FFR latency values using syllable /da/of 40-ms duration performed on babies with normal hearing (silent background) [19].
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Until recently, electrophysiological evaluations were performed exclusively with nonverbal stimuli such as clicks and tone bursts which allow rapid and synchronous stimulation of neurons. However, the use of verbal stimuli, such as speech sounds, allows a more accurate analysis of the auditory system, especially if the aim is to investigate how the system decodes speech sounds involved in daily communication. Verbal and nonverbal stimuli are decoded in different ways and follow different trajectories through the central auditory nervous system.
\nHuman communication consists predominantly of verbal stimuli, and it is important to understand how verbal sounds are coded at various levels of the auditory system. The need to develop research methods that are objective and accurately represent daily listening led to the development early this century of electrophysiological tests for measuring how speech sounds are perceived [1, 2]. Subsequently, a number of research groups have focused their efforts on using complex stimuli such as speech for diagnostic purposes [3, 4, 5, 6, 7, 8, 9, 10].
\nThe initial studies were performed in animal models [11] aiming to evaluate how the temporal and spectral properties of verbal stimuli were coded, and later human responses were also analyzed [12]. Among the electrophysiological procedures for investigating the processing and coding of verbal sounds, we highlight the frequency following response (FFR).
\nAcquisition of an FFR is very similar to collecting an ABR with a click stimulus. However, interpretation of an FFR requires that the audiologist has a more sophisticated knowledge base. Speech stimuli allow a more complex analysis of the responses, such as their:
timing;
magnitude;
frequency content and magnitude;
frequency tracking;
phase consistency;
intrinsic factors; and
difference between individual responses.
An FFR evaluation can be performed on different clinical populations and age groups, and below we give details of how the procedure varies depending on the patient’s age. Because FFR is a relatively new procedure, initial work was done on adult subjects. Afterward, researchers turned their interest to the study of responses in infants and young children, children and adolescents, and the elderly.
\nIn order for an FFR assessment to be useful in identifying auditory disorders at an early stage, normative values using different equipment and recording parameters need to be established and compared with language acquisition markers.
\nThe distinctive features of FFRs in different age groups will be presented in three parts:
evaluation in infants;
evaluation in children and adolescents;
evaluation in adults and the elderly.
In clinical practice, a comprehensive hearing evaluation for infants and young children is essential, since the integrity of their auditory system is the basis for acquiring oral language. In this context, if one measures only the functioning of the peripheral auditory pathway, perhaps by recording and analyzing otoacoustic emissions and/or auditory brainstem evoked potentials, it significantly constrains one’s knowledge of the patient’s hearing status. Moreover, behavioral assessments of hearing in very young children are often inconclusive, considering the diversity of neuropsychomotor development in this age group.
\nThe perception of speech is important for the development of receptive and expressive language [13]. Through auditory experiences, infants and toddlers acquire and master the linguistic elements necessary for effective communication. The experiences are associated with information from the other senses, and together they allow the acquisition and development of oral language. Through listening, the subject understands oral language and creates concepts, finally inter-relating them and expressing them through speech [14]. Thus, the importance of hearing for the acquisition and development of language is vital, and any disturbance to the auditory pathway has implications for oral communication as a whole [14].
\nFFR testing can be used with infants and young children as a predictor of the extent of future language appropriation—in other words as a way of identifying children who are at risk of deficits in oral language acquisition [2, 15]. Assessment by FFR of infants and young children is relatively recent, and published studies of its potential have only been done over the last decade. Before discussing what is known about FFR in this population, it is first necessary to clarify an important factor: maturation of the auditory pathway.
\nIt is known that peripheral hearing is functional even before birth, whereas myelination and the organization of neural connections keep developing after birth [16, 17]. Indeed, the central structures, such as the subcortex and cortex, develop throughout the early years of human life. There is an ascending myelination of the auditory pathway, evidenced by magnetic resonance imaging. Up to the 13th week of life, there is an increase in myelination density of the cochlear nucleus, the superior olivary complex, and the lateral lemniscus, with the inferior colliculus demonstrating an increase in density around the 39th week of life [18]. This continuous process of myelination of the higher structures of the auditory pathway during the first year of life must be considered when evaluating the FFR, for it means that the lower the age of the evaluated subject, the greater the latency of the FFR waves [19, 20]. This increase in latency can also be seen in other auditory evoked potentials [21]. An FFR can be recorded from a neonate, but the responses only become readily apparent from the third month of age [15]. The existence of a series of FFR waves—V, A, C, D, E, F, and O—in neonates has been pointed out by several researchers [15, 19, 22, 23, 24, 25, 26]. FFR evaluations have been performed with the vowel /i/ [15, 24], the syllables /ba/ and /ga/ [26], and the syllable /da/ [23].
\nThe FFR has been studied in neonates of different nationalities (Chinese, American) during the first days after birth, and the FFRs were nearly the same. This finding makes it possible to infer that, independent of the mother tongue, there is an innate capacity for speech coding in neonates at the subcortical level [22].
\nThe evaluation of subcortical representation of speech coding was studied by evaluating FFRs in 28 healthy North American infants, 3–10 months of age. The study focused on the fundamental frequency (F0), the response time of the FFR, and the representation of harmonics. To analyze the data in the frequency domain, spectral amplitudes were calculated by fast Fourier transform (FFT) and divided into three frequency ranges: F0, 103–125 Hz; first formant (F1), 220–720 Hz; and high harmonics (HH), 720–1120 Hz. The F0 responses were more robust in infants 3 months of age and the amplitude of F0 did not show significant changes over the entire 6 months. For the F1 and HH frequencies, there was a rapid and systematic increase of amplitude from 3 to 6 months of age.
\nTo analyze the data in the time domain, the peaks were identified manually and confirmed by a second observer. Waves I, III, and V were first identified in response to a click, and then, in the FFR, the same peak and following valley (V and A), the peaks (D, E, and F), and the displacement peak (O). Non-detectable peaks were marked as missing data points and were excluded from analysis. The latencies and amplitudes (baseline to peak) were extracted from the identified waves. The time domain analysis demonstrated a decrease in neural conduction time and an improvement in amplitude with increasing age. The latencies of A and O, the time interval between A and O, and the slope between V and A were shown to have a negative correlation between latency and age. In addition, there was an improvement in the morphology of all waves as age increased. It was also observed that infants 3–5 months of age had longer latencies, smaller intervals between A and O, and a lower V/A slope compared to those 6–10 months of age. This negative correlation between the latencies and the age of the infants, as well as the decrease of slope in the smaller children, is due to a maturational process occurring in the subcortical auditory system and shows that there is less neural synchrony in younger infants [23]. The authors also note that these findings indicate that at approximately 6 months of age, the coding of speech characteristics, both spectrally and temporally, becomes more like those of an adult, although the changes continue through to school age. These findings indicate that FFR evaluation can detect early disorders in the perception of speech sounds.
\nThe researchers also investigated the development of subcortical speech processing in Chinese infants born in households in which the mother tongue was Mandarin. They recorded FFRs at two ages: 1–3 days of life and at 3 months. This prospective-longitudinal design study included only infants who had undergone auditory screening at birth, who had no obvious neurological disorders, and did not have any risk indicator for hearing loss. Initially, 44 newborns were tested by FFR during natural sleep. After that, the sample was divided into groups. For each group, the researchers selected different speech stimuli for the evaluation of FFR (monosyllables contrasting with Mandarin). Only 13 infants completed the follow-up protocol at the third month. The processing and tracking of the fundamental frequencies of human speech at the subcortical level, evidenced by the FFR, showed more robust responses when the babies were 3 months old. Researchers acknowledged the limitations of the study, including statistical analysis and data interpretation. A research weakness was the relatively low completion rate (i.e., 17/44 infants or 38.64%). This factor undermined the power of the conclusions and prevented the possibility of performing statistical analyses for each Mandarin tone used. Despite the limitations of the study, the findings fill a gap in understanding the developmental trajectory of subcortical processing during the first 3 months of life [25].
\nFrom the theoretical assumptions highlighted in the previous reference, it should be noted that the linguistic environment of a newborn has a substantial effect on the development of its speech perception. Even at birth, children are able to detect subtle differences in verbal sounds. Newborns can effectively differentiate all the features of human speech and most infants who participated in an FFR follow-up showed improvement in pitch tracking and response amplitudes at 3 months of age [25]. Such neural refinements observed by FFR are often highlighted in the literature for both infants [22, 24] and young infants [15, 23]. For example, in a longitudinal case report of one infant, the researchers obtained FFR records when the infant was 1, 3, 5, 7, and 10 months old. The results showed an evolving trajectory of development with a transition point of about 3 months [15].
\nUsing FFR evaluation in preterm infants may also be an alternative for the early diagnosis of auditory disorders in this population related to the perception of speech sounds. Premature babies are at high risk of developing language disorders, so using FFR may be a way of measuring immature neural activity and predicting possible changes in the processing of verbal sounds. In order to do so, one study evaluated 12 premature Indian infants through FFR with the aim of exploring how an immature auditory system responds to complex acoustic stimuli such as speech [27]. Peaks V, A, C, D, E, and F were detected in almost all babies and with latencies and amplitudes similar to those reported in the literature. The waves could be replicated. The authors conclude that FFR may be a way of understanding how the human brain-stem receives speech signals and that such an assessment might be important for all high-risk babies. Although the findings of this study cannot be generalized, mainly due to the limited data (small sample and absence of a controls, among others), they point out the potential of FFR in evaluating infants from neonatal intensive care units.
\nMore recently, studies that record FFRs in the presence of background noise have been published. It is known that competing noise can make speech comprehension more difficult in people of all ages. Speech-in-noise tests are clinically available but cannot be given to infants. Thus, the use of FFRs in noise may be an alternative for evaluating impaired speech perception in young children who are unable to respond to behavioral tests.
\nIn this context, with the objective of examining the electrophysiological responses in the presence of noise, researchers have evaluated the FFR in 30 children with typical development under conditions with and without noise (a signal-to-noise ratio of +10 dB in the former) [28]. Babies were divided into two age groups: 7–12 and 18–24 months. For all infants, frequency analysis of the FFR with a Fourier transform was performed, analyzing the latency and amplitude of waves V, A, D, E, and F, and correlation tests were carried out. In both groups, the mean latency of all recorded waves was higher in the presence of noise. According to the authors, this suggests that, at least for infants up to 24 months, the presence of noise causes a delay in the appearance of FFR waves independent of age. In addition, they observed a greater amplitude of F0 in the noise condition in the group of older babies; this difference was not seen in the silent condition. Thus, the authors point out that, at 2 years of age, infants are less vulnerable to the degrading effects of noise compared to children younger than 12 months.
\nThe development of phase lock and frequency representation has also been evaluated in infants. This was the focus of a study that included an initial sample of 56 typical babies, aged between 2 and 12 months, and evaluated the FFR with /ba/ and /ga/ stimuli presented in the right ear using the SmartEP equipment from Intelligent Hearing Systems [26]. These responses were also obtained in young adults to provide a reference for the course of development of neural synchrony (represented by phase lock) and response amplitude (represented by spectral magnitude). The results obtained in this study demonstrate that the strength of phase-lock in the fine structure at CV transition is higher in young adults compared to infants. However, phase lock for F0 was equivalent between adults and infants. The frequency of F0 was found to be higher in older infants compared to younger infants and adults. Thus, these data demonstrate that speech coding can be evaluated in infants from 2 months of age and that such data are of value in a clinical setting, since it is known that performing electrophysiological evaluation of hearing in young children is difficult because they are less able to remain still during a test. The data indicate that the FFR may be a way of testing babies who are at risk of developing a language disorder, examining the auditory coding mainly of the midbrain, but also reflecting contributions from the auditory nerve, brain stem, and cortex.
\nThe most commonly used parameters in FFR evaluations are: monoaural stimulus, right ear stimulation, intensity of 80 dB SPL, syllable /da/ speech stimulus, alternating polarity, presentation rate of 10.9 stimuli per second, vertical placement of electrodes, insert headphones, and the subject sitting distracted or awake during recording [29].
\nRegarding the latency parameters, when FFR is done with the Navigator Pro AEP System (Natus Medical, Inc.) and a syllable stimulus, one group of researchers [19] pointed out that in 23 normal-hearing babies (0–12 months) the wave latencies were on average: V = 7.22 ms, A = 8.22 ms, D = 23.14 ms, E = 31.5 ms, F = 39.91 ms, and O = 49.64 ms. FFR wave latencies were also investigated in 53 children aged 3–5 years (Tables 1 and 2).
\nWaves | \n||||||
---|---|---|---|---|---|---|
\n | V | \nA | \nD | \nE | \nF | \nO | \n
\n | Lat | \nLat | \nLat | \nLat | \nLat | \nLat | \n
∑ | \n7.22 | \n8.22 | \n23.14 | \n31.51 | \n39.91 | \n49.64 | \n
SD | \n0.42 | \n0.43 | \n0.66 | \n0.49 | \n0.45 | \n1.32 | \n
Detect (%) | \n86.9 | \n86.96 | \n91.30 | \n91.30 | \n82.61 | \n65.22 | \n
FFR latency values using syllable /da/of 40-ms duration performed on babies with normal hearing (silent background) [19].
∑: average (ms), SD: standard deviation, Detect: the percent detectability for each peak.
Sample: 23 babies (0–1 years old).
Waves | \n||||||
---|---|---|---|---|---|---|
\n | V | \nA | \nD | \nE | \nF | \nO | \n
\n | Lat | \nLat | \nLat | \nLat | \nLat | \nLat | \n
∑ | \n6.59 | \n7.56 | \n22.36 | \n30.90 | \n39.34 | \n48.14 | \n
SD | \n0.26 | \n0.35 | \n0.38 | \n0.37 | \n0.32 | \n0.42 | \n
Detect | \n100 | \n100 | \n88.67 | \n98.11 | \n100 | \n90.57 | \n
FFR latency values using syllable /da/ of 40-ms duration performed in children with normal hearing (in silence) [19].
∑: average (ms), SD: standard deviation, Detect: the percent detectability for each peak.
Sample: 53 children (3–5 years old).
Parameters of FFR evaluation in infants and young children used in the Hearing Electrophysiology Service of the Federal University of Santa Maria, Brazil, are presented in Table 3.
\nPresentation parameters | \nSetting | \n
---|---|
Equipment | \nSmartEP, Intelligent Hearing Systems (IHS) | \n
Transducer | \nInsert phones | \n
Electrodes | \nFz; Fpz; M1; M2 or Cz, M1, M2 | \n
Stimulation | \nRight ear | \n
Stimulus | \nSyllable /da/ | \n
Duration of stimulus | \n40 ms | \n
Presentation rate | \n10.9/s | \n
Window | \n80–100 ms | \n
Filter | \nLow pass of 100 Hz and high pass of 2000 Hz Low pass of 100 Hz and high pass of 3000 Hz | \n
Polarity | \nAlternating | \n
Intensity | \n80 dBnHL | \n
Number of stimuli | \n6000 | \n
Reproducibility | \n2 × 3000 stimuli | \n
Condition of evaluation | \nAwake and quiet | \n
Impedance | \n3k Ohms | \n
Artifact rejection | \nAcceptance if <10% | \n
Parameters of FFR in infants and young children.
ms, millisecond; s, second; Hz, hertz; dB, decibel; HL, hearing level.
The early identification of hearing disorders through FFR evaluation allows a speech-language pathologist to intervene, lessening the damage that this disorder can have on the development of speech skills in early childhood [2, 20, 22, 31]. This assertion can be understood by appreciating the relationship between language development and the presence of stimulating auditory experiences in the first few months of life.
\nFuture studies evaluating FFRs in infants will no doubt benefit from interdisciplinary collaboration which seeks to deepen understanding of the underlying mechanisms involved in the typical and atypical development of the auditory system during early childhood.
\nAuditory impairment is almost invariably associated with language and communication deficits. Learning a spoken language depends on assimilating the acoustic and phonetic elements of a language [32]. The development of the central auditory nervous system begins in intrauterine life and continues until adolescence, over which time hearing abilities become more complex and elaborate.
\nBecause of the close relationship between hearing, language, and learning, it is extremely important to monitor hearing over the course of life. Especially in children, be it pre-school or school age, the aim should be to monitor auditory function, either through behavioral or electrophysiological assessments. The ideal would be a combination of both behavioral and electrophysiological methods, so that with numerous evaluations there are crosschecks which allow a more accurate diagnosis to be made.
\nThe electrophysiological procedure traditionally used in clinical practice is the click ABR. However, in evaluating children with language deficits, this type of sound stimulus is not ideal for making diagnoses. Assessments using verbal sound stimuli, such as used in FFR, appear to be more effective and reliable in cases of learning problems or school difficulties [6]. Evaluation via an FFR allows a detailed analysis of how verbal stimuli are encoded in the central auditory nervous system to be done.
\nThe FFR allows fine-grained auditory processing deficits associated with real-world communication skills to be identified. As well as being used for the early identification of auditory processing, it can also be used to assess hearing across different clinical populations [33, 34]. This electrophysiological procedure can provide reliable and objective information about acoustic patterns such as timing, pitch, and timbre [35]. These three elements can be evaluated using different parts of the FFR, as follows:
timing—via analysis of the onset and offset portions;
pitch—by analysis of the fundamental frequency (F0);
timbre—from analysis of the harmonics of F0.
Simplistically, it can be said that the FFR helps in understanding which speech sounds were spoken (their timing and harmonic cues) and who said it (pitch cues) [36]. In addition, an FFR test can be performed under two conditions: (i) in silence (presentation of verbal stimuli only), and (ii) in noise (presentation of verbal stimuli plus background noise).
\nIn children and adolescents, studies have shown that FFRs change in latency as age increases. FFRs of children aged around 5 years appear to be very similar to the responses of children aged 8–12. However, the FFR pattern of children under 5 years has a somewhat different morphology and latency. According to Johnson et al. [33], the differences in children younger than 3 years are more evident in the initial portion of the responses (the onset), while in older children the change is more evident in the final portion (the offset) [3, 37].
\nInitial studies have focused on understanding the FFRs in children and adolescents under silent conditions and in subjects who have normal hearing and typical development. For the benefit of clinical audiologists, some of these studies are summarized below (Tables 4–9).
\nSource | \nLatency (ms) | \nAmplitude (μV) | \nVA measures | \n|||
---|---|---|---|---|---|---|
\n | ∑ | \nSD | \n∑ | \nSD | \n∑ | \nSD | \n
V | \n6.61 | \n0.25 | \n0.31 | \n0.15 | \n\n | \n |
A | \n7.51 | \n0.34 | \n0.65 | \n0.19 | \n\n | \n |
C | \n17.69 | \n0.48 | \n0.36 | \n0.09 | \n\n | \n |
F | \n39.73 | \n0.61 | \n0.43 | \n0.19 | \n\n | \n |
Slope VA (μV/ms) | \n\n | \n | 0.13 | \n0.05 | \n||
Area VA (μV × ms) | \n\n | \n | 1.70 | \n1.23 | \n
FFR latency and amplitude values using the syllable/da/of 40-ms duration, performed in children with normal hearing on the right ear (silent conditions) [12].
∑: average, SD: standard deviation.
Sample: 36 and 38 children and adolescents (8–12 years old) with normal hearing.
Waves | \n|||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
\n | \n | V | \nA | \nC | \nD | \nE | \nF | \nO | \n|||||||
\n | Sex | \nLat | \nAmp | \nLat | \nAmp | \nLat | \nAmp | \nLat | \nAmp | \nLat | \nAmp | \nLat | \nAmp | \nLat | \nAmp | \n
∑ | \nM | \n6.53 | \n0.10 | \n7.53 | \n0.19 | \n18.43 | \n0.08 | \n22.29 | \n0.17 | \n30.86 | \n0.21 | \n39.31 | \n0.17 | \n48.02 | \n0.13 | \n
F | \n6.49 | \n0.13 | \n7.43 | \n0.23 | \n18.33 | \n0.12 | \n22.28 | \n0.15 | \n30.81 | \n0.29 | \n39.27 | \n0.24 | \n47.95 | \n0.21 | \n|
Med | \nM | \n6.49 | \n0.10 | \n7.53 | \n0.18 | \n18.28 | \n0.07 | \n22.24 | \n0.09 | \n30.86 | \n0.21 | \n39.28 | \n0.7 | \n48.11 | \n0.13 | \n
F | \n6.49 | \n0.12 | \n7.37 | \n0.22 | \n18.37 | \n0.09 | \n22.11 | \n0.13 | \n30.78 | \n0.22 | \n39.11 | \n0.24 | \n47.86 | \n0.21 | \n|
SD | \nM | \n0.19 | \n0.05 | \n0.32 | \n0.04 | \n0.44 | \n0.05 | \n0.32 | \n0.07 | \n0.53 | \n0.07 | \n0.44 | \n0.08 | \n0.45 | \n0.07 | \n
F | \n0.22 | \n0.07 | \n0.35 | \n0.90 | \n0.44 | \n0.11 | \n0.67 | \n0.09 | \n0.58 | \n0.35 | \n0.56 | \n0.26 | \n0.75 | \n0.28 | \n
FFR latency and amplitude values for males and females using syllable /da/ of 40-ms duration performed in children with normal hearing (silent conditions) [30].
∑: average, Med: median, SD: standard deviation, M: male, F: female.
Sample: 40 children and adolescents (8–16 years old).
\n | \n | Complex VA | \n|
---|---|---|---|
\n | Sex | \nSlope VA (ms/μV) | \nArea VA (ms × μV) | \n
∑ | \nM | \n0.31 | \n0.29 | \n
\n | F | \n0.39 | \n0.34 | \n
Med | \nM | \n0.29 | \n0.31 | \n
\n | F | \n0.36 | \n0.31 | \n
SD | \nM | \n0.11 | \n0.09 | \n
\n | F | \n0.14 | \n0.14 | \n
Complex VA (slope and area) values for males and females using syllable/da/of 40-ms duration performed in children with normal hearing (silent conditions) [30].
∑: average, Med: median, SD: standard deviation, M: male, F: female.
Sample: 40 children and adolescents (8–16 years old).
Waves | \n|||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
\n | \n | V | \nA | \nC | \nD | \nE | \nF | \nO | \n|||||||
\n | Ear | \nLat | \nAmp | \nLat | \nAmp | \nLat | \nAmp | \nLat | \nAmp | \nLat | \nAmp | \nLat | \nAmp | \nLat | \nAmp | \n
∑ | \nR | \n6.50 | \n0.12 | \n7.46 | \n0.22 | \n18.33 | \n0.10 | \n22.21 | \n0.14 | \n30.89 | \n0.30 | \n39.37 | \n0.24 | \n48.00 | \n0.21 | \n
L | \n6.51 | \n0.11 | \n7.48 | \n0.21 | \n18.41 | \n0.11 | \n22.36 | \n0.13 | \n30.78 | \n0.23 | \n39.20 | \n0.19 | \n47.95 | \n0.16 | \n|
Med | \nR | \n6.45 | \n0.12 | \n7.45 | \n0.21 | \n18.33 | \n0.08 | \n22.12 | \n0.14 | \n30.86 | \n0.23 | \n39.24 | \n0.19 | \n47.99 | \n0.15 | \n
L | \n6.53 | \n0.11 | \n7.41 | \n0.21 | \n18.33 | \n0.09 | \n22.28 | \n0.11 | \n30.78 | \n0.21 | \n39.07 | \n0.18 | \n48.03 | \n0.15 | \n|
SD | \nR | \n0.21 | \n0.06 | \n0.33 | \n0.09 | \n0.42 | \n0.08 | \n0.66 | \n0.09 | \n0.50 | \n0.39 | \n0.55 | \n0.29 | \n0.75 | \n0.30 | \n
L | \n0.21 | \n0.06 | \n0.36 | \n0.07 | \n0.46 | \n0.10 | \n0.44 | \n0.08 | \n0.61 | \n0.09 | \n0.47 | \n0.09 | \n0.54 | \n0.12 | \n
FFR latency and amplitude values for right and left ears using syllable/da/of 40-ms duration performed on children with normal hearing (silent conditions) [30].
∑: average, Med: median, SD: standard deviation, R: right, L: left.
Sample: 40 children and adolescents (8–16 years old).
Complex VA | \n|||
---|---|---|---|
\n | Ear | \nSlope VA (ms/μV) | \nArea VA (ms × μV) | \n
∑ | \nR | \n0.37 | \n0.33 | \n
\n | L | \n0.34 | \n0.31 | \n
Med | \nR | \n0.32 | \n0.31 | \n
\n | L | \n0.32 | \n0.31 | \n
SD | \nR | \n0.14 | \n0.13 | \n
\n | L | \n0.13 | \n0.13 | \n
Complex VA (slope and area) values for right and left ears using syllable/da/of 40 ms duration performed on children with normal hearing (silent conditions) [30].
∑: average, Med: median, SD: standard deviation, R: right, L: left.
Sample: 40 children and adolescents (8–16 years old).
Waves | \n|||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
\n | \n | V | \nA | \nC | \nD | \nE | \nF | \nO | \n|||||||
\n | Age range | \nLat | \nAmp | \nLat | \nAmp | \nLat | \nAmp | \nLat | \nAmp | \nLat | \nAmp | \nLat | \nAmp | \nLat | \nAmp | \n
∑ | \n8–11 | \n6.53 | \n0.12 | \n7.44 | \n0.22 | \n18.37 | \n0.11 | \n22.26 | \n0.15 | \n30.80 | \n0.25 | \n39.34 | \n0.21 | \n47.95 | \n0.17 | \n
12–16 | \n6.46 | \n0.11 | \n7.51 | \n0.21 | \n18.36 | \n0.10 | \n22.32 | \n0.10 | \n30.89 | \n0.28 | \n39.19 | \n0.21 | \n48.02 | \n0.21 | \n|
Med | \n8–11 | \n6.53 | \n0.11 | \n7.45 | \n0.21 | \n18.37 | \n0.09 | \n22.20 | \n0.14 | \n30.78 | \n0.23 | \n39.28 | \n0.20 | \n47.95 | \n0.15 | \n
12–16 | \n6.45 | \n0.12 | \n7.45 | \n0.17 | \n18.28 | \n0.08 | \n22.20 | \n0.09 | \n30.86 | \n0.20 | \n39.11 | \n0.15 | \n48.03 | \n0.13 | \n|
SD | \n8–11 | \n0.23 | \n0.06 | \n0.32 | \n0.10 | \n0.46 | \n0.09 | \n0.53 | \n0.08 | \n0.62 | \n0.19 | \n0.56 | \n0.11 | \n0.75 | \n0.14 | \n
12–16 | \n0.17 | \n0.06 | \n0.37 | \n0.07 | \n0.41 | \n0.08 | \n0.63 | \n0.45 | \n0.43 | \n0.22 | \n0.42 | \n0.32 | \n0.46 | \n0.33 | \n
FFR latency and amplitude values for various age ranges using syllable/da/of 40-ms duration performed on children with normal hearing (silent conditions) [30].
∑: average, Med: median, SD: standard deviation, R: right, L: left.
Sample: 40 children and adolescents (8–16 years old).
Table 10 shows the parameters used in children and adolescents at the Electrophysiology Department of the State University of Campinas using Biologic equipment and BioMARK software.
\nParameter | \nSettings | \n
---|---|
Equipment | \nBiologic Navigator Pro | \n
Software | \nBioMARK | \n
Electrode montage | \nCz, M1, and M2 | \n
Stimulated ear | \nRight ear | \n
Stimulus | \nSpeech | \n
Stimulus type | \nSyllable /da/ | \n
Stimulus duration | \n40 ms | \n
Stimulus polarity | \nAlternating | \n
Stimulus intensity | \n80 dB SPL | \n
Stimulus rate | \n10.9/s | \n
Number of sweeps | \n6000 | \n
Replicability | \nTwice for 3000 sweeps | \n
Transducer | \nInsert | \n
Assessment condition | \nWatching a movie | \n
Impedance | \n1k Ohms | \n
Window 85.33 ms | \n85.33 ms | \n
Filter | \n100–2000 Hz | \n
Artifact rejection | \n>10% | \n
Parameters of FFR in children and adolescents.
Cz: vertex, M1: left mastoid, M2: right mastoid, ms: millisecond, dB: decibel, SPL: sound pressure level, s: second, Hz: hertz.
Because FFR is a new procedure, unstudied pathologies are gradually being added and, little by little, we are gaining new information about what effects the pathologies have on the responses of affected children and adolescents.
\nThe FFRs of children diagnosed as poor readers frequently present as alterations in the timing and magnitude of timbre components [38]. The perception of the duration of a sound stimulus is essential for proficient reading, and the FFR can evaluate or monitor a decline in temporal and spectral precision. Children and adolescents with dyslexia commonly have difficulty perceiving speech sounds either in silence or in competing noise backgrounds. If a child has difficulty in perceiving speech sounds, their reading can be severely impaired [39]. Recently, Sanfins et al. [6] highlighted the importance of FFR as a biological marker in scholastic difficulties.
\nFFR evaluation in children who have suffered from secretory otitis media in the first 6 years of life, and who have undergone myringotomy for bilateral ventilation tube placement, exhibit changes in their FFR compared to normal children [5]. This study found that evaluating the FFR seems to be a promising method of identifying changes in the coding of speech stimuli in these children which might be undetected using traditional electrophysiological evaluation. The changes in their electrophysiological responses might serve as an alert to parents and educators, who can then adopt strategies to minimize the negative consequences on language development and academic achievement.
\nAnother possibility for using FFR assessment may be in monitoring an auditory training program or even tracking the effect of therapeutic interventions. Studies have shown that children with learning disabilities can benefit from an auditory remediation program, and it might therefore be usefully accompanied by FFR examinations (because FFRs have good repeatability in test and retest) [40, 41]. In addition, bilingual children can also be monitored through FFR assessment. Researchers have confirmed that neural perception of speech seems to be more consistent in bilinguals than in monolinguals [42, 43]. Bilingual experience during childhood may favor plasticity in the neuronal coding of sound and improve fundamental frequency perception (F0).
\nRecently, the neurophysiological aspects of speech perception have been investigated in cases of autism spectrum disorder (ASD). The results showed that children with ASD tend to have changes in the sensation of pitch (frequency), which might explain a withdrawal from speech reception. The fundamental frequency (F0) and its harmonics contain speech information which is essential in conveying affect [44], so changes in FFRs are consistent with a defect in perceiving prosody. The inference is that prosody deficits in some ASD patients may derive from an inability to encode and transmit auditory information in the brainstem [45].
\nTraditionally, FFR testing is done by presenting verbal stimuli through an insert earphone with a silent background. However, the perception of speech in a noisy background is a much discussed topic. In the presence of noise, normally hearing individuals need to make constant adjustments in their central auditory nervous system to satisfactorily understand and process speech information. Of course, there are others who, in the presence of competing noise, experience great difficulty in understanding speech [46].
\nThe evaluation of FFR in the presence of noise can be effectively used to diagnose children with learning disabilities [47]. Thus, identification of such children could lead to improvements in their reading and writing skills and in daily communication.
\nIn the adult and elderly population, the need for detailed audiological investigation increases when the patient complains of hearing difficulties, even if auditory thresholds appear normal.
\nThe evaluation of the FFR first involves time and prosody recordings, which provide important information about consonant and vowel discrimination and also aid in the perception of intonation [48]. For adults, but especially in the elderly, participation in these sorts of tests can assist in rehabilitation, either using a hearing aid or auditory training (or both).
\nThe clinical usefulness of the FFR in gauging how well auditory information is being processed is unquestionable. In adults and the elderly, many studies have already been done to identify how the FFR can help in diagnosing complaints related to central auditory processing, thereby allowing better rehabilitation.
\nThe latencies (mean and standard deviation) for adults and the elderly are presented in Table 11. The values come from Skoe et al. [19] who used Biologic and Navigator Pro equipment. In this study, subjects aged between 18 and 72 years and distributed in 6 age brackets were used. In the case of adults, the authors list values for subjects aged 21–30 years (n = 143) and found that latency values tended to increase with age. Thus, the researchers emphasized the importance of conducting research on FFRs in different age groups, since normative values can be modified with the aging process.
\nComplex VA | \n|||
---|---|---|---|
\n | Age range | \nSlope VA (ms/μV) | \nArea VA (ms × μV) | \n
∑ | \n8–11 | \n0.38 | \n0.31 | \n
\n | 12–16 | \n0.33 | \n0.34 | \n
Med | \n8–11 | \n0.37 | \n0.31 | \n
\n | 12–16 | \n0.28 | \n0.31 | \n
SD | \n8–11 | \n0.12 | \n0.11 | \n
\n | 12–16 | \n0.16 | \n0.16 | \n
Complex VA (slope and area) values for age range using syllable/da/of 40-ms duration performed in children with normal hearing (silent conditions) [30].
∑: average, Med: median, SD: standard deviation, R: right, L: left.
Sample: 40 children and adolescents (8–16 years old).
In Table 12 the maximum values of each wave are listed by adding two standard deviations to those in Table 13. Assuming the distribution is Gaussian means that this measure will cover 95% of the population.
\nAge (years) | \nNumber | \nLatencies (maximum in milliseconds + 2 SD) | \n|||||
---|---|---|---|---|---|---|---|
\n | \n | V | \nA | \nD | \nE | \nF | \nO | \n
17–21 | \n54 | \n7.04 | \n8.15 | \n23.21 | \n31.9 | \n39.50 | \n48.94 | \n
21–30 | \n143 | \n7.17 | \n8.28 | \n23.4 | \n32.54 | \n40.84 | \n49.79 | \n
30–40 | \n32 | \n7.27 | \n8.39 | \n23.64 | \n32.09 | \n40.38 | \n49.13 | \n
40–50 | \n11 | \n7.05 | \n8.22 | \n24.26 | \n31.86 | \n39.93 | \n49.6 | \n
50–60 | \n26 | \n7.5 | \n8.77 | \n24.5 | \n32.97 | \n41.46 | \n50.72 | \n
60–73 | \n24 | \n7.68 | \n8.81 | \n24.27 | \n32.47 | \n40.60 | \n50.02 | \n
Age | \nNumber | \nLatency ∑ (mean in milliseconds) | \nStandard deviation | \n||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
\n | \n | V | \nA | \nD | \nE | \nF | \nO | \nV (SD) | \n% | \nA (SD) | \n% | \nD (SD) | \n% | \nE (SD) | \n% | \nF (SD) | \n% | \nO (SD) | \n% | \n
117–21 | \n54 | \n6.58 | \n7.53 | \n22.41 | \n31.02 | \n39.50 | \n48.26 | \n0.23 | \n100 | \n0.31 | \n96.30 | \n0.40 | \n92.6 | \n0.44 | \n94.44 | \n0.46 | \n98.15 | \n0.34 | \n98.15 | \n
221–30 | \n143 | \n6.65 | \n7.60 | \n22.60 | \n31.12 | \n39.61 | \n48.33 | \n0.26 | \n100 | \n0.34 | \n100 | \n0.67 | \n95.8 | \n0.71 | \n100 | \n0.62 | \n99.30 | \n0.73 | \n97.90 | \n
330–40 | \n32 | \n6.61 | \n7.53 | \n22.52 | \n31.09 | \n39.54 | \n48.21 | \n0.33 | \n100 | \n0.43 | \n100 | \n0.56 | \n96.88 | \n0.50 | \n96.88 | \n0.42 | \n96.88 | \n0.46 | \n93.75 | \n
440–50 | \n11 | \n6.67 | \n7.64 | \n22.84 | \n31.26 | \n39.49 | \n48.30 | \n0.19 | \n100 | \n0.29 | \n100 | \n0.71 | \n90.90 | \n0.30 | \n100 | \n0.22 | \n100 | \n0.65 | \n90.90 | \n
550–60 | \n26 | \n6.86 | \n7.89 | \n23.08 | \n31.57 | \n39.92 | \n48.72 | \n0.32 | \n92.31 | \n0.44 | \n92.31 | \n0.71 | \n76.92 | \n0.70 | \n96.15 | \n0.77 | \n92.31 | \n1.00 | \n88.46 | \n
660–73 | \n24 | \n6.92 | \n7.89 | \n23.05 | \n31.37 | \n39.68 | \n48.84 | \n0.38 | \n91.67 | \n0.46 | \n91.67 | \n0.61 | \n83.33 | \n0.55 | \n83.33 | \n0.46 | \n83.33 | \n0.59 | \n100 | \n
FFR latency values for syllable /da/ of 40-ms duration, (silence) performed in adults and the elderly with normal hearing [19].
∑: Average (ms), SD: standard deviation, %: percent detectability for each peak.
Undoubtedly, the largest number of FFR studies have been performed using the Navigator Pro model from Biologic. Researchers tend to use this equipment together with the Intelligent Hearing Systems and SmartEP software [7, 49, 50].
\nOne study aimed to assess the processing of auditory information in those with hearing loss through an evaluation of eight individuals, aged 46–58 years, with hearing loss [7]. FFRs (collected by SmartEP) were correlated with results from two auditory processing behavioral tests—the masking level difference test and the random gap detection test. No correlation was found between FFR and these tests. The researchers found that the generation of this potential is extremely complex and could encompass several functions and does not depend on just temporal resolution or selective attention [7]. Also seeking to correlate FFRs with hearing loss, Peixe et al. [49] evaluated 11 individuals, aged 23–59 years, with moderately severe hearing loss. They concluded that hearing loss may cause an increase in the FFR wave latency, but the waves are still present so long as the stimulus intensity is adjusted. In other words, the presence of FFR waves is related to the audibility of the signal.
\nAnother interesting study was conducted with 30 young Indian adults aged 18–25 years [50]. The evaluation was carried out with the SmartEP equipment, and FFRs were present in all subjects evaluated. The latency and amplitude values of the analyzed elements were: wave V (lat = 6.81 ms and amp = 0.19 μV), wave C (lat = 16.82 ms and amp = 0.24 μV), wave D (lat = 24.75 ms and amp = 0.32 μV), wave E (lat = 31.36 ms and amp = 0.37 μV), and wave F (lat = 40.04 ms and amp = 0.29 μV).
\nWorldwide, there is a large increase in the number of elderly people. This entails providing better care for the elderly in all aspects of their health. With aging, there are structural changes in the peripheral and central auditory system which can lead to a decline in hearing. This, in turn, causes complaints of difficulty in understanding speech, especially in unfavorable environments [51, 52]. These impairments have a great impact on the life of the elderly, since in addition to causing social isolation, it can also lead to a depression and reduce cognitive function [53].
\nOnly a few studies have focused on FFR in the elderly, with the most reported population being young adults [54]. Some researchers have pointed to the clinical applicability of FFR in different populations and with different pathologies [7, 19, 37, 55].
\nThe effects of presbycusis on FFRs have been investigated in 18 individuals aged 61–78 years with hearing loss at frequencies of 2, 4, and 8 kHz (and compared with the responses of a control group of 19 young adults aged 20–26 years with normal hearing) [37]. The elderly group had lower amplitudes and increased latencies compared to the control group, demonstrating that the FFR can be affected by aging as well as hearing loss, but in different ways.
\nThe effects of hearing loss on FFRs were described in a sample of 30 elderly individuals aged 60–71 years who were divided into two groups matched by gender and intelligence quotient: (i) normal hearing, and (ii) mild to moderate hearing loss [35]. With ABR clicks, all subjects had normal responses. FFR testing indicated that individuals with hearing loss could be assessed with this procedure, but there were changes in the frequency responses. In the elderly with hearing loss, there was a breakdown in the perception of the speech signal, which resulted in differences in signal parameters compared to the group with normal thresholds. This breakdown in neural synchrony may explain the greater difficulty subjects with hearing loss have in speech perception.
\nThe evaluation of FFR in noisy environments is becoming more widespread, Thus, one study was carried out with 111 individuals between 45 and 78 years of age (mean 61.1 years) with normal to moderate hearing loss [56]. All subjects presented values within normal limits for the Montreal Cognitive Assessment (MoCA) and click ABR. In addition, they were tested on the SSQ (Speech, Spatial, and Qualities of Hearing Scale) which relates to auditory quality, as well as to the Quick Speech-in-Noise test (QuickSIN), in which phrases are presented binaurally with a verbal background babble. The FFR assessment demonstrated an increase in O-wave latency associated with speech comprehension difficulty in competing noise environments.
\nSupporting the observation that FFR traces are affected by increasing age, research on 34 individuals aged 22–77 years with normal hearing [57] found a decrease of the amplitude was associated with an increase in latency (Figures 1 and 2).
\nFFRs of an infant 13 days old. Authors’ data with FFR performed using SmartEP.
FFRs of two 9-year-old-children. The top trace represents a normal response and the second represents an abnormal response. Authors’ data using BioMARK software and Biologic equipment.
Figure 3 shows an FFR done on an adult aged 25 and on one aged 70. The shape of the FFR is similar in both, but there is an increase in latencies and some waves appear to be absent.
\nFFRs of an adult aged 25 years (top) and another aged 70 (bottom). Note the increase in latency of the waves. Authors’ data using SmartEP equipment.
In these FFR tracings, it can be seen that the elderly subject had an increase in latency of all waves compared to the younger adult. Aging causes a progressive loss of structure or functioning of neurons, which can be seen as decreased auditory evoked potentials. Through the FFR, it is seen that there is also a reduction in the speed of neural activation from brainstem to cortical structures.
\nOur FFR evaluation in adults and the elderly used IHS equipment and the parameters are shown in Table 14.
\nPresentation parameters | \nSetting | \n
---|---|
Equipment | \nSmartEP Intelligent Hearing Systems (IHS) | \n
Transducer | \nInsert phones | \n
Electrodes | \nFz, Fpz, M1, M2 or Cz, M1, M2 | \n
Stimulation | \nRight ear | \n
Stimulus | \nSyllable /da/ | \n
Stimulus duration | \n40 ms | \n
Presentation rate | \n10.9/s | \n
Window | \n80–100 ms | \n
Filter | \nLow pass of 100 Hz and high pass of 2000 Hz Low pass of 100 Hz and high pass of 3000 Hz | \n
Polarity | \nAlternating | \n
Intensity | \n80 dBnHL | \n
Number of stimuli | \n6000 | \n
Reproducibility | \n2 × 3000 stimuli | \n
Condition of evaluation | \nawake and quiet | \n
Impedance | \n3k Ohms | \n
Artifact rejection | \n>10% | \n
Parameters of FFR in adults and the elderly.
FFR evaluations can be included as an extra examination in diagnostic testing and have an important role in crosschecking the results. It can also greatly assist making differential diagnoses in different clinical populations. However, each age group has FFRs with specific characteristics, so it is important that the audiologist has access to good normative values for the different age groups (infants and toddlers, young children, children and adolescents, adults and the elderly).
\n\n a standard system for electrode location auditory brainstem response auditory evoked potential. Evoked potential when using an auditory stimulus Biological Marker of Auditory Processing is software that compares responses from a click to those from a synthetic syllable (usually /da/) central auditory nervous system central auditory processing central auditory processing disorder central nervous system a phoneme produced by a consonant and a vowel frequency following response the first part of an FFR that reflects the consonant Scale of Auditory Behavior, a questionnaire for monitoring auditory processing skills the second part of an FFR that reflects the vowel Synthesized speech Artificial human speech produced by a computer
Cancer cells arise in non-malignant tissue due to the sequential acquisition of molecular alterations that drive proliferation, permit the evasion of growth suppression and apoptosis signals and promote angiogenesis, invasion and metastasis [1]. This process is stochastic, and over time the tumour continues to evolve in a dynamic manner, generating a group of cells harbouring different genetic and epigenetic features [2]. The resulting heterogeneity is the basis of tumour evolution and leads to the selection of tumour cells. These cells often present with rewired signalling networks and often oncogene addiction [3].
\nThe uncontrolled growth of cancer cells can in part be explained by their aberrant gene expression patterns. While most cancer genes are characterized as either oncogenes or tumour suppressors based on their typical behaviour in tumours, some genes display dual oncogenic and tumour suppressive functions [4, 5]. The majority of these genes encode multiple isoforms, which are further post-translationally modified and form a variety of protein complexes, generating a context-dependent cellular network [6]. In diploid organisms, gain-of-function (GOF) mutations in oncogenes are typically dominant (single events are sufficient to promote tumourigenesis), while loss-of-function alterations are recessive in TSGs (requires two inactivation events) [7]. For example, for a TSG with dual oncogenic roles, one gain-of-function mutation can potentially cease its tumour suppressive function and turn on oncogenic signalling [5].
\nRecently, genes with both oncogenic and tumour-suppressive functions were described across 12 main cancer types using The Cancer Genome Atlas (TCGA) database [5]. Using a text mining approach, the authors identified genes mainly represented by kinases (e.g. BCR, CHEK2, MAP2K4, NTRK3 and SYK) or transcription factors (e.g. BRCA1, EZH2, NOTCH1, NOTCH2, STAT3 and TP53) and evaluated them at the genomic and gene expression levels. Using an in silico analysis, it was shown that genes with dual functions interact with more partners and are more important hub-genes in protein-protein interaction networks.
\nIn this chapter, we discuss TSGs with both tumour suppressive and oncogenic functions in lung cancer.
\nLung cancer is one of the most common cancers and the leading cause of cancer-related deaths worldwide [8]. In the United States, lung cancer accounts for 13.5% of all new cancer cases and 25.3% of all cancer deaths. The five-year survival rate is dismal, with only 18.6% of patients surviving 5 years [9]. The majority of lung cancer cases (approximately 80%) are attributed to cigarette smoking [10]. About 10–25% of cases occur in people who have never smoked [11]. The aetiology behind these cases is most likely a combination of genetic factors, as well as the effects of exposure to environmental carcinogens such as asbestos, radon gas or other forms of pollution [12].
\nLung cancer is classified according to histological type. There are two major types: small cell lung cancer (SCLC), which accounts for 15–20% of lung cancer patients, and non-small cell lung cancer (NSCLC), comprising the remaining 80–85% (Figure 1) [13]. SCLC, primarily originating from the central airways, is thought to be derived from neuroendocrine cells [14]. NSCLC is composed of three major histological subtypes: adenocarcinoma (LUAD), squamous cell carcinoma (LUSC) and large cell carcinoma (LCC). LUAD is the most common, accounting for approximately 40% of all lung cases [15]. LUAD typically arises from glandular epithelium, from bronchioalveolar stem cells, club (Clara) cells or type II pneumocytes in the lung periphery [13]. LUAD is also the predominant subtype that arises in patients who have never smoked [15]. LUSC develops primarily in the central airways and segmental bronchi, strongly associates with a history of smoking and accounts for approximately 20% of all lung cancer cases. LCC may arise anywhere in the lung and are classified as tumours without general features associated with SCLC, LUAD or LUSC [13].
\nHistological classification of lung cancer. (A) Lung cancer histological types. (B) Location of the tumours and cell origins. SCLC, small cell lung cancer; NSCLC, non-small cell lung cancer; LUAD, lung adenocarcinoma; LUSC, lung squamous cell carcinoma; LCC, large cell carcinoma.
Beyond the histological heterogeneity of lung cancer, genomic studies of large cohorts have uncovered the complex molecular landscape of lung tumours. Indeed, it has been observed that a wide variety of oncogenes and TSGs can be altered in lung cancer, and these molecular events are vastly different between histological subtypes [16, 17].
\nClinical studies have shown that molecularly defined lung cancer subgroups can correlate with characteristics such as ethnicity [18], smoking history [19], treatment sensitivity [20] or prognosis [21]. Many of the commonly identified gain-of-function alterations in proto-oncogenes have been actively investigated for therapeutic purposes. For example, EGFR, ALK, ROS1, BRAF, MET, RET and HER2 are routinely assessed in the clinic to offer targeted therapy for eligible LUAD patients [22].
\nThree TSGs are frequently mutated in all three major lung cancer subtypes: TP53, LRP1B and CSMD3. Other TSGs of particular interest in lung cancer are as follows RB1 and CREBBP in SCLC, KEAP1 and STK11 in LUAD, CDKN2A in LUSC, NOTCH1 and PTEN in both SCLC and LUSC and NF1 in both LUAD and LUSC (Figure 2). Mutations in these TSGs are usually mutually exclusive, indicating that individual genes are capable of driving lung cancer progression.
\nMutational frequency of TSGs in small cell lung cancer (SCLC; n = 110) [16], lung adenocarcinoma (LUAD; n = 660) [23] and lung squamous cell carcinoma (LUSC; n = 484) [23]. TSGs were defined according to COSMIC Cancer Gene Census (https://cancer.sanger.ac.uk/census) and mutation frequency of the most commonly disrupted TSGs in these subtypes of lung cancer were retrieved using cBioPortal (http://www.cbioportal.org/).
Several TSGs in lung cancer have also been shown to behave as oncogenes, depending on the molecular context and/or the mechanism by which they are altered (Table 1). Among them are TP53, NFIB, members of the NOTCH family, NKX2-1, NFE2L2, as well as some non-coding RNAs (MALAT1, mir-125, and mir-378), which will be discussed in detail below.
\nGene | \nMain function | \nRole as TSG | \nRole as oncogene | \n
---|---|---|---|
TP53 | \nTF: regulates cell cycle, DNA repair, senescence and apoptosis | \nTSG in several tissues: frequently lost through mutations [24] | \nMissense mutations confer gain-of-function oncogenic properties [31] | \n
NFIB | \nTF: crucial in lung development | \nUnderexpressed in NSCLC and associated with poor survival in LUAD [32] | \nAmplified and OE in SCLC: inducing chromatin reprogramming during metastasis [33] | \n
NOTCH1/NOTCH2 | \nTransmembrane receptors: proliferation, differentiation and survival | \nInactivated by inhibitor ligands and through mutations, especially in SCLC [34] | \nMaintains stem cell features; promotes proliferation in LUAD [35] | \n
NFE2L2 | \nTF: cellular defense mechanism against oxidative stress | \nProtects lung tissue against exposure to oxidative stress [36] | \nMutational activation: aids cells to escape from endogenous tumour suppression [37] | \n
NKX2-1 | \nTF: essential for lung development | \nActs as a TSG in KRAS-driven p53-mutant LUAD [38] | \nEnhanced oncogenic signals in EGFR-driven LUAD [39] | \n
STK11 | \nSerine-threonine kinase: regulation of energetic metabolism and cell polarity | \nMutational inactivation promotes cancer development [40] | \nOE maintains metabolic homeostasis and attenuates oxidative stress [40] | \n
TGFB | \nCytokine: regulates development, differentiation and homeostasis | \nExpression loss leads to growth arrest in early-stage lung and other cancers [41] | \nOE promotes tumour growth in advanced cancer stages [42] | \n
TUSC3 | \nEndoplasmic reticulum protein in magnesium uptake, glycosylation and embryonic development | \nHypermethylation; expression loss in NSCLC; inhibits cell proliferation and promotes apoptosis [43] | \nOE in NSCLC accelerates cancer growth; induces EMT [44] | \n
WT1 | \nTF: role in urogenital system development | \nLoss of function enhances cell viability and proliferation in Wilms’ tumour [45] | \nOE promotes survival in KRAS-mutated NSCLC [46] | \n
MALAT1 | \nLong non-coding RNA | \nOE reduces invasiveness in PTEN expressing tumours [47] | \nOE associated with chemotherapy resistance in NSCLC [48] | \n
miR-125b | \nmicroRNA | \nOE induces apoptosis [49] | \nOE promotes metastasis [50] | \n
miR-378 | \nmicroRNA | \nOE reverses chemoresistance to cisplatin in LUAD [51] | \nOE is associated with invasion and brain metastasis [52] | \n
Main TSGs with dual functions reported in lung cancer.
TF, transcription factor; OE, overexpression; EMT, epithelial-mesenchymal transition. Numbers in brackets refer to the list of reference.
TP53 is a well-known TSG, representing the most common somatically mutated gene in human cancer, especially in lung tumours [24]. The classic functions of the encoded p53 protein are cell cycle regulation, DNA repair, senescence mediated by stress, apoptosis and angiogenesis. These functions mainly occur through the binding of a p53 tetramer to the promoter of target genes [25]. In many cancer types, TP53 mutation is associated with poor prognosis, including local and distant metastases events, resistance to treatment and decreased survival [26, 27].
\nDespite having a reputation as a ‘guardian of the genome’, recent work has shown that activating TP53 alterations can act to promote cancer development and progression [25, 28]. Depending on the location of the mutation within the TP53 gene, protein structure and subsequent DNA binding activity can be lost or altered, resulting in either loss or gain of function [25]. In contrast to the majority of TSGs, TP53 is not commonly inactivated by deletions or truncating mutations. Indeed, 74% of mutations within the TP53 locus are missense point mutations, which can be found in proteins in human tumours [25]. In fact, altered TP53 was initially considered as a cancer antigen with putative oncogenic properties [25]. Together, this highlights the dichotomous role of TP53 disruptions, in that both the loss of wild-type p53 and gain-of-function mutations can provide a growth advantage to tumours [28].
\nLung cancer is commonly associated with tobacco use, where the prolonged exposure to carcinogens damages the DNA of the exposed cells. These alterations are especially enriched in missense mutations in TP53, leading to GOF-p53 [29]. The oncogenic GOF mutation in p53 was previously shown to be related with the inactivation of AMP-activated protein kinase (AMPK) signalling in head and neck cancer and another tobacco-related cancer [30]. AMPK is a master regulator of metabolic homeostasis and GOF-mutated p53 is able to physically interact and inhibit AMPK, stimulating aerobic glycolysis under energetic stress conditions and leading to invasive growth.
\nIn lung cancer mouse models, prevention of tumour formation by inhibiting GOF p53 mutants has been demonstrated [53]. Although the highly aberrant genomes in p53-mutated tumours should lead to unfeasible mitosis, these mutations facilitate the survival and proliferation of these cells through stabilizing replication forks and promoting micronuclei arrangement [31].
\nGOF p53 mutants are most likely involved in multiple mechanisms that coordinate tumour progression. For example, GOF-p53 (R175H, R273H and D281G) was demonstrated to upregulate CXCL5, CXCL8 and CXCL12 through its transcription factor activity, promoting migration of lung cancer cell lines [54]. CXCL5 expression was shown to be elevated in human lung tumour samples harbouring GOF-p53, and its inhibition could reverse cell motility in lung cancer and melanoma cell lines [54]. In NSCLC, it was recently reported that GOF-p53 can physically interact with HIF-1 and binds to the SWI/SNF chromatin remodelling complex, inducing the expression of hypoxia-responsive genes [55]. Importantly, specific extracellular matrix components are upregulated by this process and mediate pro-tumourigenic features in NSCLC [55].
\nNuclear factor I (NFI) is a transcription factor family, comprising NFIA, NFIB, NFIC and NFIX, that plays important roles in normal development and in numerous diseases [56]. These proteins bind to specific DNA sequences leading to repression or activation of gene expression in a context-dependent manner, regulating cell differentiation and proliferation through their target genes [57]. NFIB, in particular, has been implicated in a wide range of malignancies, being described as both an oncogene and a potential TSG [58].
\nUsing an in vivo model, it was demonstrated that NFIB is a metastatic driver in SCLC, inducing global chromatin reprogramming during metastasis [33]. The authors isolated tumour cells from primary and metastatic sites of genetically engineered mice, and using genome-wide analysis, they showed a pronounced increase in chromatin accessibility during tumour progression, resulting from NFIB copy number amplifications. Interestingly, the distal regions that became accessible upon NFIB upregulation were similar to open regions found in neural tissue. Recently, the same group described two metastatic models in SCLC, one dependent and other independent of NFIB amplification [59]. NFIB was likewise reported as amplified and/or overexpressed in melanoma [60], breast [61], oesophagus [62] and salivary gland malignancies [63].
\nA gene fusion involving NFIB (MYB-NFIB) is frequently found in adenoid cystic carcinomas from salivary glands [64] and in adenoid cystic carcinoma from other topologies [65]. Despite the putative oncogenic function of NFIB, studies have focused on its fusion partner MYB as the main oncogenic driver in these cancers [66]. Given the fact that other fusion partners of NFIB have been reported in adenoid cystic carcinomas [67] and that MYB-NFIB fusions lead to NFIB truncation [68], NFIB may have a possible independent role as a TSG in these malignancies.
\nWhile the MYB-NFIB fusion is not observed in lung cancers, NFIB is frequently underexpressed in NSCLC tissues [32] and during epithelial-to-mesenchymal transition in NSCLC cell lines [69]. NFIB is an essential transcriptional factor in lung development [70] and was demonstrated to be targeted by many microRNAs that recapitulate their foetal lung expression patterns in NSCLC [32]. Lower expression of this gene was associated with shorter overall survival, less-differentiated tumour features and repressed expression of cell differentiation markers in LUAD patients [32]. Therefore, contrary to the established oncogenic role of NFIB in SCLC, these observations suggest a tumour suppressive role in NSCLC.
\nThe Notch signalling pathway is important in the regulation of cell fate during embryogenesis and maintenance of homeostasis in adult tissues [71]. It includes Notch receptors (NOTCH1, NOTCH2, NOTCH3 and NOTCH4) and ligands from the DSL family, which suppress or induce tumour-related mechanisms under specific cellular contexts [71].
\nIn SCLC, Notch signalling is frequently inactivated by either a mutation in Notch receptors or the overexpression of ligands that inhibit downstream signalling [34]. Despite this potential role as a TSG, Notch signalling in lung tumours is complex, as it has also been shown to be related to chemoresistance in SCLC [72]. In addition, the overactivation of this pathway through several mechanisms acts like an oncogene in LUAD by preserving stem cell features and promoting proliferation [35, 73]. Notch1 expression is required in Kras-driven LUAD carcinogenesis, suppressing apoptosis via the p53 pathway [35]. The inhibition of the Notch pathway is able to restrain lung cancer stem cell maintenance, which is characterized by subpopulations of cells expressing aldehyde dehydrogenase [74].
\nConversely, loss-of-function mutations of Notch receptors generating truncated receptors imply a TSG role in LUSC [75]. Although functional studies to further corroborate this hypothesis are still needed, reports in other squamous cell carcinomas substantiate the idea that the inactivation of this signalling pathway promotes tumourigenesis [76].
\nNkx2-1 is a homeobox-containing transcription factor that is essential for lung development and is expressed in type II pneumocytes and bronchiolar cells in adults [77]. It is expressed in 40–50% of lung cancers and is amplified and overexpressed in 6–11% of LUAD [78].
\nNkx2-1 acts as a lineage-specific oncogene in some LUAD cases [79], enhancing cell viability and proliferation in lung cancer cell lines [78]. This function relies on the activation of (i) the pro-survival PI3K-AKT pathway, through ROR1 kinase-dependent c-Src activation as well as maintaining the EGFR-ERBB3 association [80], and (ii) LMO3, a member of the LMO family of oncogenes that is translocated in T-ALL [81].
\nOn the other hand, Nkx2-1 expression has been associated with good patient outcome [82] and the loss of Nkx2-1 expression was associated with the aggressive behaviour of NSCLCs [83]. Mechanistically, tumour suppressive functions of Nkx2-1 in lung adenocarcinoma rely on the restriction of cell motility, invasion and metastatic ability, through the inhibition of the TGF-β [41] and IKK-B/NFk-B [39] pathways. The dual role of Nkx2-1 is dependent on EGFR, KRAS and TP53 status in LUAD: NKX2-1 acts as a TSG in KRAS-driven and TP53-mutant tumours, whereas it enhances EGFR-driven tumourigenesis [84, 85].
\nNFE2L2 encodes a transcription factor that regulates proteins involved in cellular defense mechanisms against metabolic, xenobiotic and oxidative stress [86]. NFE2L2 has been often considered a TSG due to its protective role against genome-damaging agents, the higher propensity to cancer development in NFE2L2-deficient mice and its protective effects in cancer chemoprevention [87].
\nDue to the constant exposure to oxidative stress in the lung, the NFE2L2 pathway is important to guarantee the genomic stability of these cells [88]. However, once transformation of normal to cancer cells occurs, NFE2L2 favours tumour development by acting to protect against oxidative stress resulting from the tumour microenvironment and exposure to genotoxic agents during patient treatment [86]. In fact, mutations in NFE2L2 and KEAP1, an important member of the NFE2L2 signalling, are very common and mutually exclusive in NSCLC [89]. Curiously, a recent study demonstrated that lung cancer patients presenting NFE2L2 or KEAP1 mutations are highly resistant to chemotherapy [89]. However, the relation between the NFE2L2 pathway and treatment response prediction needs further investigation.
\nWhile large-scale genomic sequencing efforts have uncovered an invaluable number of genetic alterations related to cancer biology, in the past, they were commonly focused on the 2% of the genome that encodes protein [90]. In the last decade, non-coding RNA transcripts have been shown to have important regulatory functions in normal and disease biology [91]. Indeed, many non-coding genes have been shown to play tumour-suppressive or oncogenic roles in numerous cancer types [92].
\nMetastasis-associated lung adenocarcinoma transcript 1 (MALAT1) was one of the first cancer-related long non-coding RNAs to be described [93]. MALAT1 is broadly expressed in normal cells, where it has been shown to regulate the alternative splicing of pre-mRNAs by changing the distribution of splicing regulators in nuclear speckles [94]. MALAT1 was primarily identified as an oncogenic transcript in lung cancer and has since been widely considered a marker of metastasis, poor patient survival [93] and chemotherapy resistance in NSCLC [48]. Mechanistically, MALAT1 has been shown to promote carcinogenesis through P53 deacetylation [95] and enhance cell migration through Akt/mTOR signalling [96] and TGF-β-induced endothelial-to-mesenchymal transition [97]. Conversely, MALAT1 has also been shown to reduce invasiveness by modulating the expression of EpCAM and ITGB4 in PTEN-expressing tumours [47] and by downregulation of MMP2 and inactivation of ERK/MAPK signalling [98]. MALAT1 also binds the nuclear p65/p50 heterodimer and thus inhibits NF-κB-dependent pathways [99] and is thought to be involved in the response to DNA damage [100]. Furthermore, MALAT1 reduces the invasiveness of cerebral metastases by sustaining the blood-brain barrier [101]. MALAT1 expression and subcellular location is finely tuned through various regulatory mechanisms [102], which may drive its pro- or anti-tumour effects [103]. Analysis of the dual role of MALAT1 highlights not only the complexity of non-coding RNA function but also their relevance to broad areas of cancer biology and management.
\nMicroRNAs (miRNAs) are short transcripts that typically regulate coding genes post-transcriptionally through direct interaction with mRNA transcripts. Many are deregulated in lung cancer [104], where they have documented tumour-suppressive and oncogenic roles [105]. For example, miRNA-125b has been shown to have a multifaceted function as a tumour suppressor and oncogene, being underexpressed in bladder [106] and ovarian cancer [107] and overexpressed in glioma [108] and prostate cancer [109]. It was shown that miRNA-125b induces apoptosis in cancer cell lines exposed to nutrient starvation and chemotherapy, including in lung cancer [49]. On the other hand, miRNA-125b may also function as an oncogene in NSCLC, as it is able to promote metastasis by targeting TP53INP1 [50]. In addition, inhibition of miR-125b can also decrease the invasive potential and leads to cell cycle arrest and apoptosis in NSCLC [110]. Similarly, miR-378 was reported to be overexpressed in lung cancer and other tumour types, inducing cell migration, invasion and tumour angiogenesis [111]. However, it was previously demonstrated that upregulation of this miRNA sensitizes lung cancer cell lines to cisplatin [51].
\nHere, we summarize the commonly disrupted genes in lung cancer with dual roles as both tumour suppressors and oncogenes. These conflicting roles are a result from the complexity of biological pathways and the heterogeneity of cancer cells.
\nMost of the current molecular therapies are based on hyperactivated oncogene inhibitors. In lung cancer, only a fraction of the cases exhibit alterations in targetable genes, such as EGFR, BRAF and MET mutations and ALK, RET and ROS1 fusions [112]. Therefore, there is an urgent need for the development of novel therapeutic strategies exploiting non-oncogene alterations of lung tumour cells.
\nConsidering that TSGs are found altered more frequently than oncogenes in human tumours [113], the existence of TSGs with dual oncogenic roles opens a new window of opportunities for the development of new targeted therapies. However, therapeutic action against TSGs remains challenging, as many are not amenable to current pharmacologic inactivation strategies. Most of the TSGs are not a kinase that can be pharmacologically blocked and are not located at the cell surface to be targeted by an antibody.
\nIn summary, there is an unmet need to clarify the ambiguity found within genes, both coding and non-coding, with both pro- and anti-tumour functions. Broadening our understanding of these features may enable the development of novel and specific therapeutic strategies that consider both molecular and tissue contexts.
\nThis work was supported by grants from the Canadian Institutes for Health Research (CIHR FDN-143345) and scholarships from CIHR, the BC Cancer Foundation, the Ligue nationale contre le cancer, the Fonds de Recherche en Santé Respiratoire (appel d’offres 2018 emis en commun avec la Fondation du Souffle), the Fondation Charles Nicolle and the São Paulo Research Foundation (FAPESP 2015/17707-5 and 2018/06138-8). D.D.B.S. and E.A.M. are Vanier Canada Scholars.
\nThe authors have no conflicts to declare.
IntechOpen aims to ensure that original material is published while at the same time giving significant freedom to our Authors. To that end we maintain a flexible Copyright Policy guaranteeing that there is no transfer of copyright to the publisher and Authors retain exclusive copyright to their Work.
',metaTitle:"Publication Agreement - Chapters",metaDescription:"IN TECH aims to guarantee that original material is published while at the same time giving significant freedom to our authors. For that matter, we uphold a flexible copyright policy meaning that there is no transfer of copyright to the publisher and authors retain exclusive copyright to their work.\n\nWhen submitting a manuscript the Corresponding Author is required to accept the terms and conditions set forth in our Publication Agreement as follows:",metaKeywords:null,canonicalURL:"/page/publication-agreement-chapters",contentRaw:'[{"type":"htmlEditorComponent","content":"The Corresponding Author (acting on behalf of all Authors) and INTECHOPEN LIMITED, incorporated and registered in England and Wales with company number 11086078 and a registered office at 5 Princes Gate Court, London, United Kingdom, SW7 2QJ conclude the following Agreement regarding the publication of a Book Chapter:
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\\n\\n3. CORRESPONDING AUTHOR'S DUTIES
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\\n\\nIn case of termination, IntechOpen will notify the Corresponding Author, in writing, of the decision.
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\\n\\n6.1 Unless prevented from doing so by events outside its reasonable control, IntechOpen, in its discretion, agrees to publish the Chapter attributing it to the Corresponding Author and any Co-Author.
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\\n\\n6.3 IntechOpen is granted the authority to enforce the rights from this Publication Agreement, on behalf of the Corresponding Author and any Co-Author, against third parties (for example in cases of plagiarism or copyright infringements). In respect of any such infringement or suspected infringement of the copyright in the Chapter, IntechOpen shall have absolute discretion in addressing any such infringement which is likely to affect IntechOpen's rights under this Publication Agreement, including issuing and conducting proceedings against the suspected infringer.
\\n\\n7. MISCELLANEOUS
\\n\\n7.1 Further Assurance: The Corresponding Author shall and will ensure that any relevant third party (including any Co-Author) shall, execute and deliver whatever further documents or deeds and perform such acts as IntechOpen reasonably requires from time to time for the purpose of giving IntechOpen the full benefit of the provisions of this Publication Agreement.
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\\n\\n7.4 Waiver: No failure or delay by a party to exercise any right or remedy provided under this Publication Agreement or by law shall constitute a waiver of that or any other right or remedy, nor shall it preclude or restrict the further exercise of that or any other right or remedy. No single or partial exercise of such right or remedy shall preclude or restrict the further exercise of that or any other right or remedy.
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\\n\\n7.8 Governing law: This Publication Agreement and any dispute or claim (including non-contractual disputes or claims) arising out of or in connection with it or its subject matter or formation shall be governed by and construed in accordance with the law of England and Wales. The parties submit to the exclusive jurisdiction of the English courts to settle any dispute or claim arising out of or in connection with this Publication Agreement (including any non-contractual disputes or claims).
\\n\\nLast updated: 2020-11-27
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The Corresponding Author (acting on behalf of all Authors) and INTECHOPEN LIMITED, incorporated and registered in England and Wales with company number 11086078 and a registered office at 5 Princes Gate Court, London, United Kingdom, SW7 2QJ conclude the following Agreement regarding the publication of a Book Chapter:
\n\n1. DEFINITIONS
\n\nCorresponding Author: The Author of the Chapter who serves as a Signatory to this Agreement. The Corresponding Author acts on behalf of any other Co-Author.
\n\nCo-Author: All other Authors of the Chapter besides the Corresponding Author.
\n\nIntechOpen: IntechOpen Ltd., the Publisher of the Book.
\n\nBook: The publication as a collection of chapters compiled by IntechOpen including the Chapter. Chapter: The original literary work created by Corresponding Author and any Co-Author that is the subject of this Agreement.
\n\n2. CORRESPONDING AUTHOR'S GRANT OF RIGHTS
\n\n2.1 Subject to the following Article, the Corresponding Author grants and shall ensure that each Co-Author grants, to IntechOpen, during the full term of copyright and any extensions or renewals of that term the following:
\n\nThe aforementioned licenses shall survive the expiry or termination of this Agreement for any reason.
\n\n2.2 The Corresponding Author (on their own behalf and on behalf of any Co-Author) reserves the following rights to the Chapter but agrees not to exercise them in such a way as to adversely affect IntechOpen's ability to utilize the full benefit of this Publication Agreement: (i) reprographic rights worldwide, other than those which subsist in the typographical arrangement of the Chapter as published by IntechOpen; and (ii) public lending rights arising under the Public Lending Right Act 1979, as amended from time to time, and any similar rights arising in any part of the world.
\n\nThe Corresponding Author confirms that they (and any Co-Author) are and will remain a member of any applicable licensing and collecting society and any successor to that body responsible for administering royalties for the reprographic reproduction of copyright works.
\n\nSubject to the license granted above, copyright in the Chapter and all versions of it created during IntechOpen's editing process (including the published version) is retained by the Corresponding Author and any Co-Author.
\n\nSubject to the license granted above, the Corresponding Author and any Co-Author retains patent, trademark and other intellectual property rights to the Chapter.
\n\n2.3 All rights granted to IntechOpen in this Article are assignable, sublicensable or otherwise transferrable to third parties without the Corresponding Author's or any Co-Author’s specific approval.
\n\n2.4 The Corresponding Author (on their own behalf and on behalf of each Co-Author) will not assert any rights under the Copyright, Designs and Patents Act 1988 to object to derogatory treatment of the Chapter as a consequence of IntechOpen's changes to the Chapter arising from translation of it, corrections and edits for house style, removal of problematic material and other reasonable edits.
\n\n3. CORRESPONDING AUTHOR'S DUTIES
\n\n3.1 When distributing or re-publishing the Chapter, the Corresponding Author agrees to credit the Book in which the Chapter has been published as the source of first publication, as well as IntechOpen. The Corresponding Author warrants that each Co-Author will also credit the Book in which the Chapter has been published as the source of first publication, as well as IntechOpen, when they are distributing or re-publishing the Chapter.
\n\n3.2 When submitting the Chapter, the Corresponding Author agrees to:
\n\nThe Corresponding Author will be held responsible for the payment of the Open Access Publishing Fees.
\n\nAll payments shall be due 30 days from the date of the issued invoice. The Corresponding Author or the payer on the Corresponding Author's and Co-Authors' behalf will bear all banking and similar charges incurred.
\n\n3.3 The Corresponding Author shall obtain in writing all consents necessary for the reproduction of any material in which a third-party right exists, including quotations, photographs and illustrations, in all editions of the Chapter worldwide for the full term of the above licenses, and shall provide to IntechOpen upon request the original copies of such consents for inspection (at IntechOpen's option) or photocopies of such consents.
\n\nThe Corresponding Author shall obtain written informed consent for publication from people who might recognize themselves or be identified by others (e.g. from case reports or photographs).
\n\n3.4 The Corresponding Author and any Co-Author shall respect confidentiality rights during and after the termination of this Agreement. The information contained in all correspondence and documents as part of the publishing activity between IntechOpen and the Corresponding Author and any Co-Author are confidential and are intended only for the recipient. The contents may not be disclosed publicly and are not intended for unauthorized use or distribution. Any use, disclosure, copying, or distribution is prohibited and may be unlawful.
\n\n4. CORRESPONDING AUTHOR'S WARRANTY
\n\n4.1 The Corresponding Author represents and warrants that the Chapter does not and will not breach any applicable law or the rights of any third party and, specifically, that the Chapter contains no matter that is defamatory or that infringes any literary or proprietary rights, intellectual property rights, or any rights of privacy. The Corresponding Author warrants and represents that: (i) the Chapter is the original work of themselves and any Co-Author and is not copied wholly or substantially from any other work or material or any other source; (ii) the Chapter has not been formally published in any other peer-reviewed journal or in a book or edited collection, and is not under consideration for any such publication; (iii) they themselves and any Co-Author are qualifying persons under section 154 of the Copyright, Designs and Patents Act 1988; (iv) they themselves and any Co-Author have not assigned and will not during the term of this Publication Agreement purport to assign any of the rights granted to IntechOpen under this Publication Agreement; and (v) the rights granted by this Publication Agreement are free from any security interest, option, mortgage, charge or lien.
\n\nThe Corresponding Author also warrants and represents that: (i) they have the full power to enter into this Publication Agreement on their own behalf and on behalf of each Co-Author; and (ii) they have the necessary rights and/or title in and to the Chapter to grant IntechOpen, on behalf of themselves and any Co-Author, the rights and licenses expressed to be granted in this Publication Agreement. If the Chapter was prepared jointly by the Corresponding Author and any Co-Author, the Corresponding Author warrants and represents that: (i) each Co-Author agrees to the submission, license and publication of the Chapter on the terms of this Publication Agreement; and (ii) they have the authority to enter into this Publication Agreement on behalf of and bind each Co-Author. The Corresponding Author shall: (i) ensure each Co-Author complies with all relevant provisions of this Publication Agreement, including those relating to confidentiality, performance and standards, as if a party to this Publication Agreement; and (ii) remain primarily liable for all acts and/or omissions of each such Co-Author.
\n\nThe Corresponding Author agrees to indemnify and hold IntechOpen harmless against all liabilities, costs, expenses, damages and losses and all reasonable legal costs and expenses suffered or incurred by IntechOpen arising out of or in connection with any breach of the aforementioned representations and warranties. This indemnity shall not cover IntechOpen to the extent that a claim under it results from IntechOpen's negligence or willful misconduct.
\n\n4.2 Nothing in this Publication Agreement shall have the effect of excluding or limiting any liability for death or personal injury caused by negligence or any other liability that cannot be excluded or limited by applicable law.
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\n\n5.1 IntechOpen has a right to terminate this Publication Agreement for quality, program, technical or other reasons with immediate effect, including without limitation (i) if the Corresponding Author or any Co-Author commits a material breach of this Publication Agreement; (ii) if the Corresponding Author or any Co-Author (being an individual) is the subject of a bankruptcy petition, application or order; or (iii) if the Corresponding Author or any Co-Author (being a company) commences negotiations with all or any class of its creditors with a view to rescheduling any of its debts, or makes a proposal for or enters into any compromise or arrangement with any of its creditors.
\n\nIn case of termination, IntechOpen will notify the Corresponding Author, in writing, of the decision.
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\n\n6.1 Unless prevented from doing so by events outside its reasonable control, IntechOpen, in its discretion, agrees to publish the Chapter attributing it to the Corresponding Author and any Co-Author.
\n\n6.2 IntechOpen has the right to use the Corresponding Author’s and any Co-Author’s names and likeness in connection with scientific dissemination, retrieval, archiving, web hosting and promotion and marketing of the Chapter and has the right to contact the Corresponding Author and any Co-Author until the Chapter is publicly available on any platform owned and/or operated by IntechOpen.
\n\n6.3 IntechOpen is granted the authority to enforce the rights from this Publication Agreement, on behalf of the Corresponding Author and any Co-Author, against third parties (for example in cases of plagiarism or copyright infringements). In respect of any such infringement or suspected infringement of the copyright in the Chapter, IntechOpen shall have absolute discretion in addressing any such infringement which is likely to affect IntechOpen's rights under this Publication Agreement, including issuing and conducting proceedings against the suspected infringer.
\n\n7. MISCELLANEOUS
\n\n7.1 Further Assurance: The Corresponding Author shall and will ensure that any relevant third party (including any Co-Author) shall, execute and deliver whatever further documents or deeds and perform such acts as IntechOpen reasonably requires from time to time for the purpose of giving IntechOpen the full benefit of the provisions of this Publication Agreement.
\n\n7.2 Third Party Rights: A person who is not a party to this Publication Agreement may not enforce any of its provisions under the Contracts (Rights of Third Parties) Act 1999.
\n\n7.3 Entire Agreement: This Publication Agreement constitutes the entire agreement between the parties in relation to its subject matter. It replaces and extinguishes all prior agreements, draft agreements, arrangements, collateral warranties, collateral contracts, statements, assurances, representations and undertakings of any nature made by or on behalf of the parties, whether oral or written, in relation to that subject matter. Each party acknowledges that in entering into this Publication Agreement it has not relied upon any oral or written statements, collateral or other warranties, assurances, representations or undertakings which were made by or on behalf of the other party in relation to the subject matter of this Publication Agreement at any time before its signature (together "Pre-Contractual Statements"), other than those which are set out in this Publication Agreement. Each party hereby waives all rights and remedies which might otherwise be available to it in relation to such Pre-Contractual Statements. Nothing in this clause shall exclude or restrict the liability of either party arising out of its pre-contract fraudulent misrepresentation or fraudulent concealment.
\n\n7.4 Waiver: No failure or delay by a party to exercise any right or remedy provided under this Publication Agreement or by law shall constitute a waiver of that or any other right or remedy, nor shall it preclude or restrict the further exercise of that or any other right or remedy. No single or partial exercise of such right or remedy shall preclude or restrict the further exercise of that or any other right or remedy.
\n\n7.5 Variation: No variation of this Publication Agreement shall be effective unless it is in writing and signed by the parties (or their duly authorized representatives).
\n\n7.6 Severance: If any provision or part-provision of this Publication Agreement is or becomes invalid, illegal or unenforceable, it shall be deemed modified to the minimum extent necessary to make it valid, legal and enforceable. If such modification is not possible, the relevant provision or part-provision shall be deemed deleted.
\n\nAny modification to or deletion of a provision or part-provision under this clause shall not affect the validity and enforceability of the rest of this Publication Agreement.
\n\n7.7 No partnership: Nothing in this Publication Agreement is intended to, or shall be deemed to, establish or create any partnership or joint venture or the relationship of principal and agent or employer and employee between IntechOpen and the Corresponding Author or any Co-Author, nor authorize any party to make or enter into any commitments for or on behalf of any other party.
\n\n7.8 Governing law: This Publication Agreement and any dispute or claim (including non-contractual disputes or claims) arising out of or in connection with it or its subject matter or formation shall be governed by and construed in accordance with the law of England and Wales. The parties submit to the exclusive jurisdiction of the English courts to settle any dispute or claim arising out of or in connection with this Publication Agreement (including any non-contractual disputes or claims).
\n\nLast updated: 2020-11-27
\n\n\n\n
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