostela, 1960) is a doctor in biology from the University of Santiago and a Professor of zoology at the Department of Ecology and Animal Biology at the University of Vigo. He has developed his research activity in the fields of fauna and soil ecology, and in the treatment of organic waste, having been the founder and principal investigator of the Environmental Biotechnology Group of the University of Vigo.\r\nHis research activity in the field of Environmental Biotechnology has been focused on the development of novel organic waste treatment systems through composting. The result of this line of work are three invention patents and various scientific and technical publications in prestigious international journals.",institutionString:null,institution:{name:"University of Vigo",institutionURL:null,country:{name:"Spain"}}},editorTwo:{id:"60498",title:"Prof.",name:"Josefina",middleName:null,surname:"Garrido",slug:"josefina-garrido",fullName:"Josefina Garrido",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRj1VQAS/Profile_Picture_2022-03-31T10:06:51.jpg",biography:"Josefina Garrido González (Paradela de Abeleda, Ourense 1959), is a doctor in biology from the University of León and a Professor of Zoology at the Department of Ecology and Animal Biology at the University of Vigo. She has focused her research activity on the taxonomy, fauna and ecology of aquatic beetles, in addition to other lines of research such as the conservation of biodiversity in freshwater ecosystems; conservation of protected areas (Red Natura 2000) and assessment of the effectiveness of wetlands as priority areas for the conservation of aquatic invertebrates; studies of water quality in freshwater ecosystems through biological indicators and physicochemical parameters; surveillance and research of vector arthropods and invasive alien species.",institutionString:null,institution:{name:"University of Vigo",institutionURL:null,country:{name:"Spain"}}},editorThree:{id:"464288",title:"Dr.",name:"Francisco",middleName:null,surname:"Ramil",slug:"francisco-ramil",fullName:"Francisco Ramil",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003RI7lHQAT/Profile_Picture_2022-03-31T10:15:35.png",biography:"Fran Ramil Blanco (Porto de Espasante, A Coruña, 1960), is a doctor in biology from the University of Santiago de Compostela and a Professor of Zoology at the Department of Ecology and Animal Biology at the University of Vigo. His research activity is linked to the taxonomy, fauna and ecology of marine benthic invertebrates and especially the Cnidarian group. Since 2004, he has been part of the EcoAfrik project, aimed at the study, protection and conservation of biodiversity and benthic habitats in West Africa. He also participated in the study of vulnerable marine ecosystems associated with seamounts in the South Atlantic and is involved in training young African researchers in the field of marine research.",institutionString:null,institution:{name:"University of Vigo",institutionURL:null,country:{name:"Spain"}}}},{id:"41",title:"Water Science",coverUrl:"https://cdn.intechopen.com/series_topics/covers/41.jpg",isOpenForSubmission:!0,annualVolume:11969,editor:{id:"349630",title:"Dr.",name:"Yizi",middleName:null,surname:"Shang",slug:"yizi-shang",fullName:"Yizi Shang",profilePictureURL:"https://mts.intechopen.com/storage/users/349630/images/system/349630.jpg",biography:"Prof. Dr. Yizi Shang is a pioneering researcher in hydrology and water resources who has devoted his research career to promoting the conservation and protection of water resources for sustainable development. He is presently associate editor of Water International (official journal of the International Water Resources Association). He was also invited to serve as an associate editor for special issues of the Journal of the American Water Resources Association. He has served as an editorial member for international journals such as Hydrology, Journal of Ecology & Natural Resources, and Hydro Science & Marine Engineering, among others. He has chaired or acted as a technical committee member for twenty-five international forums (conferences). Dr. Shang graduated from Tsinghua University, China, in 2010 with a Ph.D. in Engineering. Prior to that, he worked as a research fellow at Harvard University from 2008 to 2009. Dr. Shang serves as a senior research engineer at the China Institute of Water Resources and Hydropower Research (IWHR) and was awarded as a distinguished researcher at National Taiwan University in 2017.",institutionString:"China Institute of Water Resources and Hydropower Research",institution:{name:"China Institute of Water Resources and Hydropower Research",institutionURL:null,country:{name:"China"}}},editorTwo:null,editorThree:null}]},overviewPageOFChapters:{paginationCount:17,paginationItems:[{id:"81791",title:"Self-Supervised Contrastive Representation Learning in Computer Vision",doi:"10.5772/intechopen.104785",signatures:"Yalin Bastanlar and Semih Orhan",slug:"self-supervised-contrastive-representation-learning-in-computer-vision",totalDownloads:12,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Pattern Recognition - New Insights",coverURL:"https://cdn.intechopen.com/books/images_new/11442.jpg",subseries:{id:"26",title:"Machine Learning and Data Mining"}}},{id:"79345",title:"Application of Jump Diffusion Models in Insurance Claim Estimation",doi:"10.5772/intechopen.99853",signatures:"Leonard Mushunje, Chiedza Elvina Mashiri, Edina Chandiwana and Maxwell Mashasha",slug:"application-of-jump-diffusion-models-in-insurance-claim-estimation-1",totalDownloads:2,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Data Clustering",coverURL:"https://cdn.intechopen.com/books/images_new/10820.jpg",subseries:{id:"26",title:"Machine Learning and Data Mining"}}},{id:"81557",title:"Object Tracking Using Adapted Optical Flow",doi:"10.5772/intechopen.102863",signatures:"Ronaldo Ferreira, Joaquim José de Castro Ferreira and António José Ribeiro Neves",slug:"object-tracking-using-adapted-optical-flow",totalDownloads:11,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Information Extraction and Object Tracking in Digital Video",coverURL:"https://cdn.intechopen.com/books/images_new/10652.jpg",subseries:{id:"24",title:"Computer Vision"}}},{id:"81558",title:"Thresholding Image Techniques for Plant Segmentation",doi:"10.5772/intechopen.104587",signatures:"Miguel Ángel Castillo-Martínez, Francisco Javier Gallegos-Funes, Blanca E. Carvajal-Gámez, Guillermo Urriolagoitia-Sosa and Alberto J. Rosales-Silva",slug:"thresholding-image-techniques-for-plant-segmentation",totalDownloads:15,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Information Extraction and Object Tracking in Digital Video",coverURL:"https://cdn.intechopen.com/books/images_new/10652.jpg",subseries:{id:"24",title:"Computer Vision"}}}]},overviewPagePublishedBooks:{paginationCount:9,paginationItems:[{type:"book",id:"7723",title:"Artificial Intelligence",subtitle:"Applications in Medicine and Biology",coverURL:"https://cdn.intechopen.com/books/images_new/7723.jpg",slug:"artificial-intelligence-applications-in-medicine-and-biology",publishedDate:"July 31st 2019",editedByType:"Edited by",bookSignature:"Marco Antonio Aceves-Fernandez",hash:"a3852659e727f95c98c740ed98146011",volumeInSeries:1,fullTitle:"Artificial Intelligence - Applications in Medicine and Biology",editors:[{id:"24555",title:"Dr.",name:"Marco Antonio",middleName:null,surname:"Aceves Fernandez",slug:"marco-antonio-aceves-fernandez",fullName:"Marco Antonio Aceves Fernandez",profilePictureURL:"https://mts.intechopen.com/storage/users/24555/images/system/24555.jpg",biography:"Dr. Marco Antonio Aceves Fernandez obtained his B.Sc. 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This includes, but is not limited to: single-neuron modeling, sensory processing, motor control, memory, and synaptic plasticity, attention, identification, categorization, discrimination, learning, development, axonal patterning, guidance, neural architecture, behaviors, and dynamics of networks, cognition and the neuroscientific basis of consciousness. 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Novel computational algorithms for image analysis, scene understanding, biometrics, deep learning and their software or hardware implementations for natural and medical images, robotics, VR/AR, applications are some research directions relevant to this topic.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/24.jpg",keywords:"Image Analysis, Scene Understanding, Biometrics, Deep Learning, Software Implementation, Hardware Implementation, Natural Images, Medical Images, Robotics, VR/AR"},{id:"25",title:"Evolutionary Computation",scope:"Evolutionary computing is a paradigm that has grown dramatically in recent years. This group of bio-inspired metaheuristics solves multiple optimization problems by applying the metaphor of natural selection. It so far has solved problems such as resource allocation, routing, schedule planning, and engineering design. Moreover, in the field of machine learning, evolutionary computation has carved out a significant niche both in the generation of learning models and in the automatic design and optimization of hyperparameters in deep learning models. This collection aims to include quality volumes on various topics related to evolutionary algorithms and, alternatively, other metaheuristics of interest inspired by nature. For example, some of the issues of interest could be the following: Advances in evolutionary computation (Genetic algorithms, Genetic programming, Bio-inspired metaheuristics, Hybrid metaheuristics, Parallel ECs); Applications of evolutionary algorithms (Machine learning and Data Mining with EAs, Search-Based Software Engineering, Scheduling, and Planning Applications, Smart Transport Applications, Applications to Games, Image Analysis, Signal Processing and Pattern Recognition, Applications to Sustainability).",coverUrl:"https://cdn.intechopen.com/series_topics/covers/25.jpg",keywords:"Genetic Algorithms, Genetic Programming, Evolutionary Programming, Evolution Strategies, Hybrid Algorithms, Bioinspired Metaheuristics, Ant Colony Optimization, Evolutionary Learning, Hyperparameter Optimization"},{id:"26",title:"Machine Learning and Data Mining",scope:"The scope of machine learning and data mining is immense and is growing every day. It has become a massive part of our daily lives, making predictions based on experience, making this a fascinating area that solves problems that otherwise would not be possible or easy to solve. This topic aims to encompass algorithms that learn from experience (supervised and unsupervised), improve their performance over time and enable machines to make data-driven decisions. It is not limited to any particular applications, but contributions are encouraged from all disciplines.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/26.jpg",keywords:"Intelligent Systems, Machine Learning, Data Science, Data Mining, Artificial Intelligence"},{id:"27",title:"Multi-Agent Systems",scope:"Multi-agent systems are recognised as a state of the art field in Artificial Intelligence studies, which is popular due to the usefulness in facilitation capabilities to handle real-world problem-solving in a distributed fashion. The area covers many techniques that offer solutions to emerging problems in robotics and enterprise-level software systems. Collaborative intelligence is highly and effectively achieved with multi-agent systems. Areas of application include swarms of robots, flocks of UAVs, collaborative software management. Given the level of technological enhancements, the popularity of machine learning in use has opened a new chapter in multi-agent studies alongside the practical challenges and long-lasting collaboration issues in the field. It has increased the urgency and the need for further studies in this field. We welcome chapters presenting research on the many applications of multi-agent studies including, but not limited to, the following key areas: machine learning for multi-agent systems; modeling swarms robots and flocks of UAVs with multi-agent systems; decision science and multi-agent systems; software engineering for and with multi-agent systems; tools and technologies of multi-agent systems.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/27.jpg",keywords:"Collaborative Intelligence, Learning, Distributed Control System, Swarm Robotics, Decision Science, Software Engineering"}],annualVolumeBook:{},thematicCollection:[],selectedSeries:{title:"Artificial Intelligence",id:"14"},selectedSubseries:null},seriesLanding:{item:{id:"25",title:"Environmental Sciences",doi:"10.5772/intechopen.100362",issn:"2754-6713",scope:"
\r\n\tScientists have long researched to understand the environment and man’s place in it. The search for this knowledge grows in importance as rapid increases in population and economic development intensify humans’ stresses on ecosystems. Fortunately, rapid increases in multiple scientific areas are advancing our understanding of environmental sciences. Breakthroughs in computing, molecular biology, ecology, and sustainability science are enhancing our ability to utilize environmental sciences to address real-world problems. \r\n\tThe four topics of this book series - Pollution; Environmental Resilience and Management; Ecosystems and Biodiversity; and Water Science - will address important areas of advancement in the environmental sciences. They will represent an excellent initial grouping of published works on these critical topics.
",coverUrl:"https://cdn.intechopen.com/series/covers/25.jpg",latestPublicationDate:"April 13th, 2022",hasOnlineFirst:!1,numberOfOpenTopics:4,numberOfPublishedChapters:9,numberOfPublishedBooks:1,editor:{id:"197485",title:"Dr.",name:"J. Kevin",middleName:null,surname:"Summers",fullName:"J. Kevin Summers",profilePictureURL:"https://mts.intechopen.com/storage/users/197485/images/system/197485.jpg",biography:"J. Kevin Summers is a Senior Research Ecologist at the Environmental Protection Agency’s (EPA) Gulf Ecosystem Measurement and Modeling Division. He is currently working with colleagues in the Sustainable and Healthy Communities Program to develop an index of community resilience to natural hazards, an index of human well-being that can be linked to changes in the ecosystem, social and economic services, and a community sustainability tool for communities with populations under 40,000. He leads research efforts for indicator and indices development. Dr. Summers is a systems ecologist and began his career at the EPA in 1989 and has worked in various programs and capacities. This includes leading the National Coastal Assessment in collaboration with the Office of Water which culminated in the award-winning National Coastal Condition Report series (four volumes between 2001 and 2012), and which integrates water quality, sediment quality, habitat, and biological data to assess the ecosystem condition of the United States estuaries. He was acting National Program Director for Ecology for the EPA between 2004 and 2006. He has authored approximately 150 peer-reviewed journal articles, book chapters, and reports and has received many awards for technical accomplishments from the EPA and from outside of the agency. Dr. Summers holds a BA in Zoology and Psychology, an MA in Ecology, and Ph.D. in Systems Ecology/Biology.",institutionString:null,institution:{name:"Environmental Protection Agency",institutionURL:null,country:{name:"United States of America"}}},subseries:[{id:"38",title:"Pollution",keywords:"Human activity, Pollutants, Reduced risks, Population growth, Waste disposal, Remediation, Clean environment",scope:"
\r\n\tPollution is caused by a wide variety of human activities and occurs in diverse forms, for example biological, chemical, et cetera. In recent years, significant efforts have been made to ensure that the environment is clean, that rigorous rules are implemented, and old laws are updated to reduce the risks towards humans and ecosystems. However, rapid industrialization and the need for more cultivable sources or habitable lands, for an increasing population, as well as fewer alternatives for waste disposal, make the pollution control tasks more challenging. Therefore, this topic will focus on assessing and managing environmental pollution. It will cover various subjects, including risk assessment due to the pollution of ecosystems, transport and fate of pollutants, restoration or remediation of polluted matrices, and efforts towards sustainable solutions to minimize environmental pollution.
",annualVolume:11966,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/38.jpg",editor:{id:"110740",title:"Dr.",name:"Ismail M.M.",middleName:null,surname:"Rahman",fullName:"Ismail M.M. Rahman",profilePictureURL:"https://mts.intechopen.com/storage/users/110740/images/2319_n.jpg",institutionString:null,institution:{name:"Fukushima University",institutionURL:null,country:{name:"Japan"}}},editorTwo:{id:"201020",title:"Dr.",name:"Zinnat Ara",middleName:null,surname:"Begum",fullName:"Zinnat Ara Begum",profilePictureURL:"https://mts.intechopen.com/storage/users/201020/images/system/201020.jpeg",institutionString:null,institution:{name:"Fukushima University",institutionURL:null,country:{name:"Japan"}}},editorThree:null,editorialBoard:[{id:"252368",title:"Dr.",name:"Meng-Chuan",middleName:null,surname:"Ong",fullName:"Meng-Chuan Ong",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRVotQAG/Profile_Picture_2022-05-20T12:04:28.jpg",institutionString:null,institution:{name:"Universiti Malaysia Terengganu",institutionURL:null,country:{name:"Malaysia"}}},{id:"63465",title:"Prof.",name:"Mohamed Nageeb",middleName:null,surname:"Rashed",fullName:"Mohamed Nageeb Rashed",profilePictureURL:"https://mts.intechopen.com/storage/users/63465/images/system/63465.gif",institutionString:null,institution:{name:"Aswan University",institutionURL:null,country:{name:"Egypt"}}},{id:"187907",title:"Dr.",name:"Olga",middleName:null,surname:"Anne",fullName:"Olga Anne",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSBE5QAO/Profile_Picture_2022-04-07T09:42:13.png",institutionString:null,institution:{name:"Klaipeda State University of Applied Sciences",institutionURL:null,country:{name:"Lithuania"}}}]},{id:"39",title:"Environmental Resilience and Management",keywords:"Anthropic effects, Overexploitation, Biodiversity loss, Degradation, Inadequate Management, SDGs adequate practices",scope:"
\r\n\tThe environment is subject to severe anthropic effects. Among them are those associated with pollution, resource extraction and overexploitation, loss of biodiversity, soil degradation, disorderly land occupation and planning, and many others. These anthropic effects could potentially be caused by any inadequate management of the environment. However, ecosystems have a resilience that makes them react to disturbances which mitigate the negative effects. It is critical to understand how ecosystems, natural and anthropized, including urban environments, respond to actions that have a negative influence and how they are managed. It is also important to establish when the limits marked by the resilience and the breaking point are achieved and when no return is possible. The main focus for the chapters is to cover the subjects such as understanding how the environment resilience works, the mechanisms involved, and how to manage them in order to improve our interactions with the environment and promote the use of adequate management practices such as those outlined in the United Nations’ Sustainable Development Goals.
",annualVolume:11967,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/39.jpg",editor:{id:"137040",title:"Prof.",name:"Jose",middleName:null,surname:"Navarro-Pedreño",fullName:"Jose Navarro-Pedreño",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRAXrQAO/Profile_Picture_2022-03-09T15:50:19.jpg",institutionString:"Miguel Hernández University of Elche, Spain",institution:null},editorTwo:null,editorThree:null,editorialBoard:[{id:"177015",title:"Prof.",name:"Elke Jurandy",middleName:null,surname:"Bran Nogueira Cardoso",fullName:"Elke Jurandy Bran Nogueira Cardoso",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRGxzQAG/Profile_Picture_2022-03-25T08:32:33.jpg",institutionString:"Universidade de São Paulo, Brazil",institution:null},{id:"211260",title:"Dr.",name:"Sandra",middleName:null,surname:"Ricart",fullName:"Sandra Ricart",profilePictureURL:"https://mts.intechopen.com/storage/users/211260/images/system/211260.jpeg",institutionString:null,institution:{name:"University of Alicante",institutionURL:null,country:{name:"Spain"}}}]},{id:"40",title:"Ecosystems and Biodiversity",keywords:"Ecosystems, Biodiversity, Fauna, Taxonomy, Invasive species, Destruction of habitats, Overexploitation of natural resources, Pollution, Global warming, Conservation of natural spaces, Bioremediation",scope:"
\r\n\tIn general, the harsher the environmental conditions in an ecosystem, the lower the biodiversity. Changes in the environment caused by human activity accelerate the impoverishment of biodiversity.
\r\n
\r\n\tBiodiversity refers to “the variability of living organisms from any source, including terrestrial, marine and other aquatic ecosystems and the ecological complexes of which they are part; it includes diversity within each species, between species, and that of ecosystems”.
\r\n
\r\n\tBiodiversity provides food security and constitutes a gene pool for biotechnology, especially in the field of agriculture and medicine, and promotes the development of ecotourism.
\r\n
\r\n\tCurrently, biologists admit that we are witnessing the first phases of the seventh mass extinction caused by human intervention. It is estimated that the current rate of extinction is between a hundred and a thousand times faster than it was when man first appeared. The disappearance of species is caused not only by an accelerated rate of extinction, but also by a decrease in the rate of emergence of new species as human activities degrade the natural environment. The conservation of biological diversity is "a common concern of humanity" and an integral part of the development process. Its objectives are “the conservation of biological diversity, the sustainable use of its components, and the fair and equitable sharing of the benefits resulting from the use of genetic resources”.
\r\n
\r\n\tThe following are the main causes of biodiversity loss:
\r\n
\r\n\t• The destruction of natural habitats to expand urban and agricultural areas and to obtain timber, minerals and other natural resources.
\r\n
\r\n\t• The introduction of alien species into a habitat, whether intentionally or unintentionally which has an impact on the fauna and flora of the area, and as a result, they are reduced or become extinct.
\r\n
\r\n\t• Pollution from industrial and agricultural products, which devastate the fauna and flora, especially those in fresh water.
\r\n
\r\n\t• Global warming, which is seen as a threat to biological diversity, and will become increasingly important in the future.
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\r\n\tWater is not only a crucial substance needed for biological life on Earth, but it is also a basic requirement for the existence and development of the human society. Owing to the importance of water to life on Earth, early researchers conducted numerous studies and analyses on the liquid form of water from the perspectives of chemistry, physics, earth science, and biology, and concluded that Earth is a "water polo". Water covers approximately 71% of Earth's surface. However, 97.2% of this water is seawater, 21.5% is icebergs and glaciers, and only 0.65% is freshwater that can be used directly by humans. As a result, the amount of water reserves available for human consumption is limited. The development, utilization, and protection of freshwater resources has become the focus of water science research for the continued improvement of human livelihoods and society.
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\r\n\tWater exists as solid, liquid, and gas within Earth’s atmosphere, lithosphere, and biosphere. Liquid water is used for a variety of purposes besides drinking, including power generation, ecology, landscaping, and shipping. Because water is involved in various environmental hydrological processes as well as numerous aspects of the economy and human society, the study of various phenomena in the hydrosphere, the laws governing their occurrence and development, the relationship between the hydrosphere and other spheres of Earth, and the relationship between water and social development, are all part of water science. Knowledge systems for water science are improving continuously. Water science has become a specialized field concerned with the identification of its physical, chemical, and biological properties. In addition, it reveals the laws of water distribution, movement, and circulation, and proposes methods and tools for water development, utilization, planning, management, and protection. Currently, the field of water science covers research related to topics such as hydrology, water resources and water environment. It also includes research on water related issues such as safety, engineering, economy, law, culture, information, and education.
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