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Barely three months into the new year and we are happy to announce a monumental milestone reached - 150 million downloads.
\n\nThis achievement solidifies IntechOpen’s place as a pioneer in Open Access publishing and the home to some of the most relevant scientific research available through Open Access.
\n\nWe are so proud to have worked with so many bright minds throughout the years who have helped us spread knowledge through the power of Open Access and we look forward to continuing to support some of the greatest thinkers of our day.
\n\nThank you for making IntechOpen your place of learning, sharing, and discovery, and here’s to 150 million more!
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2022",book:{id:"10780",title:"Current Trends in Orthodontics",subtitle:null,fullTitle:"Current Trends in Orthodontics",slug:"current-trends-in-orthodontics",publishedDate:"August 17th 2022",bookSignature:"Farid Bourzgui",coverURL:"https://cdn.intechopen.com/books/images_new/10780.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"52177",title:"Prof.",name:"Farid",middleName:null,surname:"Bourzgui",slug:"farid-bourzgui",fullName:"Farid Bourzgui"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"422659",title:"Ph.D. Student",name:"Cristiane",middleName:null,surname:"Barros André",fullName:"Cristiane Barros André",slug:"cristiane-barros-andre",email:"kika@kikaortodontia.com.br",position:null,institution:null},{id:"424426",title:"MSc.",name:"Bruno",middleName:null,surname:"Pasqua",fullName:"Bruno Pasqua",slug:"bruno-pasqua",email:"brunompasqua@yahoo.com",position:null,institution:{name:"University of Sao Paulo",institutionURL:null,country:{name:"Brazil"}}},{id:"424427",title:"Prof.",name:"José",middleName:null,surname:"Rino Neto",fullName:"José Rino Neto",slug:"jose-rino-neto",email:"jrneto@usp.br",position:null,institution:{name:"University of Sao Paulo",institutionURL:null,country:{name:"Brazil"}}},{id:"424428",title:"Prof.",name:"Fábio",middleName:null,surname:"Dupart Nascimento",fullName:"Fábio Dupart Nascimento",slug:"fabio-dupart-nascimento",email:"fdnascimento@gmail.com",position:null,institution:{name:"Universidade de Mogi das Cruzes",institutionURL:null,country:{name:"Brazil"}}}]},book:{id:"10780",title:"Current Trends in Orthodontics",subtitle:null,fullTitle:"Current Trends in Orthodontics",slug:"current-trends-in-orthodontics",publishedDate:"August 17th 2022",bookSignature:"Farid Bourzgui",coverURL:"https://cdn.intechopen.com/books/images_new/10780.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"52177",title:"Prof.",name:"Farid",middleName:null,surname:"Bourzgui",slug:"farid-bourzgui",fullName:"Farid Bourzgui"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}}},ofsBook:{item:{type:"book",id:"11867",leadTitle:null,title:"Echocardiography",subtitle:null,reviewType:"peer-reviewed",abstract:"
\r\n\tAlthough the diagnosis and overall survival of patients with various cardiac diseases have improved in the last years, there still remains a significant proportion of patients with unfavorable prognoses. The evaluation of these patients necessitates effective imaging techniques in both diagnosis and long-term follow-up. Even though Cardiac Magnetic Resonance imaging is currently the imaging modality of choice for tissue characterization, advanced echocardiography represents a modern alternative. Speckle tracking echocardiography can be used to assess myocardial deformation at both segmental and global levels. Since distinct myocardial pathologies affect deformation differently, information about the underlying tissue can be offered by strain imaging. Echocardiography advances also show promising results in the improvement of diagnostic accuracy, management, and follow-up and a major advantage of echocardiography over other imaging modalities is the ability to use it in real-time, in the cardiac catheterization laboratory, allowing for the performance of imaging immediately before, during, and after interventional procedures. Furthermore, the prevalence of adult congenital heart disease continues to grow due to advances in surgical and diagnostic techniques. Echocardiography has proven to be a useful tool in the diagnosis and follow-up of these patients, both after percutaneous and surgical procedures, and its utility has expanded significantly due to the development of better technology. In addition, stress echocardiography could be useful in the evaluation of several cardiac diseases and should be preferred over other imaging modalities due to the lower cost, wider availability, and radiation-free nature.
\r\n\tThis book intends to provide the reader with a comprehensive overview of the current state-of-the-art novel imaging techniques by focusing on the most important evidence-based developments in this area.
When we humans perform a physical activity, it is contraction of skeletal muscles that is responsible as its driving force. Active state of a skeletal muscle during motion can be viewed on an electromyogram (EMG). Because it is non-invasive and easy to handle, surface EMG has been widely used in the field of rehabilitation as in therapeutic exercise, training, motion analysis, and research.
When a peripheral nerve is subjected to percutaneous electrical stimulation, action potentials are induced in the innervated skeletal muscle. The induced action potential is recorded by evoked EMG, which includes the H-wave, the M-wave, and the F-wave (Fig. 1). The H-wave is a good indicator of the strength and distribution of the stimulus input from muscle spindle to the motor neuron pool, which lies at the site of the anterior horn of the spinal cord. The H-wave is commonly used, therefore, in the diagnosis of peripheral neuropathy (Kaeser 1973). The H-wave is also used to examine the state of muscle tone and spasticity, or other movement disorders of the central nervous system.
The name H-wave was derived from that of Johann Hoffmann, who found the response for the first time in 1918. Weak electrical stimulation can excite group Ia fibers from muscle spindle, and the antidromic impulse gets conducted to the spinal cord. Afferent fibers connect, via a synapse, with the alpha motor neuron in the spinal cord. Excitatory postsynaptic potential (EPSP) causes the excitement of the alpha motor neuron of the anterior horn cells in the spinal cord. The action potential that reaches from excitatory alpha motor neuron to skeletal muscle is called H-wave or H-response. With soleus or flexor carpi radialis muscle the H-wave is observed at rest, but in other muscles the H-wave can only be induced with mild voluntary contraction.
Evoked EMG
Alpha motor neurons are activated directly by a gradual increase in the intensity of electrical stimulation, which occurs as the activity of Ia fiber is enhanced. The action potential of the skeletal muscle caused by this excitement is called M-wave or M-response.
If an alpha motor neuron receives a strong electrical stimulation, its antidromic impulse is conducted to axons of all motor neurons that have received the stimulus. The impulse is to reach the innervated skeletal muscle after re-firing at part of the axon hillock of anterior horn cells in the spinal cord. The action potential in question is called F-wave or F-response. The F-wave is said to be evoked on any peripheral muscle.
With evoked EMG, the action potential is derived from a skeletal muscle that is innervated by electrical stimulation conducted to peripheral nerves.
In this section, we briefly introduce the measurement method of H-wave in soleus muscle in accordance with the guidelines of clinical neurophysiology test as stipulated by International Federation of Clinical Neurophysiology. Kaeser advocated that the measurement of H-wave be standardized in the study of spinal reflex (Kaeser 1973). It is not always easy to apply his method in clinical situations, but we recommend that you should examine his method carefully because it is considered to be a correct way of recording the H-wave.
Because H-wave is susceptible to the effects of posture, it is necessary to maintain the same posture during the measurement. A change in posture gives rise to changes in the length of muscles, which in turn bring on a change in the activity of muscle spindle receptors involved in the H-wave. That is how postural change can cause variability in H-wave.
When you try to evoke the H-wave of soleus muscle, it is important to prevent soleus muscle, and gastrocnemius muscle, from stretching. For the preventive purpose, you instruct the subject to mildly flex the knee joint (about 30 degrees). And because the H-wave of soleus muscle is inhibited by ankle dorsiflexion, the ankle joint is fixed at a mild plantar flexion position (about 20 degrees).
The optimal duration of stimulation to elicit the H-wave is 0.5 ms or 1.0 ms; the choice is due to the difference in the strength-duration curves between axons of motor neurons and afferent group Ia fibers. Optimal conditions to excite group Ia fibers are 1) stimulation at a low enough intensity not to excite the axons of motor neurons, and 2) placement of the cathode of the stimulating electrode on the nerve, with the anode placed distal from the cathode on the run of the nerve. Because it is a reflex through a synapse, H-wave is easy to cause “habituation”. That means that shorter stimulation intervals would tend to inhibit H-wave due to the decreased synaptic connection in the spinal cord. It is therefore important that the interval of stimulations be long enough, but you must also remember that the subjects would sometimes be poised when the stimulation interval is more than 5 seconds. For removal of the inhibitive influence of habituation, it is desirable to set the interval for stimuli at 10 seconds or more.
Clinically, it is often convenient, and optimal, to start with a rate of 1 Hz for H-wave measurement; the rate of stimulation is then decreased step by step (by 0.2-0.3 Hz) so that latency and amplitude can be measured.
H-wave recording is often done with surface EMG. The skin surface is wiped clean before attaching an electrode to keep electrical resistance as low as possible. To record the H-wave from soleus muscle selectively, an electrode is firstly affixed between medial head and lateral head of gastrocnemius, and another is attached 3-5 cm distal from the first. It is important that electrodes be aligned along the long axis of the muscle for accurate measurement; values of the potential vary significantly if electrodes are placed across, at right angles or otherwise, in relation to the muscle’s long axis.
Prevention of contamination from artifacts is also a major issue. Contamination of the potential induced by the latency of about 10 ms after the stimulus is highly likely specifically in terms of the inception and waveform of the H-wave. To remove artifact contamination, it is important that electrodes be securely earthed and the width and size of square wave of electrical stimulation be closely monitored.
As for H-wave amplitude, it increases as the motor neuron pool becomes more excitable due to weak voluntary muscle contraction, but H-wave latency hardly changes. Based on this characteristic, those muscle groups from which H-wave is hardly recorded at rest (e.g., tibialis anterior, extensor carpi radialis, and abductor pollicis brevis) can be induced to elicit recordable levels of H-wave.
Recording method
To elicit H-reflex from soleus muscle, a low-intensity electrical stimulation is applied on tibial nerve in the popliteal space, whereupon only those group Ia fibers with low threshold levels become selectively excited. The waveform which appears in the 20-30 ms latency is the H-wave from soleus muscle. When the intensity of an electrical stimulus is gradually raised, group Ia fibers will be excited more. At the same time, alpha motor neuron which runs from the spinal cord to muscle fiber also becomes excited.
M-wave will appear at the 5-10 ms latency. If the stimulus intensity is raised, excitement of group Ia fibers will be lost and excitement of alpha motor neuron will become greater. H-wave amplitude decreases, whereas M-wave amplitude increases. H-wave is lost before M-wave reaches the maximum amplitude; only the M-wave may remain (Fig. 1).
H-wave latency is measured at the time when the value shows the first deflection from baseline. In the soleus H-wave, the first rising edge of the positive waveform is adopted as its latency because it is impossible to affix the recording electrode on the motor point. And its H-wave amplitude is defined by the difference in potential either from baseline to the top of negative waveform, or from the top of negative waveform to the top of next positive waveform.
It is important to ensure that the same measurement method is used for H-wave and M-wave amplitude. If these two amplitudes were measured differently, the H/M amplitude ratio would lose its reliability in the analysis of evoked EMG study.
Under uniform stimulus conditions, the amplitude size of an H-wave is determined by the strength of the stimulus and the excitability of the reflex arc. Thus, H-wave has been used as an indicator of the excitability of motor neurons in the anterior horn of the spinal cord.
In clinical practice, the ratio between the maximum amplitude of H-wave (Hmax) and that of M-wave (Mmax), or H/M ratio, is often adopted as a good index. The Hmax is taken to reflect the number of excited alpha motor neurons in the anterior horn of the spinal cord, when the condition is adjusted so as to maximize the input from group Ia fibers upon electrical stimulation. The Mmax, on the other hand, is thought to show the amplitude of complex muscle action potential when all the alpha motor neurons dominating the muscle (soleus muscle here) are excited synchronously. That is, of all the alpha motor neurons that dominate the targeted muscle (e.g., soleus muscle), the H/M ratio shows the percentage of excited alpha motor neurons upon electrical stimulation. In fact, correlation has been observed between the H/M ratio and the degree of spasticity. The H/M ratio shows marked increases in the elevated excitability of alpha motor neurons in the spinal cord, or in patients with spasticity.
Conversely, in cases of peripheral neuropathy, this H/M ratio is decreased. Because there is a great difference between individuals in the H/M ratio, it is more useful as a therapeutic tool in the same patient rather than as a general diagnostic tool. The H/M ratio would work when you tried to make an objective judgment of therapeutic effects on immediate change in the same patient, or when you tried to make a longitudinal change in a given condition also in the same patient.
It is surmised that if you observe changes in the H-wave at the time of intervention such as muscle contraction, vibration stimulation to the tendon, or muscle stretching, then those changes have in fact been brought on by the intervention, and not due to alterations in the physical condition such as electrode attachment and the like.
Vibration stimulation has been used as one of the treatment modes for conditions of muscle tone of skeletal muscle, including spasticity. Its effects have in fact been reported. Unlike manual therapy, vibration stimulation is an excellent treatment method because it is expected to show a certain effect regardless of who uses it.
Though its detailed mechanism has not been elucidated, vibration stimulation acts directly on the contracted muscle cells to relax them (Vukas 1978, Ljung 1972, Ljung 1975).
When skeletal muscle during a maximum contraction receives vibration stimulation, the muscle’s action potential on EMG, nerve activity, and muscle output are reduced (Bongiovanni 1989, Kouzaki 2000, Stephen 2003, Konishi 2009). The inhibitory effect of muscle contraction is dependent on the conditions of vibration stimulation: the effect is greater if the frequency of the vibration stimulation is low, or if its amplitude is large (Desmedt 1978).
In recent reports, when stroke patients with a spastic upper limb received vibration stimulation on the limb, their upper limb function was shown to improve with a suppression of muscle tone (Noma 2012, Caliandro 2012).
In patients who underwent ACL reconstructive surgery or those with osteoarthritis, vibration stimulation to their quadriceps femoris muscle brought about neither an increase in neural activity as evaluated by integrated EMG nor a decrease in muscle output as evaluated by peak torque (Konishi 2002, Rice 2011). It is thought that this outcome was due to a failure in Ia afferent feedback, including dysfunction of the gamma-loop.
Muscle spindle senses a very small change in muscle length when a skeletal muscle receives vibration stimulation. And this information is transmitted to the fibers of group Ia or II, eventually to reach the spinal cord. In the spinal cord, the information serves as presynaptic inhibition through an interstitial cell and suppresses the alpha motor neuron (Gillies 1969, Shinohara 2005).
In addition, sustained vibration stimulation will selectively excite group Ia fibers. That will then bring about, in nerve endings, depletion of neurotransmitters and a rising threshold of group Ia fibers (Kouzaki 2000). It is believed that this is one of the reasons why a decrease is observed in the excitability of motor neurons in the spinal cord.
The equipment that is used to apply vibration stimulation may vary from researcher to researcher, but the effect seems to be uniform as long as stimulation conditions are controlled in the same way. Stimulation conditions inevitably differ according to the research objective, but they are generally set at a frequency of 50-100 Hz and amplitude of 1-2 mm. The equipment is contacted at 20-30N on the body or tendon of the targeted skeletal muscle.
Effects that vibration stimulation has on the body depend on the duration of stimulation. The H/M ratio decreases immediately after the application of stimulation, and the inhibitory effect on spasticity has been confirmed in 5 minutes of stimulation (Noma 2012). Muscle output is reduced by a sustained stimulation of at least 20 minutes (Bongiovanni 1989, Kouzaki 2000, Stephen 2003, Konishi 2009).
Vibration stimulation on a skeletal muscle of healthy adults is known to bring on effects such as reflexivity contraction of an agonist muscle by muscle spindle Ia afferent nerve excitability, and inhibition of the antagonist muscle, called “tonic vibration reflex”. Vibration stimulation also causes inhibition of monosynaptic reflexes such as the tendon reflex and stretch reflex while stimulation with vibration continues. These effects vary depending on stimulus conditions.
As a result of vibration stimulation on the triceps surae of healthy adults, the H/M ratio continues to decrease from 1 to 3 minutes after stimulus onset. After 4 minutes into stimulation, though the ratio continues to decrease somewhat, no significant difference was found between values at after 4 minutes and the value at 3 minutes of stimulation.
From these findings, it has been clarified that excitability of alpha motor neurons gets suppressed immediately after the intervention with vibration stimulation. Also clarified was that the decline of the H/M ratio reaches a steady state after 3 minutes of stimulation from its onset.
If vibration stimulation is to be adopted in clinical settings, it is essential that an appropriate set of stimulus conditions should be considered for each of the clinically different cases. A site of stimulation is certainly one of the factors for the treating therapist to take into account.
Based on the results of our study, the H/M ratio was significantly lower after the onset of vibration stimulation on both muscle belly and the tendon (p<0.01). In addition, when stimulus to the belly was compared with stimulus to the tendon, the H/M ratio was significantly lower in the latter (p<0.05). In other words, to suppress muscle tone using a vibration stimulus, it is recommended that a stimulus be applied on the tendon.
When vibration stimulation is applied on skeletal muscle, the amount of output and muscle activity of the stimulated skeletal muscle is decreased. This finding should help to bring on a change in the pattern of muscle activity during action (Table 1).
It may be possible to facilitate the activity of the muscle that is important to knee joint extension, namely vastus lateralis muscle, when vibration stimulation decreases its activity. In fact, we have confirmed that, when vastus lateralis muscle was stimulated by vibration, the reduction in the amount of muscle activity was observed in only vastus lateralis muscle among quadriceps femoris muscles (Table 2).
There may be a possibility of enhancing the activity of inner muscles, which were long assumed to be unsusceptible to strengthening, provided that you can selectively suppress just those muscles you want to suppress. It is hoped that our future studies will clarify this issue as well.
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t
250.0 ± 25.4 | \n\t\t\t220.5 ± 16.2 | \n\t\t
Muscle force of quadriceps femoris muscle before and after vibration stimulation (%BW).
Mean±standard deviation
\n\t\t\t | \n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t
Rectus femoris muscle | \n\t\t\t174.5 ± 29.2 | \n\t\t\t121.2 ± 52.3 | \n\t\t
Vastus medialis muscle | \n\t\t\t143.8 ± 34.2 | \n\t\t\t102.1 ± 68.5 | \n\t\t
Vastus lateralis muscle | \n\t\t\t113.6 ± 49.1 | \n\t\t\t95.5 ± 37.8 * | \n\t\t
Muscle activity of quadriceps femoris muscle before and after vibration stimulation (%iEMG).
*p<0.05: pre-vibration vs post-vibration
Mean±standard deviation
If vibration stimulation of about 5 to 10 minutes is applied on the spastic muscle of a stroke patient’s upper limb, the following will be observed: a decrease in the H/M ratio indicative of the excitability level of anterior horn cells in the spinal cord; improvement of motor function and of Modified Ashworth Scale indicative of the degree of spasticity; and improvement of Functional Ability Scale using Wolf Motor Function Test. In some treatment cases, an immediate effect was recorded after the intervention.
The nervous system of a spastic stroke patient may be restructured and/or strengthened by adjusting the level of CNS excitability using a vibration stimulus in combination with training on the nervous system. It is anticipated that further effects that vibration stimulation has on spastic muscle in stroke patients will be revealed in the near future.
Vibration stimulation on a sustained maximum muscle contraction case can reduce the firing frequency of the nerve cells involved in the maximum contraction, and subsequently the muscle output will decrease. In addition, more than 20 minutes of vibration stimulation on quadriceps femoris muscle can bring on a reduction in the peak torque and integrated EMG.
If you apply these findings clinically, it is possible to suppress the excessive and abnormal muscle activity that occurs as a compensatory motion during action, and subsequently to let the patient have efficient training.
However, in patients with osteoarthritis of the knee and also in patients who have undergone ACL reconstruction and therefore need onerous training, no decrease of the peak torque and integrated EMG occurs after the vibration stimulation. Abnormal gamma motor neurons are believed to be involved, and the abnormality results from reduced afferent nerve activity of the joints.
All in all, clinical application of vibration stimulation on patients with musculoskeletal disorders awaits further trials because there remain some unsettled issues.
This section provides an overview of the effects of inhibition and facilitation by physical stimuli on skeletal muscle of healthy subjects. We shall then consider the current state surrounding the physical stimulus in the field.
A decreased H/M ratio was observed by air pressure in the splint on triceps surae muscle of the lower limb (Robichaud et al., 1992) and radiocarpal flexor muscle of the upper limb (Agostinucci et al., 2006) both in healthy subjects.
Pressure stimulation causes a decrease in blood flow, leads to the state of lack of oxygen, and adversely affects the site of compression of the cell, tissue, or organ. What then would be an appropriate duration and compression strength to apply without bringing on undesirable effects? In a study of healthy Japanese youths, the condition of 5 minutes at 50 mmHg was recommended as appropriate (Miura et al., 2011). A pressure of up to 50 mmHg did not result in any statistically significant differences in blood flow compared with no-addition pressure stimuli. But at this time the excitability of soleus muscle motor neurons was inhibited in the spinal cord.
Studies using WBV include the examination of its longitudinal and acute effects. Indices that are adopted to verify or refute those effects are as follows: muscle activity, muscle strength, power, height by counter jump, body balance, and mechanical competence of bones.
Neuromuscular stimulation derived from WBV is the likely source of previously observed changes in athletic performance. The tonic vibration reflex is a response elicited from vibration directly applied to a muscle belly or tendon. This reflex is characterized by activation of muscle spindles primarily though Ia afferents and activation of extrafusal muscle fibers through alpha motor neurons (Cormie et al., 2006).
Vibration has been shown to stimulate transient increases in certain hormones, such as growth hormone and IGF-I (Cormie et al., 2006).
A study exists in which the flexibility of hamstring muscle of the lower limb was examined by varying the frequency of vibration stimulation. It showed that there was a 10% increase in flexibility at 20 Hz and no change at 40 Hz (Cardinale et al., 2003).
Vibration is detected not only by spindle, but also by the skin, the joint and secondary endings. All those structures contribute to the facilitatory input to the gamma-system which in turn affects sensitivity of the primary endings. Modulation of neuromuscular response to vibration is then to be referred not just to spindle activation, but to all the sensory systems in the body. Various parameters can affect the synergies in the sensory system and determine specific responses. Vibration is thought mainly to inhibit the contraction on antagonist muscles via Ia inhibitory neurons. However there is some evidence as well that vibrations can also produce co-activation (Cardinale et al., 2003).
A previous study investigated the acute effects of WBV on back and abdominal muscle activity. Muscle activity with vibration showed a low to moderate increase in trunk muscle activation (Wirth et al., 2011).
A 4-month WBV-loading induced a significant 8.5% mean increase in jump height of young healthy adults. This improvement was already seen after 2 months of the vibration. Lower limb extension strength was also enhanced by the 2-month vibration period. Intervention with a 4-month WBV enhanced jumping power in young adults, suggesting neuromuscular adaptation to the vibration stimulation. On the other hand, the vibration-intervention showed no effect on dynamic or static balance of the subjects (Torvinen et al., 2002).
There are many reports in which knee extensor strength and jump performance improved after stimulation with WBV in healthy subjects. In contrast, no improvement was observed in sprint-trained athletes and elite female field hockey players. This means either that the effect of daily training was greater than the stimulatory effect with WBV or that its cumulative activity and inhibitory effects were retained in the body system. It is suggested that the stimulating effect of WBV is probably greater in subjects that do not exercise every day.
Section 4 presents an overview of the effects of inhibition and facilitation provided by the physical stimulus on skeletal muscles in people with pathological disorder. We shall then consider the existing state surrounding the equipment used in rehabilitation.
In the field of rehabilitation, people with muscle hypo-tone are induced to undergo activities that facilitate muscle activity, and those with muscle hyper-tone are given activities that inhibit muscle activity. In general, when standing position is sustained there will be increases in muscle tone from that posture. Therapists often suppress the excessive muscle activity in such cases. Muscle hypo-tone from paralysis or hemiplegia is usually treated with a facilitative method using electrical stimulation or proprioceptive neuromuscular stimulation. At the present time, it is not clear to what extent these physical means are effective; it needs continued investigation. Physical therapy stands for intervention with physical means in people with physical disturbance so that their physical disorder is alleviated. For that purpose, application of clinical and kinesiologic EMG is one of the most effective methods.
Cerebrovascular Accident (CVA) is a general term for diseases such as subarachnoid hemorrhage, rupture of a cerebral aneurysm, and cerebral infarction. Disturbances after a CVA are various in severities. What was the onset of a CVA like, was there early treatment, or was the site known at the time of its onset? These are the questions that help determine how severe CVAs turn out to be. Sequelae such as motor paralysis, sensory disturbances, and language disorder occur in about one-third of the patients who suffered CVA.
When the antagonist muscle of spastic paralysis undergoes electrical stimulation, its muscle spasticity is suppressed. This suppression is brought on by reciprocity through the Ia inhibition in the spinal cord, which in turn results from an adjustment of the reflective circuit. If the spastic muscle itself is subjected to electrical stimulation in such a case, a decrease in muscle tone occurs through the antagonist inhibition. Upon application of electrical stimulation to rectus femoris muscle of the lower limb, facilitation of the flexion of the hip joint and the extension of the knee joint occurs through suppression of the muscle tone of hip flexor muscle and knee extensor muscle, respectively. Thus, gait itself turns out to show improvement.
If a muscle receives electrical stimulation, what will be the reaction of the muscle? Electrical stimulation to a paralyzed muscle, for instance, will cause the amount of muscle activity to increase. This is referred to as the carry over effect.
Pressure stimulation on spastic muscle of people with CVA brings about an effect that is similar to the effect it has on healthy people. Air pressure in a splint to triceps surae muscle of the lower limb in people with spastic paralysis caused a decrease in the H/M ratio (Robichaud et al., 1992). And the same was seen in spastic muscle of the upper limb: radiocarpal flexor muscle in people with neurological diseases, when stimulated by air pressure in the splint, registered a lowered H/M ratio (Agostinucci et al., 2006).
Spinal cord injury (SCI) is a disorder caused by damage to the spinal nerve running through the spinal canal. SCI often brings on motor paralysis or sensory disturbances caused by their proprioceptive CNS diseases, leading eventually to impaired autonomic nervous system. Hypertensive tendon reflexes are often seen in the patient.
When air pressure in a splint is applied to soleus muscle of the lower limb in people with SCI, alpha motor neuron reflex excitability is suppressed (Robichaud et al., 1992).
When people with SCI were given massage treatment for 3 minutes, there was a decrease in the amplitude of H-reflex when compared with what it was before the massage (Goldberg et al., 1994).
When WBV is applied on a person with SCI, residual effects of medication for muscle spasticity will sometimes be recognized. And because the duration of stimulation differs among researchers, a simple comparison is difficult (Ness et al., 2009).
There is a report in which the adopted cycle of WBV treatment consists of the following: 4 bouts of 45 seconds with one minute of seated rest between bouts, done on 3 days a week lasting for 4 weeks.
Parkinson’s disease (PD), often caused by depletion of dopamine in the substantia nigra of the midbrain, is a disease that indicates a variety of movement disorders. Rigidity, tremor, akinesia, amimia, and pill-rolling phenomenon are the characteristic symptoms. By taking L-dopa, people with PD can alleviate these symptoms.
With WBV, scores of Unified Parkinson’s Disease Rating Scale (UPDRS) tremor and rigidity improved compared with no intervention. There is no evidence, however, that WBV is effective in improving knee proprioception and other clinical measures of sensorimotor performance, such as balance and mobility (Lau et al., 2011).
WBV had no significant effects, or was only slightly effective, on UPDRS motor scores (Lau et al., 2011).
Multiple sclerosis (MS) is a chronic inflammatory, demyelinating disease of the central nervous system. The most prevalent symptoms of this disease include sensory changes, visual disturbances, fatigue, and micturition disorders (Jackson et al., 2008).
There is no evidence that WBV is effective in improving peak torque values for both quadriceps and hamstring muscles (Jackson et al., 2008).
Under the duration of 5 training sessions per 2-week cycle for 20 weeks, WBV did not improve leg muscle performance or functional capacity in mildly to moderately impaired people with MS (Broekmans et al., 2010). Also 8-week exercise is effective in improving standing balance and timed up-and-go test (Mason et al., 2012). But there are differences in stimulation frequency and duration between the two reports. That makes it difficult to determine whether WBV is or is not effective in the long run.
Previous research investigated WBV as an alternative strengthening regimen in the rehabilitation of people with total knee arthroplasty (TKA) compared with traditional progressive resistance exercise (TPRE). Post-TKA subjects received physical therapy with WBV or with TPRE for 4 weeks. There was a significant increase in knee extensor strength and improvements in mobility both with WBV and with TPRE.
With an addition of WBV to squat training, elderly people with knee osteoarthritis (OA) were evaluated on functional performance and self-report of disease. A total of 23 elderly subjects participated. There was no statistically significant difference in functional performance and self-report of disease status between groups of squat training with or without WBV.
We therapists realize after all that, at the present time, WBV effectiveness against SCI, PD, MS, and knee OA has not been established. There are reasons for that: disease mechanisms have not been clarified, and optimum conditions such as stimulation frequency are not definitely set yet. And in intervention studies, one cannot completely eliminate the influence of other factors. It is unfortunate that not enough high-level evidence-based research has been done or published.
Though rather limited in scope, we therapists can help people with disabilities, or even people without disabilities, by suppressing the muscle tone of a given muscle through the spinal cord loop.
In research using EMG, there are two groups of studies: clinical and kinesiologic. Kinesiologic EMG is to record the response during motion of the body.
Clinical EMG
EMG as a diagnostic aid in cases in which causes of muscle weakness and muscle atrophy are neurogenic or myogenic
EMG as a means to confirm the lesion site and properties of peripheral nerve injury
EMG as a means to confirm abnormal muscle activity
EMG in cases that are not classifiable as 1, 2, or 3 above
Likely target diseases are amyotrophic lateral sclerosis, polymyositis, carpal tunnel syndrome, and Bell’s palsy.
Cases of kinesiologic EMG are as in the following:
EMG to check presence or absence of muscle activity
EMG to measure timing and duration of muscle activity
EMG to measure amount of muscle activity
EMG as basis of biofeedback to patients
EMG to determine matters relative to muscle fatigue
EMG to measure reaction time on external stimuli
EMG to evaluate motor control
EMG to assess gait
EMG to evaluate motor learning
EMG for purposes not classifiable as 1 to 9 above.
In recent years, the study of human-machine interfaces became fairly popular. For example, equipment is used to amplify muscle activities of a person with disabilities, which will then be relayed to a robot so it can put them into effect for the disabled person. Or EMG is made use of as a vital part of technique to convey information from a robot to a human subject through the human senses. We shall introduce some of these studies.
In the field of rehabilitation, the type of equipment has been developed that controls movements of a joint by the muscle discharge in people with disabilities. The equipment sends a command from electrodes attached to the forearm of the robot to its artificially created fingers to control. The number of sensors attached on the disabled person increased gradually, so it became possible to control the intensity of such delicate movements as tapping or lifting. Numerous researches have also been done on motion control by an exoskeleton. The target joints now include forearm, elbow joint, shoulder joint, upper limb, cervix, hip joint, knee joint and lower limb, as well as a wide variety of fingers and hands. In upper limb research, starting from motions of three degrees of freedom (3-DOF), it has now reached the level of 7-DOF motions. Research on reaction time has also shown improvement; in the line of research on hand reactions, delays of only 100 ms have been attained. Research has also been done on robot-assisted therapy on upper limb recovery after stroke, but not much that is revolutionary has come out of it so far. Perhaps we can expect to see this line of research grow in the future.
We consider it possible that robot-assisted therapy may eventually help an individual patient become free from environmental and personal factors. Introduction of the so-called ICF (International Classification of Functioning, Disability and Health) model may be something that is revolutionary.
Verification of inhibitory effects of muscle tone by vibration stimulation as we did above, though it is only the beginning, seems to point to further development in the future. Significance may be found in the fact that healthy people can be checked using simple equipment. In the literature, a certain level of effectiveness of vibration stimulation is found in people with disabilities; determination of the optimum stimulation conditions will certainly be researchers’ next point of interest. In studies using other physical means, it seems necessary to set conditions for measuring the effectiveness of the given means. Overall, studies of equipment-aided therapies tell us that aided-therapies seem to be superior to non-aided therapies because you can minimize the individual difference between techniques of intervention. This may be true in day-to-day therapeutic sessions as well as in the examination of the effect of physical therapy.
Over the past decades, the treatment of localized cancers was mostly focused on surgery and radiotherapy and advanced neoplasia was treated using nonspecific cytotoxic agents. Despite the increasing 5-year survival rate, there is also still a large number of nonresponsive patients, mostly due to the diversity of genetic profiles among the worldwide population, also the heterogeneity within the tumor itself [1, 2, 3].
Neoplasia develops under a various number of molecular and genetic malfunctions that regulate cell division, cell differentiation, and programmed cell death [4, 5]. Tumor suppressor genes and proteins encoded by these genes play a major role in cellular growth regulation, cell signaling, and DNA repair. Oncogenes are mutated forms of normal genes and are associated with cellular proliferation.
Molecular biology focuses on the study of physiological and pathological changes in the body. It helps to develop tools for early diagnosis of these changes and ways to reverse them. In recent years, considerable efforts have been made to elucidate the molecular mechanisms of malignant transformation that have the role of personalized medicine (especially oncology) in order to maximize the effectiveness of the therapeutic response but also to minimize side effects. In this sense, understanding the process of carcinogenesis helps to diagnose at an early stage, an accurate diagnosis but also of the different behavior of tumor subtypes, in order to establish the appropriate therapy [6, 7, 8, 9, 10, 11].
BCG (Calmette-Guérin bacillus) immunological therapy in the treatment of bladder cancer is an excellent starting point for the usefulness of molecular studies on immunotherapy in genitourinary cancers. Being a nonspecific agent, there are many gaps regarding its mechanism of action but it paved the way for a different approach, that of inducing an immune response against cancer via cancer vaccines. Prostate and kidney cancer are also considered for this kind of treatment [11].
From a clinical point of view, the most obvious mechanism is the limitation of the specific antigen immune response by CD4 and CD8 (tumor-infiltrating lymphocytes) with significant importance in limiting the antitumor response thus preventing a significant proportion the clinical remission of tumors. Thus, a therapeutic line has been developed that targets an immune checkpoint blockade in order to bypass the mechanisms that limit the response, and which in the case of bladder tumors, in combination with conventional chemotherapy, or VEGF inhibition (vascular endothelial growth factor) in kidney cancer and last but not least, in prostate cancer—hormone therapy, increase the effectiveness of treatment [11].
In this chapter, we discuss the most significant urological cancers including prostate cancer, urothelial carcinoma, and renal highlighting their molecular mechanisms and the related studied biomarkers for precision diagnosis and therapeutic management.
Cancer is one of the most complex diseases to understand. It is characterized by the rapid growth and spread of its cells, its resistance to conventional treatments, and its ability to invade and displace normal tissue. Malignant cells, regardless of type, usually share some common features—reprogrammed energy metabolism, sustained cell growth signals, evasion of growth suppressors, resistance to apoptosis, facilitation of replicative immortality, induction of angiogenesis, resistance to destruction by the immune system, and promotion of cell invasion and metastasis. These recognized characteristics have led to a deeper understanding of this disease. However, the reality is that our overall ability to cure cancer has not yet improved significantly, especially for adult cancers, which account for 99% of all cancers. [12, 13, 14].
The major challenges facing clinical oncologists include not only the considerable heterogeneity and different genetic backgrounds even within the same type of cancer, but also the fact that effective drugs lose their efficacy due to the ability of cancer to evolve rapidly, especially with regard to the emergence of drug-resistant subpopulations [12, 13, 14].
One of the many reasons why our knowledge is so sparse is the lack of molecular-level data, the full analysis, and interpretation of which can reveal the full complexity of developing cancer. Although large amounts of genomic, epigenomic, transcriptomic, metabolomic, and proteomic data have been obtained for a variety of cancers, few cancer studies are designed to fully exploit all the information that can be derived from the available omic data [12, 13, 14]. Integrative analyses of multiple data types may prove to be essential to gain a full and systems-level understanding of cancer’s evolution dynamics, including the elucidation of its true drivers as well as key facilitators at different developmental stages of cancer. We anticipate that only when all of the key information hidden in omic data can be fully derived and utilized can we expect a meaningful breakthrough in our understanding of cancer [12, 13, 14].
The understanding of the human genome combined with technologies such as DNA and protein arrays or mass spectrometry has improved the simultaneous study of numerous genes and proteins in single experiments and has rekindled interest in the search for novel biomarkers for cancers such as but not limited to, renal, urothelial, and prostate cancers [15, 16, 17, 18, 19, 20, 21]. Modern technology allows for parallel studies as compared to the serial analyses used in older methods. This allows the identification of distinct patterns for cancer diagnosis and classification, as well as for prediction of therapeutic response. In addition, these technologies enable the discovery of new individual tumor markers through the use of acceptable hypotheses and novel analytical methods [15, 16, 17, 18, 19, 20, 21]. Although new technologies and tactics often fail in the discovery of established cancer biomarkers and focus on identifying high-incidence compounds, they have the potential to revolutionize biomarker discovery. It is now critical to focus on thorough validation studies to discover the most effective techniques and biomarkers and bring them to the clinic as quickly as possible [15, 16, 17, 18, 19, 20, 21].
Bioinformatics and computational techniques have been well applied in the studies of various tumors (urologic, digestive gynecologic, etc.), and confirmed to be efficient and reliable in identifying novel tumor markers for cancer diagnosis and targeted treatments [22].
The very large pool of publicly available cancer-omic data, which includes transcriptomic, genomic, metabolomic, and epigenomic data, contains a considerable amount of information about the activities of individual biochemical pathways, their dynamics, and the complex relationships between them, as well as information about various microenvironmental factors. When the right questions are asked, powerful statistical analysis techniques can be very helpful in uncovering such information. Such targeted questions provide a framework for hypothesis-driven data analysis and evaluation that can be used to test the validity of the formulated hypothesis and to formulate new questions that may lead to the discovery of specific pathways or even possible causal relationships between the activities of different pathways. More effective analysis methods for different omic data formats are definitely needed to answer more difficult and in-depth questions about the data, such as deconvolution of gene expression data obtained from tissue samples with different cell types and inference of causal relationships. Effective data mining and information discovery require integrative analysis of various forms of omic and computational data [14, 15, 17, 18, 19, 20, 21].
It is considered the second most prevalent cancer among male subjects. Around one in eight men will get diagnosed with the illness during their lifetime. In 2012, around 1.1 million men were diagnosed with prostate cancer globally. Around one in 40 of them will die due to this disease [23, 24, 25].
With the discovery and introduction of PSA-based screening tests, the incidence of prostate cancer has increased dramatically. However, given the advances in molecular biology, we realize that a purely PSA-based test does not provide sufficient accuracy. To find an answer, we need to consider other possible screening methods by elucidating the molecular basis of cancer development and more specific biomarkers. [23, 24, 25].
The complexity of the diagnostic process in prostate cancer is reflected in the various interactions that occur during the course of the disease itself. The initial changes that lead to cancer are usually caused by chronic inflammation and dietary habits. They eventually lead to severe damage to the DNA of the prostate cells. Early genetic events that can promote disease progression include fusions or mutations of various genes and oncogenes (Figure 1), as well as malfunctions of molecular signaling pathways [23, 24, 25].
Alterations that occur in the malignancy of prostatic tissue. PIA - proliferative inflammatory atrophy, PIN - prostatic intraepithelial neoplasia.
The primary androgen of the prostate is dihydrotestosterone (DHT), and exposure to this androgen is considered to be a precipitating factor in the development of primary prostatic neoplasia. The androgen receptor (AR) plays a central role in the development and progression of prostate cancer. Although the relationship between androgen exposure and cancer is not yet clear, exposure to very high or low concentrations of this substance may be protective against PCa (prostate cancer). The effects of androgen on long-term male survival are still unknown. The interaction of vitamin D with its receptor may influence the aggressiveness of the disease and its risk factors, but the mechanism underlying this event is not yet fully understood [23, 24, 25].
The prostate develops just caudal to the bladder neck by the proliferation of epithelial buds growing from the urogenital sinus epithelium. Epithelial budding is strictly androgen-dependent and represents the first identifiable events in prostate development. Budding of the prostate requires complicated epithelial-mesenchymal interactions [26, 27].
High testosterone levels in male embryos promote prostate development. Testosterone is converted to DHT by 5α-reductase, an interaction that activates AR. High testosterone levels during early development led to prostate growth regardless of genetic sex, suggesting a primary role for androgens in prostate induction [26, 27].
The upregulation of Sox9 (sex-determining region Y-box 9), a transcription factor induced by the FGF pathway, is the earliest event that appears to occur in the epithelium during prostate development. This mechanism is followed by the increased expression of Nkx3.1 (NK homeobox transcription family member), which influences the degree of branching in the mature mouse prostate, where it may also act as a tumor suppressor [26, 27].
The FGF family of secreted peptides promotes cell growth by binding to cell surface proteins and activating multiple signaling cascades demonstrated for prostate, mammary and salivary glands, or lung. Fgf-7 (keratinocyte growth factor) and Fgf-10 are considered specific for the prostate [28, 29]. Fgf-7 (keratinocyte growth factor) and Fgf-10 are considered specific for the prostate. FGFR2 is expressed in developing prostatic epithelial cells (PrECs) and through interaction with Frs-2α. Both molecules are secreted by the mesenchyme of the prostate. This mechanism led to the hypothesis that they act as andromedins since they are associated with androgen-independent growth factors. Due to the absence of Fgf-10, the mice also showed prostatic hypoplasia [28, 29].
Wnt signaling plays a crucial role in the development of various organs, including the prostate. Essentially, it regulates proliferation and differentiation through a series of Wnt ligands expressed during prostate bud formation. Canonical Wnt targets, such as Lef1 and Axin2, are upregulated in prostate bud epithelium [30, 31, 32].
Prostate cancer is one of the few malignancies for which there is a clinically meaningful serum biomarker. From its discovery in 1979 to its clinical application in the late 1980s to 1990s, PSA has become an invaluable tool for detecting, grading, and monitoring prostate cancer in men.
There is also considerable overlap in serum PSA levels between men with cancer and those with the noncancerous disease. The presence of prostatic hyperplasia or inflammation may also explain the elevated serum PSA levels [33, 34]. To this end, the use of PSA derivatives such as PSA density, PSA velocity, age-adjusted values, and more recently molecular derivatives can be used to improve clinical decisions compared to the isolated use of PSA.
Several molecular approaches have been pursued in the search for the optimal biomarker for prostate cancer. An overview of basic cellular processes begins with a DNA sequence (gene) that is transcribed into mRNA (transcript) and then translated into a protein that can then perform a specific cellular function. A major goal of biomarker development is to identify the differences in the molecular structure of prostate cancer cells compared to their benign counterparts and also to distinguish the more aggressive phenotypes from the others. The identification and quantification of these molecular differences in tissues and body fluids form the basis for the discovery of biomarkers for prostate cancer.
PSMA (glycoprotein prostate-specific membrane antigen), a folate hydrolase, has been studied as a potential biomarker for prostate cancer in tissue, serum, or urine. It is found in the membrane of all prostate epithelial cells. It is a type II transmembrane protein with an extracellular C-terminus that exists as a dimer and binds glutamate and glutamate-like structures [35, 36]. Nowadays, PSMA is mainly used in targeted imaging and theranostics [37, 38]. In particular, 68Gallium positron emission tomography of prostate-specific membrane antigen (68Ga-PSMA PET) is increasingly used as a diagnostic tool in biochemical recurrence after primary therapy [39].
Human kallikrein peptidase 2 (hK2) shares many important properties with PSA and has demonstrated its potential as another tumor marker for prostate cancer. Among many other similarities, hK2 and PSA share 80% amino acid homology, show similar specificity for prostate tissue, and are hormonally regulated by androgens. One of the major functions of hK2 is to activate the zymogen (proPSA) to active PSA by cleaving the amino acid presequence. Critical to its utility as a biomarker is that hK2 expression varies independently of tissue and serum PSA expression. In BPH, PSA expression is highly expressed compared to the minimal immunoreactivity of hK2, but hK2 is also overexpressed in PCa compared to PSA. Furthermore, tissue expression of hK2 appears to correlate with more aggressive pathological features, including Gleason grade [40, 41].
Circulating tumor cells (CTCs) have long been touted as potential prognostic biomarkers and indicators of treatment response. Subsequent CTC research in prostate cancer has employed a wide range of methods utilizing characteristics such as size, surface marker expression, and cellular plasticity that distinguish CTCs from circulating blood mononuclear cells [42, 43]. Typically, CTCs are defined as CD45 and positive for an epithelial marker such as epithelial cell adhesion molecule (EpCAM) and/or cytokeratin. Although the development of CTCs as biomarkers for prostate cancer has been relatively slow, there has been considerable recent progress in the field and a growing number of clinical trials. Currently, there is only one FDA-approved method for identifying CTCs: CellSearch, which uses antibodies to EpCAM for CTC detection and then stains with antibodies to CD45 and cytokeratins 8, 18, and 19 (positive) to identify individual CTCs. Using this system, a CTC count of five or more cells per 7.5 mL of blood at any time during disease progression has been associated with poor prognosis in the prostate, breast, and colorectal cancers [42, 43].
The ease of collection of urine and the excretion of prostate cells have long made it a potential biomarker source for the early detection of prostate cancer [44]. However, only recently have urine biomarkers for prostate cancer come into clinical use. The first of these biomarkers, described in 1999, prostate cancer antigen 3 (PCA3), is not expressed outside the prostate. Studies show that PCA3 levels in prostate cancer are far higher than those in BPH, but the function of the antigen is still unknown [45, 46]. Recent studies used RT-PCR to detect PCA3 in urine and showed that PCA3 performs better than PSA in diagnosing PCa [47, 48].
Annexin A3 is a protein that is being studied as a possible biomarker for prostate cancer in urine. It belongs to a family of proteins known as phospholipid-binding proteins and shows altered expression in PCa [49].
α-Methylacyl coenzyme A racemase (AMACR) is an enzyme responsible for beta-oxidation of branched-chain fatty acids found in a diet consisting of beef and dairy products. Recent studies have shown that 88% of prostate carcinomas, as well as untreated metastases and hormone-refractory PCa, overexpress AMACR [50]. Immunohistochemical studies have shown that expression of AMACR in prostate tissue has a sensitivity of 97% and a specificity of 100% for the detection of PCa. In conjunction with other markers such as the tumor protein p63, which helps to identify basal cells that are absent in prostate cancer, measuring the expression level of AMACR also can be used for the detection of prostate cancer [51].
Detection at an early stage not only improves the outcome but also reduces mortality in PCa. Although the discovery and use of PSA have revolutionized current PCa detection and treatment, it is not enough. Due to this stage, various molecular modifications or genetic alterations have overtaken the current maximum use of this tumor marker. The use of different PSA derivatives, the discovery of molecular derivatives of PSA, new kallikrein markers, PCA3, and gene rearrangements are leading to a significant improvement in the efficiency of PCa management [24, 25].
The urothelium extends from the renal pelvis to the urethra of the prostate. Urothelial carcinomas (UCa) represent the vast majority of cancers arising in the bladder, and approximately 75% of them are noninvasive within the muscular layer. However, despite the treatment options, there is a high rate of recurrence and, in high-grade tumors, progression to muscle-invasive disease (Figure 2). The incidence of UCa increases with age. Most of them are diagnosed in patients over 65 years of age, and it is four times higher in men than in women. One of the reasons for this could be tobacco use, which is known to be a risk factor and is most common in men, although other factors such as the androgen receptor could also play a role [52, 53].
UCa localization.
UCa can present a noninvasive phenotype, in which the malignant cells are confined to the urothelial layer, and an invasive phenotype, in which the tumor cells can break through the basement membrane and invade the subepithelial connective tissue and underlying muscle. There are two types of noninvasive UCa. Exophytic papillary (Ta) tumors are prone to local recurrence but rarely break through the basement membrane or spread. CIS, on the other hand, is a flat lesion with a high susceptibility to invasion and metastasis. Patients who have only CIS lesions in their urinary system are more likely to develop synchronous and/or metachronous malignancies [54]. Ta tumors are caused by molecular abnormalities that are usually separate from CIS and invasive carcinomas, despite the fact that these pathways are not mutually exclusive [55]. The receptor tyrosine kinase-Ras pathway is frequently constitutively active in low-grade papillary carcinomas, with activating mutations in HRAS and FGFR3 [56]. Homozygous deletion of p16INK4a is a common feature in high-grade Ta tumors [57]. TP53 and retinoblastoma (RB) genes and pathways are commonly altered in CIS and invasive malignancies [58]. Although chromosomal-9 deletions can be observed in both dysplastic urothelium and CIS lesions, loss of chromosome 9q heterozygosity is more common in low-grade Ta tumors [59]. When a papillary tumor develops into an invasive phenotype, it is mainly due to the accumulation of additional mutations in the p53 pathway. Invasive cancers have also been shown to have p16 mutations. Matrix metalloproteinases (MMPs), cadherins, TSP-1 (thrombospondin-1), and vascular endothelial growth factors (VEGFs), mutations that alter the extracellular matrix and induce tumor angiogenesis are more common in muscle-invasive cancers and also play a role in nodal metastasis [60].
The most intensively studied aspects of UCa are changes in signaling pathways that affect cell cycle progression. The p53 and Rb signaling pathways, which interact with apoptosis and intracellular signaling mediators, are primarily responsible for cell cycle control. The tumor suppressor gene TP53 is located on chromosome 17p13.1 and encodes the p53 protein. By activating p21WAF1/CIP1, the protein blocks cell cycle progression at the G1-S transition. Inactivation of TP53 and loss of its tumor-suppressive activity may be caused by mutations in the 17p allele [61, 62]. In invasive UCa, loss of heterozygosity on chromosome 17 is associated with aggressive behavior. Mutations in the TP53 gene result in a protein that is resistant to ubiquitin-mediated degradation. Immunohistochemistry can detect increased intranuclear p53 accumulation as a consequence [63]. Multiple retrospective studies have found that accumulation of p53 in the nucleus is associated with poor prognosis in patients with UCa, particularly in those who have undergone radical cystectomy. From normal urothelium to superficial UCa, muscle-invasive cancer and metastatic lymph nodes, altered p53 expression has been observed to occur [64, 65]. Despite this evidence, the predictive function of p53 in the development and progression of bladder cancer is still debated, but what is certain is that a link between the accumulation of p53 in the nucleus and TP53 mutations has been demonstrated [66].
Mdm2 interacts with p53 in an autoregulatory feedback loop that regulates its activity. Increased p53 levels transactivate the promoter of MDM2, causing the translated protein to facilitate the destruction of p53 by the proteasome. MDM2 levels decrease when p53 levels decrease. In UCa, MDM2 amplification has been found to increase in frequency with tumor stage and grade [67, 68]. p14 inhibits the transcription of MDM2. p14ARF, one of two splice variants derived from the CDKN2A locus on chromosome 9p21, encodes the protein. Because the E2F transcription factor induces p14ARF, it serves as a link between the Rb and p53 pathways. The E2F transcription factor is sequestered by dephosphorylated Rb. E2F is produced when Rb is phosphorylated by cyclin-dependent kinases, leading to the transcription of genes important for DNA synthesis [69, 70].
In UCa, a decrease in Rb protein expression has been highlighted. Rb has been shown to be a predictive factor when combined with other cell cycle regulatory proteins. Cyclin/cyclin-dependent kinase complexes help phosphorylate Rb. CDKIs such as p21, p16, and p27, which act as tumor suppressors, cause negative control of cyclin-dependent kinases. Low levels of p27 have been associated with advanced-stage bladder adenocarcinomas [69, 70, 71]. In bladder UCa, p27 mutations have also been associated with poor disease-free and overall survival. In UCa patients treated with radical cystectomy, a combined assessment of p53, p21, Rb, cyclin E1, and p27 has been shown to improve accuracy against each individual molecular marker, thereby improving risk stratification [69, 70, 71].
Apoptosis is a tightly controlled process involving a series of events that occur during normal development and in response to a series of stimuli, all leading to programmed cell death. Apoptosis can be triggered in two ways. The internal process is mediated by mitochondria, while the extrinsic system involves the activation of death receptors on the cell surface. Both pathways activate caspases that cleave cellular substrates and allow apoptosis. In urothelial carcinoma cell lines, tumor-specific expression of caspase-8 has been shown to induce apoptosis
The Bcl-2 protein family comprises both antiapoptotic and proapoptotic members, such as Bcl-2, Bax, and Bad, and is involved in the intrinsic apoptotic process. In UCa patients treated with radiotherapy or synchronous chemoradiotherapy, increased Bcl-2 expression has been associated with poor outcomes. In patients with advanced UCa undergoing radiotherapy who might benefit from neoadjuvant chemotherapy, Bcl-2 could serve as a marker [72, 73]. Expression of Bcl-2 has been associated with a lower tumor-free survival rate in high-grade T1 tumors, and in combination with p53, it may be a strong prognostic indication in non-muscle-invasive UCa. In addition, a prognostic index based on Mdm2, p53, and Bcl-2 was developed, with abnormalities in all three markers corresponding to the lowest probability of survival in UCa [74, 75]. Bax expression, on the other hand, is an independent predictor of better prognosis in invasive UCa. The proapoptotic function of Bax is mediated by the activation of Apaf-1. In UCa patients, lower Apaf-1 expression has been associated with a higher mortality rate [76, 77].
Multiple cell-surface receptors modify signals from the environment and transmit them to the nucleus of urothelial cells via transduction pathways. Uncontrolled cellular proliferation and tumor growth may result from alterations in these receptors and/or the signals sent. Activating mutations of FGFR3 are the best-studied alterations in UCa in the FGFR family. FGFR3 mutations are found in nearly 60–70% of low-grade papillary Ta tumors [78].
ErbB-1 and ErbB-2 (Her2/neu), members of the epidermal growth factor receptor (EGFR) family, are overexpressed in invasive UCa. Overexpression of ErbB-1 has been associated with an increased risk of progression and mortality [79]. Increased ErbB-2 expression has also been associated with aggressive UCa as well as poor disease-specific survival. In contrast, other studies have found that ErbB-2 expression is not related to prognosis. While it has been suggested that the combined expression profile of ErbB-1 and ErbB-2 is a stronger predictor of prognosis than either marker alone, this finding remains to be confirmed [80, 81, 82].
JAK (Janus kinase) is a tyrosine kinase that is activated by cytokines and growth receptors and regulates a variety of signaling pathways. JAK signaling is thought to be increased by overexpressed preoperative plasma levels of interleukin-6, a ligand for the corresponding cytokine receptor, and is an independent predictor of UCa recurrence and survival [83]. The activation of the STAT (signal transducer and activator of transcription) pathway, which controls transcription of several key genes, is the most studied molecular event after JAK activation. STAT1 inhibits Bcl-2 expression, whereas STAT3 has the reverse effect. In UCa patients, STAT3 expression in combination with other markers can predict the likelihood of recurrence and survival [84].
Angiogenesis is the process of cancer cells producing substances that interact with stromal components to recruit endothelial cells to the site of cancer and generate a vascular supply that gives cancer cells with the nutrients they need to proliferate. [85, 86].
VEGFs are signaling proteins that stimulate angiogenesis by interacting with VEGF receptors and stimulating cellular responses (VEGFRs). The majority of known cellular responses to VEGF are mediated by VEGFR2. Advanced UCa and muscle invasion are linked to VEGFR2 expression. In UCa patients, VEGFR2 expression is also a key determinant of nodal metastasis. VEGF boosts nitric oxide synthase, which boosts nitric oxide production and tumor vascularization. In nonmuscle-invasive UCa, VEGF overexpression is linked to early recurrence and progression [87, 88]. VEGFs are signaling molecules that promote angiogenesis by interacting with VEGF receptors and stimulating cellular responses (VEGFRs). The majority of known cellular responses to VEGF are mediated by VEGFR2. Advanced UCa and muscle invasion are linked to VEGFR2 expression. In UCa patients, VEGFR2 expression is also the main predictor of nodal metastasis. VEGF boosts nitric oxide synthase, which boosts nitric oxide production and tumor vascularization. In nonmuscle-invasive UCa, VEGF overexpression is linked to early recurrence and progression [89, 90].
The ability of urothelial cancer cells to invade blood vessels and lymphatics is essential to their ability to spread to nearby structures and form distant metastases. Cadherins are intercellular adhesion mediators that have been identified in a variety of tissues. E-cadherin is the most known member of the cadherin family and is essential for epithelial cell adhesion. In UCa, lower E-cadherin expression has been linked to an increased risk of tumor recurrence and progression and shorter survival [91, 92]. The action of various protease families, including uPAs and MMPs, enhances the ability of a tumor to degrade the matrix and infiltrate the basement membrane. Thymidine phosphorylase (TYMP), an enzyme that increases MMP synthesis, is overexpressed in advanced UCa compared with superficial tumors or normal bladder tissue [93]. Increased thymidine phosphorylase nuclear reactivity has been associated with an increased prevalence of superficial UCa recurrence. MMP-2 and MMP-9 expression levels have been shown to be associated with the stage and grade of urothelial tumors. Increased MMP-2 expression may also indicate a poor prognosis for recurrence-free and disease-specific survival. In UCa patients, the ratio between MMP-9 and E-cadherin is a predictive factor for disease-specific survival [94, 95].
Integrins are transmembrane glycoproteins that can promote tumor development, invasion, and metastasis when their function is disrupted. They are protein receptors for adhesion molecules and collagen. The immunoglobulin superfamily member intercellular adhesion molecule 1 (ICAM1) interacts with particular integrin classes. ICAM1 expression is linked to an infiltrative histological phenotype, according to immunohistochemical investigations. The presence, grade, and size of bladder tumors have all been linked to serum ICAM1 levels [96].
In patients with UCa of the bladder, ICAM1 is part of a multimarker model that can predict nodal status. The α6β4 integrin is tightly connected to collagen VII in normal urothelial cells and inhibits cell migration. Superficial UCa has shown loss of polarity of α6β4 expression, and invasive tumors reveal either loss of α6β4 and/or collagen VII expression or lack of colocalization of either protein. Patients who have malignancies with weak α6β4 immunoreactivity have a better prognosis than those who have tumors with no or significant overexpression. Overall, molecular invasion indicators are relatively accurate predictors of outcome in UCa patients [97].
Circulating tumor cells are the most basic blood-based biomarker. The presence of tumor cells in the blood has been associated with advanced disease stages in various solid organ cancers. In a recent study, the predictive value of the amount of circulating tumor cells obtained with CellSearch technology was investigated in 100 UCa patients who had undergone cystectomy. About 25% of clinically localized Uca patients had circulating tumor cells, the researchers found, and they associated the results with a worse outcome for these patients [98].
Ki-67 is a nuclear protein that is synthesized by proliferating cells that is used to determine the percentage of cell growth fraction. In patients with superficial UCa, the cell proliferative index is associated with prognosis, and the Ki-67 antigen is a strong predictor of progression, recurrence, and treatment response. This result was confirmed in patients receiving cystectomy who had muscle-invasive UCa [99, 100].
Survivin is also an apoptosis inhibitor that can bind caspases after their activation and prevent them from cleaving their substrates. Survivin expression has been shown to be associated with bladder cancer progression and mortality, and its function as a prognostic indicator has been externally validated. In a multiplex panel including other apoptosis-regulating genes, survivin has been shown to predict tumor recurrence after cystectomy and mortality more accurately than clinicopathological factors alone [101].
COX-2 is an enzyme known primarily for being a target for nonsteroidal anti-inflammatory drugs. Increased levels of COX-2 have been studied in both the upper and lower urinary tract as a marker of UCa angiogenesis and tumor aggressiveness. COX-2 was increased not only in upper urinary tract carcinomas but also in nearby nontumor cells (stromal cells), suggesting an association between more aggressive upper urinary tract malignancies and worse prognosis [102, 103].
IGF (insulin growth factor) and IGFBP-3 (insulin growth factor binding protein-3) are circulating proteins that function as growth signal mediators and mitogens, respectively. IGF and IGFBP-3 levels were measured preoperatively in individuals having cystectomy to see if they may be used as blood-based predictors of UCa outcome. Although individual marker levels were not efficient, an association between the two of them (low IGF-adjusted IGFBP-3 levels) was a predictor of distant metastases and poor survival [104].
Periplakin is a protein that is found in normal cellular desmosomes and is encoded by the PPL gene. In a cohort study of UCa patients, serum circulating periplakin was investigated and compared to 30 healthy subjects. While UCa patients had considerably lower serum periplakin levels than controls, this difference was diminished in patients with invasive tumors [105].
Bladder cancer is being more recognized as a disease that cannot be treated merely based on pathologic staging; instead, therapeutic efforts must focus on molecular abnormalities in particular tumors. The formation and course of urothelial malignancies have been better understood, thanks to the availability of advanced molecular profiling and computational methods. Future Uca treatment will rely on consensus marker panels to provide accurate prognosis and therapeutic response predictions in individual patients. The disease will be effectively treated if patients are stratified based on risk factors and tumor expression signatures, followed by optimum surgical treatment and disruption of important signaling pathways through the use of therapies targeting several molecular pathways [106].
Kidney cancer is the fourteenth most prevalent cancer in the world, with men having the ninth most common case and women having the fourteenth most common incidence [107, 108].
Renal cancers in adults include malignant tumors of the renal parenchyma and pelvis, but benign tumors and inflammatory causes should also be considered in the differential diagnosis of a renal mass. The majority of tumors arising from the renal pelvis are urothelial tumors, which account for less than 10% of all renal carcinomas. Renal cell carcinoma (RCC), also known as renal adenocarcinoma, is far more common than benign tumors or other malignancies and accounts for 90% of all kidney cancers. RCC can be divided into several histological subgroups, each with its own clinical features and evolution [109].
The clear cell type of renal cell carcinoma is the most common, accounting for 75% of new cases, followed by the papillary, chromophobe, medullary, and collecting duct subtypes, which account for 10%, 5%, 1%, and 1% of new cases, respectively [107].
Von Hippel and Lindau characterized a vascularized developmental pattern of the retina that was later identified as part of an autosomal dominant disease. Hemangioblastomas, pheochromocytomas, and clear cell renal carcinomas were also common in these patients. Up to 90% of sporadic RCCs have somatic mutations, promoter methylation, or loss of heterozygosity of VHL. The VHL protein is known to function as a substrate recognition component of an E3 ligase and for ubiquitination and degradation of HIF (hypoxia-inducible factors) [110, 111, 112].
The alpha subunit of HIF heterodimerizes with HIFβ under hypoxic conditions or in the absence/inactivation of the VHL protein, translocates to the nucleus, and transcribes a variety of genes, including VEGF, PDGF, and TGF. In most spontaneous RCCs, inappropriate activation of this system is a major cause of angiogenesis, invasion, and metastasis [113].
In metastatic or unresectable RCC, targeting the VEGF pathway has been a cornerstone of treatment. In metastatic RCC, small molecule TKI (tyrosine kinase inhibitors) have proven successful in interrupting VEGF signaling, resulting in longer patient survival. Endothelial cells can be stimulated to proliferate and migrate by VEGF and PDGF [113].
The development of an increased blood supply can promote the development of metastatic niches and lead to the spread of the tumor. Because of this significant metastatic potential, no neoadjuvant systemic treatment is currently accepted for RCC with targeted therapies such as sunitinib or pazopanib. These agents are also not approved for adjuvant treatment after nephrectomy. Several studies have failed to demonstrate that adjuvant TKIs or immunotherapies improve survival after definitive surgery, underscoring the need for early intervention with surgery upfront. The most common genetic mutation in RCC is the loss of chromosome 3p. This region contains the PBRM1 gene in addition to VHL (3p21) [114].
PBRM1 is a “gatekeeper” gene that helps in DNA repair, replication, and transcription. Somatic mutations have been detected in 41% of clear cell renal carcinomas, with estimates ranging from 40 to 50%. Loss of PBRM1 is associated with advanced disease stages, a higher grade cancer, and poorer treatment outcomes [115, 116, 117].
Mutations on chromosome 3p could indicate an important genetic event, whether inherited or acquired, that drives early carcinogenesis. RCC features a number of genomic changes, including an increase in 5q with TGFB1 and CSF1R, as well as a 14q deletion with the tumor suppressor candidate NRXN3. Loss of 14q has been related to a progression of the disease and a reduced life expectancy [118, 119].
mTOR is a serine/threonine kinase that forms two different complexes with adaptor proteins—mTORC1 and mTORC2. mTORC1 activity was found in more than half of all RCCs. HIF-1α has been demonstrated to promote the expression of REDD1, a proven mTORC1 inhibitor. Stabilization of HIF1 levels under hypoxic environments causes mTOR signaling to be inhibited [120].
Mutations in TSC1 and PTEN may prevent the HIF-1 signaling axis from inhibiting mTOR, resulting in a second, independent mechanism of carcinogenesis. Everolimus as shown in Figure 3, suppresses the activity of mTORC1 via binding to FKBP-12 [121, 122].
Current therapeutic management of RCC.
Over the past two decades, research has focused on molecular events that can uncover the biological heterogeneity underlying the diverse clinical behavior of RCC, with the expectation of identifying accurate markers that can personalize prognosis and risk-stratified clinical management, as well as predict response to existing therapeutic approaches [123].
Molecular biomarkers are associated with clinical and/or pathologic characteristics of RCC and have an effect on progression-free survival, OS, cancer-specific mortality, and prognosis [124].
In addition, new research has recently been published on PBRM1 (polybromo 1), BAP1 (BRCA1-associated protein 1), and SETD2 (SET domain-containing protein 2). Although these biomarkers are targeted by a variety of RCC treatments, their prognostic and predictive value has yet to be confirmed internally and externally. All tyrosine kinase inhibitors, such as bevacizumab, target VEGF, while some others, such as cabozantinib, target a larger variety of receptors, including AXL and the protooncogene c-met [123].
As explained earlier, VHL is responsible for the degradation of HIF-α. As a result, changes in VHL proteins lead to HIF-α accumulation in addition to hypoxic cell conditions. HIF-α is a key player in cancer pathogenesis, activating approximately 30 genes involved in tumor proliferation and angiogenesis, including the overexpression of VEGF. When ccRCC (clear cell renal cancer) is compared with papillary or chromophobe forms of RCC, HIF-α expression is significantly higher. In both clear cell and papillary RCC, studies have reported no difference in survival between patients with low or high HIF-α expression, while other studies have found a worse prognosis with increased HIF-α in cancer cells [123].
VEGF is a dimeric glycoprotein that promotes tumor growth and metastasis by influencing angiogenesis in both normal and pathological situations. Due to HIF-α dysregulation and hypoxia caused by an inadequate blood supply in larger tumors, VEGF production is increased in ccRCC. RCC patients with VHL gene mutations and advanced tumor grade have higher VEGF levels and secretion. VEGF expression correlates with tumor necrosis, microvessel invasion, tumor stage, and Fuhrman grade in ccRCC, in addition to tumor grade and size. In studies, increased VEGF levels have been observed to decrease progression-free and overall survival rates of RCC [123, 125].
The additional value of VEGF, despite its promising properties, has yet to be confirmed and externally validated. C-met is a receptor tyrosine kinase and a proto-oncogene. Angiogenesis, tissue regeneration, cell proliferation, and differentiation are controlled by this protein. Mutations in the c-met signaling pathways have been linked to a variety of tumors, including all forms of RCC [123, 125]. The upregulation of c-met has been linked to the VHL mutation in ccRCC. It has been found that c-met expression is particularly high in tumors with papillary and sarcomatoid differentiation. In recent studies, increased c-met expression was found to reduce cancer-specific mortality. Further research is required to fully understand the role of c-met in the etiology of RCC [126, 127].
Transmembrane protein CAIX is linked to tumor development, poor prognosis, and aggressive phenotype. CAIX is thought to be involved in the regulation of the tumor microenvironment, particularly the fluctuations in intracellular and extracellular pH in response to hypoxia in the tumor, and is regulated by HIF. CAIX is expressed in more than 80% of RCC samples and 90% of ccRCC samples and can therefore be used to confirm the diagnosis of RCC. CAIX expression has been associated with better prognosis and survival in patients with localized RCC and mRCC, and with an inverse relationship with metastatic spread. In contrast, low CAIX expression was not associated with renal cancer mortality [128].
CAIX may be more useful in identifying small renal tumors. With the advancement of technology, three genes have been discovered to be altered in more than 10% of sporadic clear cell RCC: BAP1, PBRM1, and SETD2. We can assume that these genes play an important role in renal cell carcinoma because, as in VHL, they are tumor suppressor genes with two hits found on the short arm of chromosome 3p [129].
The mTOR pathway regulates cell proliferation, protein degradation, and angiogenesis as part of the biological response to environmental stress. PTEN (phosphatase and tensin homolog) is an upstream molecule in this process, while phosphorylated S6 ribosomal protein is a downstream molecule. The use of temsirolimus, an mTOR inhibitor, as a first-line treatment for low-risk patients is recommended in recent treatment guidelines. In addition, recent studies have shown that altering regulators of the mTOR pathway improves the accuracy of prognostic models as well as the ability to predict recurrence in ccRCC patients who had undergone nephrectomy [130, 131].
pS6 (ribosomal protein S6) is a downstream mTOR target that has been associated with the activation of the mTOR pathway. Due to phosphorylated pS6 activity, it exhibits S6 kinase activity that affects mRNA translation. PS6 is overexpressed in clear cell mRCC and could be used to predict survival in both localized and non-localized mRCC. pAkt (protein kinase B) regulates both growth and survival mechanisms by phosphorylating substrates in the cytoplasm and nucleus. Elevated pAkt is associated with lower RCC-specific survival, higher grade, and faster progression of metastasis [123, 132]. Overexpressed pAkt, on the other hand, was linked to a better prognosis in localized RCC. According to recent studies, the localization of pAkt may be essential in defining tumor behavior and thus prognostic value. They discovered a higher level of nuclear pAkt in localized RCC tissue than in mRCC tissue [123, 133].
The tumor suppressor protein PTEN is encoded by the tumor suppressor gene PTEN and is located upstream of mTOR. Via PI3K, PTEN inhibits the phosphorylation of pAkt. PTEN mutation is uncommon in renal cancer and is linked to a high mortality rate. PTEN expression is observed in cancers with a lower T stage and a nonclear cell histological subtype and increases survival [123, 133].
CAF (cytokine and angiogenic factors), survivin, caveolin-1, p53, vimentin, insulin-like growth factor II mRNA-binding protein 3, matrix metalloproteinases, fascin, ki-67, tumor necrosis, and c-reactive protein are examples of other biomarkers. Survivin is a member of the family of apoptosis inhibitors that are active in both the intrinsic and extrinsic caspase pathways [132]. It regulates mitotic progression and promotes alterations in gene expression associated with tumor cell invasiveness. Survivin mRNA is typically expressed during embryonic and fetal development and then disappears in most differentiated adult tissues. Survivin is overexpressed in a variety of malignancies, including all forms of RCC [123].
Given the importance of deregulation of apoptosis in carcinogenesis, it is not surprising that high expression of survivin is associated with poor differentiation, aggressiveness, and lower survival in ccRCC. The p53 protein is a DNA-binding molecule involved in transcription and the regulation of cell growth. When DNA damage occurs, p53 initiates apoptosis and causes cell cycle arrest. Overexpression of p53 has been found in all forms of RCC, especially papillary RCC. Although p53 has been shown to be an independent predictor of metastasis-free survival in patients with localized clear cell RCC, its prognostic significance in RCC is still debated [123].
MMPs are overexpressed in all forms of RCC cancer, especially in nonclear cell RCC tumors, and are associated with aggressive behavior, tumor grade, and survival. Batimastat (synthetic) and bryostatins (natural) are MMP inhibitors that may help to treat and prevent MMP-overexpressing malignancies [123].
IMP3 (insulin-like growth factor II mRNA-binding protein 3) is an RNA-binding protein found in oncofetal tissues. Insulin-like growth factor II mRNA transcription is regulated by it. IMP3 is expressed during embryogenesis in a variety of developing tissues, including epithelium, muscle, and the placenta. In adult tissues, however, it is expressed at low or undetectable levels. In several malignancies, including RCC, IMP3 is associated with cell proliferation and invasion. Stage, grade, sarcomatoid differentiation, regional lymph node involvement, distant metastasis, and cancer-specific mortality are all associated with IMP3. The inclusion of IMP3 expression in the tumor stage increases metastatic progression prediction of metastatic progression and the predictive value of IMP3 in ccRCC was externally validated by researchers. [123, 134, 135].
Ki-67 is a cell proliferation marker that has been linked to higher recurrence rates, a more aggressive phenotype of ccRCC, and a poor prognosis. The combination of Ki-67 and CAIX improves the predictive power of nuclear grade in assessing cancer-specific mortality. Complementary studies are needed to evaluate its significance as a prognostic factor [123].
Caveolin-1 is a structural component of caveolae, microdomains of the plasma membrane that regulate cell adhesion, growth, and survival through intracellular signaling. Caveolin-1 is detected in 86% of ccRCCs and 5% of chromophobe and papillary RCCs. The caveolin-1 expression has been linked to a poor clinical outcome in a variety of cancers [123].
One of the components of the scoring algorithm of Leibovich et al. is tumor necrosis. The importance of this component in the prognosis of RCC has led to some debate. When typical clinical and/or pathological tumor features were considered, several studies found that tumor necrosis had no additional value. In contrast, Lam et al. found that tumor necrosis improved survival prediction in patients with localized RCC [136, 137].
The inflammatory marker C-reactive protein has been shown to be a significant predictor of metastasis and overall mortality after nephrectomy for localized renal cell carcinoma. It improved the predictive accuracy of a number of known clinical and pathological predictors by up to 10%. Karakiewicz et al. studied and stated CRP as an independent predictor of mortality in RCC [138].
They also discovered that CRP improved the accuracy of the UISS prediction model. According to Michigan et al., elevated CRP was associated with increased mortality in patients undergoing nephrectomy. Erythrocyte sedimentation rate (ESR), another inflammatory marker, was also associated with higher all-cause mortality. Because they are affordable and readily available, these markers are very promising [123, 127].
Vimentin is a cytoplasmic intermediate filament that should not normally be detected in epithelial cells. Its overexpression has been observed in up to 51% of ccRCC and 61% of papillary RCC, and it has been associated with poor outcomes, regardless of T stage or grade [123].
Fascin is a globular actin cross-link protein that plays a role in cell motility and adhesion. Its overexpression has been associated with sarcomatoid tumors, their stage, grade, size, and metastatic ability [123].
CTLA-4 is a protein described on the surface of cytotoxic T lymphocytes. It is thought to reduce inflammation by preventing tumor-infiltrating lymphocytes (TILs) and T cell activation by preventing tumor cell B71 from binding to CD28. The presence of CTLA-4 has been associated with higher tumor grade in RCC. Lymphocytes also have a cell surface receptor, PD-1. It belongs to the immunoglobulin family and binds to the ligands PD-L1 and PD-L2, which are found on almost all cells, including tumor cells. They are thought to promote apoptosis by decreasing the activity of cytotoxic T cells. [139]. In addition, tumor cells are thought to express PD-L1/B7-H1 to prevent tissue destruction by an activated immune system [123, 127].
PD-1 inhibitors, particularly nivolumab, have been the subject of numerous studies, all of which have yielded promising results. The FDA approved nivolumab as second-line therapy for RCC in 2015, based on the results of a study that OS showed benefit, good tolerability, and improved health-related quality of life with nivolumab treatment. It is worth noting that ongoing trials using a mix of targeted treatments, such as anti-VEGFs, and nivolumab are showing promising results [122, 123].
The authors declare no conflict of interest.
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So, air and water can potentially become polluted everywhere. Little is known about changes in pollution rates. The increase in water-related diseases provides a real assessment of the degree of pollution in the environment. This chapter summarizes water quality parameters from an ecological perspective not only for humans but also for other living things. According to its quality, water can be classified into four types. Those four water quality types are discussed through an extensive review of their important common attributes including physical, chemical, and biological parameters. 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Accordingly, 80 medicinal plant species were reviewed; leaves and roots are the main parts of the plants used for preparation of traditional medicines. The local practitioners provided various traditional medications to their patients’ diseases such as stomachaches, asthma, dysentery, malaria, evil eyes, cancer, skin diseases, and headaches. The uses of medicinal plants for human and animal treatments are practiced from time immemorial. Stream/riverbanks, cultivated lands, disturbed sites, bushlands, forested areas and their margins, woodlands, grasslands, and home gardens are major habitats of medicinal plants. Generally, medicinal plants used for traditional medicine play a significant role in the healthcare of the majority of the people in Ethiopia. The major threats to medicinal plants are habitat destruction, urbanization, agricultural expansion, investment, road construction, and deforestation. Because of these, medicinal plants are being declined and lost with their habitats. Community- and research-based conservation mechanisms could be an appropriate approach for mitigating the problems pertinent to the loss of medicinal plants and their habitats and for documenting medicinal plants. Chromatography; electrophoretic, macroscopic, and microscopic techniques; and pharmaceutical practice are mainly used for quality control of herbal medicines.",book:{id:"8502",slug:"plant-science-structure-anatomy-and-physiology-in-plants-cultured-in-vivo-and-in-vitro",title:"Plant Science",fullTitle:"Plant Science - Structure, Anatomy and Physiology in Plants Cultured in Vivo and in Vitro"},signatures:"Admasu Moges and Yohannes Moges",authors:[{id:"249746",title:"Ph.D.",name:"Admasu",middleName:null,surname:"Moges",slug:"admasu-moges",fullName:"Admasu Moges"},{id:"297761",title:"MSc.",name:"Yohannes",middleName:null,surname:"Moges",slug:"yohannes-moges",fullName:"Yohannes Moges"}]},{id:"29764",title:"Underlying Causes of Paresthesia",slug:"underlying-causes-of-paresthesia",totalDownloads:193348,totalCrossrefCites:3,totalDimensionsCites:7,abstract:null,book:{id:"1069",slug:"paresthesia",title:"Paresthesia",fullTitle:"Paresthesia"},signatures:"Mahdi Sharif-Alhoseini, Vafa Rahimi-Movaghar and Alexander R. 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It’s a beautiful fruit with smooth, shining skin. Yellow, red, and purple fruits are available. This fruit contains vitamins, minerals, fiber, and antioxidants. It has a very low-calorie count. Breeding focuses on fruit quality through selection, hybridization, and biotechnological treatments for plantation and post-harvest management. Diseases, pests, viruses, and physiological abnormalities can be treated with plant protection techniques. Like other fruits, it’s edible after harvesting. Made into juices, concentrates, jams, gelatins, and sweets. If processing facilities and transport are available, it can be exported as pulp or concentrate. The tamarillo can diversify sub-tropical fruit production as a high-value cash crop, with excellent fruits commanding premium prices in Europe, North America, and Japan.",book:{id:"11311",title:"Tropical Plant Species",coverURL:"https://cdn.intechopen.com/books/images_new/11311.jpg"},signatures:"Rafiq Ahmad Shah, Parshant Bakshi, Hamidullah Itoo and Gaganpreet Kour"},{id:"82491",title:"Heterologous Expression of Genes in Plants for Abiotic Stresses",slug:"heterologous-expression-of-genes-in-plants-for-abiotic-stresses",totalDownloads:0,totalDimensionsCites:null,doi:"10.5772/intechopen.105171",abstract:"Abiotic stresses are considered to be the major factors causing a decrease in crop yield globally, these stresses include high and low temperature, salinity, drought, and light stress etc. To overcome the consistent food demand for the ever-growing population, various genes from micro-organisms and non-plant sources have been expressed in transgenic plants to improve their tolerance against abiotic stresses. Gene expression in transgenic plants through conventional methods are time-consuming and laborious that’s why advanced genetic engineering methods for example Agrobacterium-mediated transformation and biolistic methods are more accurate, useful, and less time-consuming. This review provides an insight into various bacterial genes for example mtID, codA, betA, ADH, IPT, DRNF1 and ggpPS, etc. that have been successfully expressed in transgenic plants against various abiotic stress for stress tolerance enhancement and crop yield improvement which exhibited good encouraging results. Genes from yeast (Saccharomyces cerevisiae) have been introduced in transgenic plants against drought and salinity stress. All these genes expressed from non-plant sources in plants can be very helpful to enhance crops for better yield productivity in the future to meet the demands of the consistently rising population of the world.",book:{id:"11330",title:"Plant Response Mechanisms to Abiotic Stresses",coverURL:"https://cdn.intechopen.com/books/images_new/11330.jpg"},signatures:"Shahzad Ali, Nadir Zaman, Waqar Ali, Majid Khan, Muhammad Aasim, Asmat Ali and Muhammad Usman"},{id:"83122",title:"New Perspectives on the Application of Chito-Oligosaccharides Derived from Chitin and Chitosan: A Review",slug:"new-perspectives-on-the-application-of-chito-oligosaccharides-derived-from-chitin-and-chitosan-a-rev",totalDownloads:0,totalDimensionsCites:null,doi:"10.5772/intechopen.106501",abstract:"The study of chitin and chitosan has stood out for many years due to their potential application in various areas such as the food industry, where they are either used as additives, prebiotics, or bio-conservatives; as to biomedical and pharmaceutical industries, where they function to treat diseases. Besides, in the agriculture field, it is known that they can cause a positive effect on the development of plants and optimize nitrogen fixation. In recent years, attention has been paid to their derivatives, chito-oligosaccharides which, unlike chitin and chitosan, they have different chemical characteristics, like their solubility, a characteristic that facilitates their use, contrary to chitin and chitosan. Moreover, the small size of chito-oligosaccharides can facilitate their entry into the cell. This review covers recent studies on the biological functions of chito-oligosaccharides and their impact on a priority area such as agriculture, where these compounds could be used to substitute the demand for chemical compounds that, until now, have generated serious health issues as well as environmental pollution.",book:{id:"11670",title:"Chitin-Chitosan - Isolation, Properties, and Applications",coverURL:"https://cdn.intechopen.com/books/images_new/11670.jpg"},signatures:"Paul Edgardo Regalado-Infante, Norma Gabriela Rojas-Avelizapa, Rosalía Núñez-Pastrana, Daniel Tapia-Maruri, Andrea Margarita Rivas-Castillo, Régulo Carlos Llarena-Hernández and Luz Irene Rojas-Avelizapa"},{id:"83015",title:"Acute Changes in Lipoprotein-Associated Oxidative Stress",slug:"acute-changes-in-lipoprotein-associated-oxidative-stress",totalDownloads:0,totalDimensionsCites:null,doi:"10.5772/intechopen.106489",abstract:"As inflammatory and oxidative stress are associated with cardiometabolic diseases, detection of abnormal fasting levels of inflammatory and oxidative biomarkers are indicative disease presence and may be too late for any preventive management. Metabolic flexibility refers to the ability of various metabolic processes to compensate for these acute changes and return all metabolites to baseline levels. By monitoring responses of key biomarkers to a standardized physiologic challenge, it is possible to assess the ability of the body to restore homeostasis, that is a measure of metabolic flexibility. Acute changes in lipoprotein-associated biomarkers of oxidative stress have been demonstrated following meal consumption. These include changes in circulating levels of oxidized low-density lipoproteins (LDL), levels of autoantibodies to malondialdehyde-modified LDL, as well as the oxidative susceptibility of isolated plasma LDL. These responses depend on the type and amount of dietary fats in the meal. Management with certain lipid-lowering drugs could also be shown to affect these meal-induced changes. However, plasma levels may be underestimated as we can demonstrate a spike in lipoprotein-associated biomarkers of oxidative stress resulting from the release oxidatively modified epitopes from the arterial wall by an intravenous bolus of heparin.",book:{id:"11671",title:"Importance of Oxidative Stress and Antioxidant System in Health and Disease",coverURL:"https://cdn.intechopen.com/books/images_new/11671.jpg"},signatures:"Ngoc-Anh Le"},{id:"83041",title:"Responses of Endoplasmic Reticulum to Plant Stress",slug:"responses-of-endoplasmic-reticulum-to-plant-stress",totalDownloads:3,totalDimensionsCites:null,doi:"10.5772/intechopen.106590",abstract:"Global climate change has resulted in alterations in the biotic and abiotic conditions of the planet. This has led to changes in the agricultural system resulting from reduced water availability, increased temperature increase in the population and occurrences of pests and diseases. Plants are adversely affected when they experience any stress retarding their growth, development and productivity. Endoplasmic Reticulum (ER) is an organelle that shows a tremendous response when subjected to stress conditions. Therefore, to explore and comprehend plants’ multidimensional interactions when subjected to stress conditions, an insight into the molecular stress signalling in the ER in response to the stress situation is discussed in this chapter.",book:{id:"11674",title:"Updates on Endoplasmic Reticulum",coverURL:"https://cdn.intechopen.com/books/images_new/11674.jpg"},signatures:"Vishwa Jyoti Baruah, Bhaswati Sarmah, Manny Saluja and Elizabeth H. Mahood"},{id:"82624",title:"Protective Forests for Ecosystem-based Disaster Risk Reduction (Eco-DRR) in the Alpine Space",slug:"protective-forests-for-ecosystem-based-disaster-risk-reduction-eco-drr-in-the-alpine-space",totalDownloads:1,totalDimensionsCites:null,doi:"10.5772/intechopen.99505",abstract:"Mountain forests are an efficient Forest-based Solution (FbS) for Ecosystem-based Disaster Risk Reduction (Eco-DRR) by lowering the frequency, magnitude, and/or intensity of natural hazards. Technical protection measures are often poor solutions as stand-alone measures to reduce disaster risk limited by material wear and fatigue or financial resources and aesthetical values. Protective forests should therefore be considered as key elements in integrated risk management strategies. However, the definition of protective forests and the understanding and assessment of their protective functions and effects differ greatly among Alpine Space countries. In this chapter, we present a short introduction to the concept of Eco-DRR and companion terms and propose a definition of FbS as a specific case of Nature-based Solutions for an ecosystem-based and integrated risk management of natural hazards. That is, we guide the reader through the maze of existing definitions and concepts and try to disentangle their meanings. Furthermore, we present an introduction to forest regulations in the Alpine Space and European protective forest management guidelines. Our considerations and recommendations can help strengthen the role of protective forests as FbS in Eco-DRR and the acknowledgment of the key protective function they have and the crucial protective effects they provide in mountain areas.",book:{id:"10812",title:"Protective forests as Ecosystem-based solution for Disaster Risk Reduction (ECO-DRR)",coverURL:"//cdnintech.com/web/frontend/www/assets/cover.jpg"},signatures:"Michaela Teich, Cristian Accastello, Frank Perzl and Frédéric Berger"}],onlineFirstChaptersTotal:604},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:11,numberOfPublishedChapters:91,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:108,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:33,numberOfPublishedChapters:333,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:14,numberOfPublishedChapters:145,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:11,numberOfPublishedChapters:144,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:124,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:113,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:23,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:12,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:"2753-6580",doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}},{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}}]},series:{item:{id:"6",title:"Infectious Diseases",doi:"10.5772/intechopen.71852",issn:"2631-6188",scope:"This series will provide a comprehensive overview of recent research trends in various Infectious Diseases (as per the most recent Baltimore classification). Topics will include general overviews of infections, immunopathology, diagnosis, treatment, epidemiology, etiology, and current clinical recommendations for managing infectious diseases. 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He is the president of the Travel Medicine Committee of the Pan-American Infectious Diseases Association (API), as well as the president of the Colombian Association of Infectious Diseases (ACIN). He is a member of the Committee on Tropical Medicine, Zoonoses, and Travel Medicine of ACIN. He is a vice-president of the Latin American Society for Travel Medicine (SLAMVI) and a Member of the Council of the International Society for Infectious Diseases (ISID). Since 2014, he has been recognized as a Senior Researcher, at the Ministry of Science of Colombia. He is a professor at the Faculty of Medicine of the Fundacion Universitaria Autonoma de las Americas, in Pereira, Risaralda, Colombia. He is an External Professor, Master in Research on Tropical Medicine and International Health, Universitat de Barcelona, Spain. He is also a professor at the Master in Clinical Epidemiology and Biostatistics, Universidad Científica del Sur, Lima, Peru. In 2021 he has been awarded the “Raul Isturiz Award” Medal of the API. Also, in 2021, he was awarded with the “Jose Felix Patiño” Asclepius Staff Medal of the Colombian Medical College, due to his scientific contributions to COVID-19 during the pandemic. He is currently the Editor in Chief of the journal Travel Medicine and Infectious Diseases. 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His later study in cooperation with experts in nephrology and immunology resulted in the designation of the new diagnostic method of UTI, patented in 2017. He is currently working at the Department of Microbiology, Medical University of Gdańsk (GUMed), Poland. Since many years, he is a member of steering committee of Gdańsk branch of Polish Society of Microbiologists, a member of ESCMID. 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Her research interest is in antibiotic resistance, host-pathogen interaction, and therapeutics development for staphylococcal pathogens, mainly Staphylococcus aureus, which causes hospital-acquired infections. Currently, her research is mostly focused on the study of oral pathogens, particularly Staphylococcus spp.",institutionString:"Medical University of Gdańsk, Poland",institution:null},editorThree:null},{id:"4",title:"Fungal Infectious Diseases",coverUrl:"https://cdn.intechopen.com/series_topics/covers/4.jpg",isOpenForSubmission:!0,editor:{id:"174134",title:"Dr.",name:"Yuping",middleName:null,surname:"Ran",slug:"yuping-ran",fullName:"Yuping Ran",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bS9d6QAC/Profile_Picture_1630330675373",biography:"Dr. Yuping Ran, Professor, Department of Dermatology, West China Hospital, Sichuan University, Chengdu, China. Completed the Course Medical Mycology, the Centraalbureau voor Schimmelcultures (CBS), Fungal Biodiversity Centre, Netherlands (2006). International Union of Microbiological Societies (IUMS) Fellow, and International Emerging Infectious Diseases (IEID) Fellow, Centers for Diseases Control and Prevention (CDC), Atlanta, USA. Diploma of Dermatological Scientist, Japanese Society for Investigative Dermatology. Ph.D. of Juntendo University, Japan. Bachelor’s and Master’s degree, Medicine, West China University of Medical Sciences. Chair of Sichuan Medical Association Dermatology Committee. General Secretary of The 19th Annual Meeting of Chinese Society of Dermatology and the Asia Pacific Society for Medical Mycology (2013). In charge of the Annual Medical Mycology Course over 20-years authorized by National Continue Medical Education Committee of China. Member of the board of directors of the Asia-Pacific Society for Medical Mycology (APSMM). Associate editor of Mycopathologia. Vice-chief of the editorial board of Chinses Journal of Mycology, China. Board Member and Chair of Mycology Group of Chinese Society of Dermatology.",institutionString:null,institution:{name:"Sichuan University",institutionURL:null,country:{name:"China"}}},editorTwo:null,editorThree:null},{id:"5",title:"Parasitic Infectious Diseases",coverUrl:"https://cdn.intechopen.com/series_topics/covers/5.jpg",isOpenForSubmission:!0,editor:{id:"67907",title:"Dr.",name:"Amidou",middleName:null,surname:"Samie",slug:"amidou-samie",fullName:"Amidou Samie",profilePictureURL:"https://mts.intechopen.com/storage/users/67907/images/system/67907.jpg",biography:"Dr. Amidou Samie is an Associate Professor of Microbiology at the University of Venda, in South Africa, where he graduated for his PhD in May 2008. He joined the Department of Microbiology the same year and has been giving lectures on topics covering parasitology, immunology, molecular biology and industrial microbiology. He is currently a rated researcher by the National Research Foundation of South Africa at category C2. He has published widely in the field of infectious diseases and has overseen several MSc’s and PhDs. His research activities mostly cover topics on infectious diseases from epidemiology to control. His particular interest lies in the study of intestinal protozoan parasites and opportunistic infections among HIV patients as well as the potential impact of childhood diarrhoea on growth and child development. He also conducts research on water-borne diseases and water quality and is involved in the evaluation of point-of-use water treatment technologies using silver and copper nanoparticles in collaboration with the University of Virginia, USA. 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His research interests involve understanding the molecular mechanisms of host defense during human viral infections and developing new predictive, preventive, and therapeutic strategies for them using Japanese encephalitis virus (JEV), HIV, and emerging viruses as a model via stem cell and cell culture technologies. His research work has been published in various high-impact factor journals (Science, PNAS, Nature Medicine) with a high number of citations. He has received many awards and honors in India and abroad including various Young Scientist Awards, BBSRC India Partnering Award, and Dr. JC Bose National Award of Department of Biotechnology, Min. of Science and Technology, Govt. of India. 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Saxena",hash:"105e347b2d5dbbe6b593aceffa051efa",volumeInSeries:1,fullTitle:"Influenza - Therapeutics and Challenges",editors:[{id:"158026",title:"Prof.",name:"Shailendra K.",middleName:null,surname:"Saxena",slug:"shailendra-k.-saxena",fullName:"Shailendra K. Saxena",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRET3QAO/Profile_Picture_2022-05-10T10:10:26.jpeg",biography:"Professor Dr. Shailendra K. Saxena is a vice dean and professor at King George's Medical University, Lucknow, India. His research interests involve understanding the molecular mechanisms of host defense during human viral infections and developing new predictive, preventive, and therapeutic strategies for them using Japanese encephalitis virus (JEV), HIV, and emerging viruses as a model via stem cell and cell culture technologies. His research work has been published in various high-impact factor journals (Science, PNAS, Nature Medicine) with a high number of citations. He has received many awards and honors in India and abroad including various Young Scientist Awards, BBSRC India Partnering Award, and Dr. JC Bose National Award of Department of Biotechnology, Min. of Science and Technology, Govt. of India. Dr. Saxena is a fellow of various international societies/academies including the Royal College of Pathologists, United Kingdom; Royal Society of Medicine, London; Royal Society of Biology, United Kingdom; Royal Society of Chemistry, London; and Academy of Translational Medicine Professionals, Austria. He was named a Global Leader in Science by The Scientist. He is also an international opinion leader/expert in vaccination for Japanese encephalitis by IPIC (UK).",institutionString:"King George's Medical University",institution:{name:"King George's Medical University",institutionURL:null,country:{name:"India"}}}]},{type:"book",id:"7064",title:"Current Perspectives in Human Papillomavirus",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7064.jpg",slug:"current-perspectives-in-human-papillomavirus",publishedDate:"May 2nd 2019",editedByType:"Edited by",bookSignature:"Shailendra K. Saxena",hash:"d92a4085627bab25ddc7942fbf44cf05",volumeInSeries:2,fullTitle:"Current Perspectives in Human Papillomavirus",editors:[{id:"158026",title:"Prof.",name:"Shailendra K.",middleName:null,surname:"Saxena",slug:"shailendra-k.-saxena",fullName:"Shailendra K. Saxena",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRET3QAO/Profile_Picture_2022-05-10T10:10:26.jpeg",biography:"Professor Dr. Shailendra K. Saxena is a vice dean and professor at King George's Medical University, Lucknow, India. His research interests involve understanding the molecular mechanisms of host defense during human viral infections and developing new predictive, preventive, and therapeutic strategies for them using Japanese encephalitis virus (JEV), HIV, and emerging viruses as a model via stem cell and cell culture technologies. His research work has been published in various high-impact factor journals (Science, PNAS, Nature Medicine) with a high number of citations. He has received many awards and honors in India and abroad including various Young Scientist Awards, BBSRC India Partnering Award, and Dr. JC Bose National Award of Department of Biotechnology, Min. of Science and Technology, Govt. of India. Dr. Saxena is a fellow of various international societies/academies including the Royal College of Pathologists, United Kingdom; Royal Society of Medicine, London; Royal Society of Biology, United Kingdom; Royal Society of Chemistry, London; and Academy of Translational Medicine Professionals, Austria. He was named a Global Leader in Science by The Scientist. He is also an international opinion leader/expert in vaccination for Japanese encephalitis by IPIC (UK).",institutionString:"King George's Medical University",institution:{name:"King George's Medical University",institutionURL:null,country:{name:"India"}}}]},{type:"book",id:"7123",title:"Current Topics in Neglected Tropical Diseases",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7123.jpg",slug:"current-topics-in-neglected-tropical-diseases",publishedDate:"December 4th 2019",editedByType:"Edited by",bookSignature:"Alfonso J. Rodriguez-Morales",hash:"61c627da05b2ace83056d11357bdf361",volumeInSeries:3,fullTitle:"Current Topics in Neglected Tropical Diseases",editors:[{id:"131400",title:"Prof.",name:"Alfonso J.",middleName:null,surname:"Rodriguez-Morales",slug:"alfonso-j.-rodriguez-morales",fullName:"Alfonso J. Rodriguez-Morales",profilePictureURL:"https://mts.intechopen.com/storage/users/131400/images/system/131400.png",biography:"Dr. Rodriguez-Morales is an expert in tropical and emerging diseases, particularly zoonotic and vector-borne diseases (especially arboviral diseases). He is the president of the Travel Medicine Committee of the Pan-American Infectious Diseases Association (API), as well as the president of the Colombian Association of Infectious Diseases (ACIN). He is a member of the Committee on Tropical Medicine, Zoonoses, and Travel Medicine of ACIN. He is a vice-president of the Latin American Society for Travel Medicine (SLAMVI) and a Member of the Council of the International Society for Infectious Diseases (ISID). Since 2014, he has been recognized as a Senior Researcher, at the Ministry of Science of Colombia. He is a professor at the Faculty of Medicine of the Fundacion Universitaria Autonoma de las Americas, in Pereira, Risaralda, Colombia. He is an External Professor, Master in Research on Tropical Medicine and International Health, Universitat de Barcelona, Spain. He is also a professor at the Master in Clinical Epidemiology and Biostatistics, Universidad Científica del Sur, Lima, Peru. In 2021 he has been awarded the “Raul Isturiz Award” Medal of the API. Also, in 2021, he was awarded with the “Jose Felix Patiño” Asclepius Staff Medal of the Colombian Medical College, due to his scientific contributions to COVID-19 during the pandemic. He is currently the Editor in Chief of the journal Travel Medicine and Infectious Diseases. His Scopus H index is 47 (Google Scholar H index, 68).",institutionString:"Institución Universitaria Visión de las Américas, Colombia",institution:null}]},{type:"book",id:"7839",title:"Malaria",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7839.jpg",slug:"malaria",publishedDate:"December 11th 2019",editedByType:"Edited by",bookSignature:"Fyson H. Kasenga",hash:"91cde4582ead884cb0f355a19b67cd56",volumeInSeries:4,fullTitle:"Malaria",editors:[{id:"86725",title:"Dr.",name:"Fyson",middleName:"Hanania",surname:"Kasenga",slug:"fyson-kasenga",fullName:"Fyson Kasenga",profilePictureURL:"https://mts.intechopen.com/storage/users/86725/images/system/86725.jpg",biography:"Dr. Kasenga is a graduate of Tumaini University, Kilimanjaro Christian Medical College, Moshi, Tanzania and Umeå University, Sweden. He obtained a Master’s degree in Public Health and PhD in Public Health and Epidemiology. He has a background in Clinical Medicine and has taken courses at higher diploma levels in public health from University of Transkei, Republic of South Africa, and African Medical and Research Foundation (AMREF) in Nairobi, Kenya. Dr. Kasenga worked in different places in and outside Malawi, and has held various positions, such as Licensed Medical Officer, HIV/AIDS Programme Officer, HIV/AIDS resource person in the International Department of Diakonhjemet College, Oslo, Norway. He also managed an Integrated HIV/AIDS Prevention programme for over 5 years. He is currently working as a Director for the Health Ministries Department of Malawi Union of the Seventh Day Adventist Church. Dr. Kasenga has published over 5 articles on HIV/AIDS issues focusing on Prevention of Mother to Child Transmission of HIV (PMTCT), including a book chapter on HIV testing counseling (currently in press). 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He was elected a Yangtze River Scholars Distinguished Professor in 2013, a member of the International Statistical Institute (ISI) in 2016, a member of the board of the International Chinese Statistical Association (ICSA) in 2018, and a fellow of the Institute of Mathematical Statistics (IMS) in 2021. He received the ICSA Outstanding Service Award in 2018 and the National Science Foundation for Distinguished Young Scholars of China in 2012. He serves as a member of the editorial board of Statistics and Its Interface and Journal of Systems Science and Complexity. He is also a field editor for Communications in Mathematics and Statistics. His research interests include biostatistics, empirical likelihood, missing data analysis, variable selection, high-dimensional data analysis, Bayesian statistics, and data science. He has published more than 190 research papers and authored five books.",institutionString:"Yunnan University",institution:{name:"Yunnan University",country:{name:"China"}}},{id:"1177",title:"Prof.",name:"António",middleName:"J. R.",surname:"José Ribeiro Neves",slug:"antonio-jose-ribeiro-neves",fullName:"António José Ribeiro Neves",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/1177/images/system/1177.jpg",biography:"Prof. António J. R. Neves received a Ph.D. in Electrical Engineering from the University of Aveiro, Portugal, in 2007. Since 2002, he has been a researcher at the Institute of Electronics and Informatics Engineering of Aveiro. Since 2007, he has been an assistant professor in the Department of Electronics, Telecommunications, and Informatics, University of Aveiro. He is the director of the undergraduate course on Electrical and Computers Engineering and the vice-director of the master’s degree in Electronics and Telecommunications Engineering. He is an IEEE Senior Member and a member of several other research organizations worldwide. His main research interests are computer vision, intelligent systems, robotics, and image and video processing. He has participated in or coordinated several research projects and received more than thirty-five awards. He has 161 publications to his credit, including books, book chapters, journal articles, and conference papers. He has vast experience as a reviewer of several journals and conferences. As a professor, Dr. Neves has supervised several Ph.D. and master’s students and was involved in more than twenty-five different courses.",institutionString:null,institution:{name:"University of Aveiro",country:{name:"Portugal"}}},{id:"11317",title:"Dr.",name:"Francisco",middleName:null,surname:"Javier Gallegos-Funes",slug:"francisco-javier-gallegos-funes",fullName:"Francisco Javier Gallegos-Funes",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/11317/images/system/11317.png",biography:"Francisco J. Gallegos-Funes received his Ph.D. in Communications and Electronics from the Instituto Politécnico Nacional de México (National Polytechnic Institute of Mexico) in 2003. He is currently an associate professor in the Escuela Superior de Ingeniería Mecánica y Eléctrica (Mechanical and Electrical Engineering Higher School) at the same institute. His areas of scientific interest are signal and image processing, filtering, steganography, segmentation, pattern recognition, biomedical signal processing, sensors, and real-time applications.",institutionString:"Instituto Politécnico Nacional",institution:{name:"Instituto Politécnico Nacional",country:{name:"Mexico"}}},{id:"428449",title:"Dr.",name:"Ronaldo",middleName:null,surname:"Ferreira",slug:"ronaldo-ferreira",fullName:"Ronaldo Ferreira",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/428449/images/21449_n.png",biography:null,institutionString:null,institution:{name:"University of Aveiro",country:{name:"Portugal"}}},{id:"165328",title:"Dr.",name:"Vahid",middleName:null,surname:"Asadpour",slug:"vahid-asadpour",fullName:"Vahid Asadpour",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/165328/images/system/165328.jpg",biography:"Vahid Asadpour, MS, Ph.D., is currently with the Department of Research and Evaluation, Kaiser Permanente Southern California. He has both an MS and Ph.D. in Biomedical Engineering. He was previously a research scientist at the University of California Los Angeles (UCLA) and visiting professor and researcher at the University of North Dakota. He is currently working in artificial intelligence and its applications in medical signal processing. In addition, he is using digital signal processing in medical imaging and speech processing. Dr. Asadpour has developed brain-computer interfacing algorithms and has published books, book chapters, and several journal and conference papers in this field and other areas of intelligent signal processing. He has also designed medical devices, including a laser Doppler monitoring system.",institutionString:"Kaiser Permanente Southern California",institution:null},{id:"169608",title:"Prof.",name:"Marian",middleName:null,surname:"Găiceanu",slug:"marian-gaiceanu",fullName:"Marian Găiceanu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/169608/images/system/169608.png",biography:"Prof. Dr. Marian Gaiceanu graduated from the Naval and Electrical Engineering Faculty, Dunarea de Jos University of Galati, Romania, in 1997. He received a Ph.D. (Magna Cum Laude) in Electrical Engineering in 2002. Since 2017, Dr. Gaiceanu has been a Ph.D. supervisor for students in Electrical Engineering. He has been employed at Dunarea de Jos University of Galati since 1996, where he is currently a professor. Dr. Gaiceanu is a member of the National Council for Attesting Titles, Diplomas and Certificates, an expert of the Executive Agency for Higher Education, Research Funding, and a member of the Senate of the Dunarea de Jos University of Galati. He has been the head of the Integrated Energy Conversion Systems and Advanced Control of Complex Processes Research Center, Romania, since 2016. He has conducted several projects in power converter systems for electrical drives, power quality, PEM and SOFC fuel cell power converters for utilities, electric vehicles, and marine applications with the Department of Regulation and Control, SIEI S.pA. (2002–2004) and the Polytechnic University of Turin, Italy (2002–2004, 2006–2007). He is a member of the Institute of Electrical and Electronics Engineers (IEEE) and cofounder-member of the IEEE Power Electronics Romanian Chapter. He is a guest editor at Energies and an academic book editor for IntechOpen. He is also a member of the editorial boards of the Journal of Electrical Engineering, Electronics, Control and Computer Science and Sustainability. Dr. Gaiceanu has been General Chairman of the IEEE International Symposium on Electrical and Electronics Engineering in the last six editions.",institutionString:'"Dunarea de Jos" University of Galati',institution:{name:'"Dunarea de Jos" University of Galati',country:{name:"Romania"}}},{id:"4519",title:"Prof.",name:"Jaydip",middleName:null,surname:"Sen",slug:"jaydip-sen",fullName:"Jaydip Sen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/4519/images/system/4519.jpeg",biography:"Jaydip Sen is associated with Praxis Business School, Kolkata, India, as a professor in the Department of Data Science. His research areas include security and privacy issues in computing and communication, intrusion detection systems, machine learning, deep learning, and artificial intelligence in the financial domain. He has more than 200 publications in reputed international journals, refereed conference proceedings, and 20 book chapters in books published by internationally renowned publishing houses, such as Springer, CRC press, IGI Global, etc. Currently, he is serving on the editorial board of the prestigious journal Frontiers in Communications and Networks and in the technical program committees of a number of high-ranked international conferences organized by the IEEE, USA, and the ACM, USA. He has been listed among the top 2% of scientists in the world for the last three consecutive years, 2019 to 2021 as per studies conducted by the Stanford University, USA.",institutionString:"Praxis Business School",institution:null},{id:"320071",title:"Dr.",name:"Sidra",middleName:null,surname:"Mehtab",slug:"sidra-mehtab",fullName:"Sidra Mehtab",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00002v6KHoQAM/Profile_Picture_1584512086360",biography:"Sidra Mehtab has completed her BS with honors in Physics from Calcutta University, India in 2018. She has done MS in Data Science and Analytics from Maulana Abul Kalam Azad University of Technology (MAKAUT), Kolkata, India in 2020. Her research areas include Econometrics, Time Series Analysis, Machine Learning, Deep Learning, Artificial Intelligence, and Computer and Network Security with a particular focus on Cyber Security Analytics. Ms. Mehtab has published seven papers in international conferences and one of her papers has been accepted for publication in a reputable international journal. She has won the best paper awards in two prestigious international conferences – BAICONF 2019, and ICADCML 2021, organized in the Indian Institute of Management, Bangalore, India in December 2019, and SOA University, Bhubaneswar, India in January 2021. Besides, Ms. Mehtab has also published two book chapters in two books. Seven of her book chapters will be published in a volume shortly in 2021 by Cambridge Scholars’ Press, UK. Currently, she is working as the joint editor of two edited volumes on Time Series Analysis and Forecasting to be published in the first half of 2021 by an international house. Currently, she is working as a Data Scientist with an MNC in Delhi, India.",institutionString:"NSHM College of Management and Technology",institution:{name:"Association for Computing Machinery",country:{name:"United States of America"}}},{id:"226240",title:"Dr.",name:"Andri Irfan",middleName:null,surname:"Rifai",slug:"andri-irfan-rifai",fullName:"Andri Irfan Rifai",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/226240/images/7412_n.jpg",biography:"Andri IRFAN is a Senior Lecturer of Civil Engineering and Planning. He completed the PhD at the Universitas Indonesia & Universidade do Minho with Sandwich Program Scholarship from the Directorate General of Higher Education and LPDP scholarship. He has been teaching for more than 19 years and much active to applied his knowledge in the project construction in Indonesia. His research interest ranges from pavement management system to advanced data mining techniques for transportation engineering. He has published more than 50 papers in journals and 2 books.",institutionString:null,institution:{name:"Universitas Internasional Batam",country:{name:"Indonesia"}}},{id:"314576",title:"Dr.",name:"Ibai",middleName:null,surname:"Laña",slug:"ibai-lana",fullName:"Ibai Laña",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/314576/images/system/314576.jpg",biography:"Dr. Ibai Laña works at TECNALIA as a data analyst. He received his Ph.D. in Artificial Intelligence from the University of the Basque Country (UPV/EHU), Spain, in 2018. He is currently a senior researcher at TECNALIA. His research interests fall within the intersection of intelligent transportation systems, machine learning, traffic data analysis, and data science. He has dealt with urban traffic forecasting problems, applying machine learning models and evolutionary algorithms. He has experience in origin-destination matrix estimation or point of interest and trajectory detection. Working with large volumes of data has given him a good command of big data processing tools and NoSQL databases. He has also been a visiting scholar at the Knowledge Engineering and Discovery Research Institute, Auckland University of Technology.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"314575",title:"Dr.",name:"Jesus",middleName:null,surname:"L. Lobo",slug:"jesus-l.-lobo",fullName:"Jesus L. Lobo",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/314575/images/system/314575.png",biography:"Dr. Jesús López is currently based in Bilbao (Spain) working at TECNALIA as Artificial Intelligence Research Scientist. In most cases, a project idea or a new research line needs to be investigated to see if it is good enough to take into production or to focus on it. That is exactly what he does, diving into Machine Learning algorithms and technologies to help TECNALIA to decide whether something is great in theory or will actually impact on the product or processes of its projects. So, he is expert at framing experiments, developing hypotheses, and proving whether they’re true or not, in order to investigate fundamental problems with a longer time horizon. He is also able to design and develop PoCs and system prototypes in simulation. He has participated in several national and internacional R&D projects.\n\nAs another relevant part of his everyday research work, he usually publishes his findings in reputed scientific refereed journals and international conferences, occasionally acting as reviewer and Programme Commitee member. Concretely, since 2018 he has published 9 JCR (8 Q1) journal papers, 9 conference papers (e.g. ECML PKDD 2021), and he has co-edited a book. He is also active in popular science writing data science stories for reputed blogs (KDNuggets, TowardsDataScience, Naukas). Besides, he has recently embarked on mentoring programmes as mentor, and has also worked as data science trainer.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"103779",title:"Prof.",name:"Yalcin",middleName:null,surname:"Isler",slug:"yalcin-isler",fullName:"Yalcin Isler",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRyQ8QAK/Profile_Picture_1628834958734",biography:"Yalcin Isler (1971 - Burdur / Turkey) received the B.Sc. degree in the Department of Electrical and Electronics Engineering from Anadolu University, Eskisehir, Turkey, in 1993, the M.Sc. degree from the Department of Electronics and Communication Engineering, Suleyman Demirel University, Isparta, Turkey, in 1996, the Ph.D. degree from the Department of Electrical and Electronics Engineering, Dokuz Eylul University, Izmir, Turkey, in 2009, and the Competence of Associate Professorship from the Turkish Interuniversity Council in 2019.\n\nHe was Lecturer at Burdur Vocational School in Suleyman Demirel University (1993-2000, Burdur / Turkey), Software Engineer (2000-2002, Izmir / Turkey), Research Assistant in Bulent Ecevit University (2002-2003, Zonguldak / Turkey), Research Assistant in Dokuz Eylul University (2003-2010, Izmir / Turkey), Assistant Professor at the Department of Electrical and Electronics Engineering in Bulent Ecevit University (2010-2012, Zonguldak / Turkey), Assistant Professor at the Department of Biomedical Engineering in Izmir Katip Celebi University (2012-2019, Izmir / Turkey). He is an Associate Professor at the Department of Biomedical Engineering at Izmir Katip Celebi University, Izmir / Turkey, since 2019. In addition to academics, he has also founded Islerya Medical and Information Technologies Company, Izmir / Turkey, since 2017.\n\nHis main research interests cover biomedical signal processing, pattern recognition, medical device design, programming, and embedded systems. He has many scientific papers and participated in several projects in these study fields. He was an IEEE Student Member (2009-2011) and IEEE Member (2011-2014) and has been IEEE Senior Member since 2014.",institutionString:null,institution:{name:"Izmir Kâtip Çelebi University",country:{name:"Turkey"}}},{id:"339677",title:"Dr.",name:"Mrinmoy",middleName:null,surname:"Roy",slug:"mrinmoy-roy",fullName:"Mrinmoy Roy",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/339677/images/16768_n.jpg",biography:"An accomplished Sales & Marketing professional with 12 years of cross-functional experience in well-known organisations such as CIPLA, LUPIN, GLENMARK, ASTRAZENECA across different segment of Sales & Marketing, International Business, Institutional Business, Product Management, Strategic Marketing of HIV, Oncology, Derma, Respiratory, Anti-Diabetic, Nutraceutical & Stomatological Product Portfolio and Generic as well as Chronic Critical Care Portfolio. A First Class MBA in International Business & Strategic Marketing, B.Pharm, D.Pharm, Google Certified Digital Marketing Professional. Qualified PhD Candidate in Operations and Management with special focus on Artificial Intelligence and Machine Learning adoption, analysis and use in Healthcare, Hospital & Pharma Domain. Seasoned with diverse therapy area of Pharmaceutical Sales & Marketing ranging from generating revenue through generating prescriptions, launching new products, and making them big brands with continuous strategy execution at the Physician and Patients level. Moved from Sales to Marketing and Business Development for 3.5 years in South East Asian Market operating from Manila, Philippines. Came back to India and handled and developed Brands such as Gluconorm, Lupisulin, Supracal, Absolut Woman, Hemozink, Fabiflu (For COVID 19), and many more. In my previous assignment I used to develop and execute strategies on Sales & Marketing, Commercialization & Business Development for Institution and Corporate Hospital Business portfolio of Oncology Therapy Area for AstraZeneca Pharma India Ltd. Being a Research Scholar and Student of ‘Operations Research & Management: Artificial Intelligence’ I published several pioneer research papers and book chapters on the same in Internationally reputed journals and Books indexed in Scopus, Springer and Ei Compendex, Google Scholar etc. Currently, I am launching PGDM Pharmaceutical Management Program in IIHMR Bangalore and spearheading the course curriculum and structure of the same. I am interested in Collaboration for Healthcare Innovation, Pharma AI Innovation, Future trend in Marketing and Management with incubation on Healthcare, Healthcare IT startups, AI-ML Modelling and Healthcare Algorithm based training module development. I am also an affiliated member of the Institute of Management Consultant of India, looking forward to Healthcare, Healthcare IT and Innovation, Pharma and Hospital Management Consulting works.",institutionString:null,institution:{name:"Lovely Professional University",country:{name:"India"}}},{id:"1063",title:"Prof.",name:"Constantin",middleName:null,surname:"Volosencu",slug:"constantin-volosencu",fullName:"Constantin Volosencu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/1063/images/system/1063.png",biography:"Prof. Dr. Constantin Voloşencu graduated as an engineer from\nPolitehnica University of Timișoara, Romania, where he also\nobtained a doctorate degree. He is currently a full professor in\nthe Department of Automation and Applied Informatics at the\nsame university. Dr. Voloşencu is the author of ten books, seven\nbook chapters, and more than 160 papers published in journals\nand conference proceedings. He has also edited twelve books and\nhas twenty-seven patents to his name. He is a manager of research grants, editor in\nchief and member of international journal editorial boards, a former plenary speaker, a member of scientific committees, and chair at international conferences. His\nresearch is in the fields of control systems, control of electric drives, fuzzy control\nsystems, neural network applications, fault detection and diagnosis, sensor network\napplications, monitoring of distributed parameter systems, and power ultrasound\napplications. He has developed automation equipment for machine tools, spooling\nmachines, high-power ultrasound processes, and more.",institutionString:'"Politechnica" University Timişoara',institution:null},{id:"221364",title:"Dr.",name:"Eneko",middleName:null,surname:"Osaba",slug:"eneko-osaba",fullName:"Eneko Osaba",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/221364/images/system/221364.jpg",biography:"Dr. Eneko Osaba works at TECNALIA as a senior researcher. He obtained his Ph.D. in Artificial Intelligence in 2015. He has participated in more than twenty-five local and European research projects, and in the publication of more than 130 papers. He has performed several stays at universities in the United Kingdom, Italy, and Malta. Dr. Osaba has served as a program committee member in more than forty international conferences and participated in organizing activities in more than ten international conferences. He is a member of the editorial board of the International Journal of Artificial Intelligence, Data in Brief, and Journal of Advanced Transportation. He is also a guest editor for the Journal of Computational Science, Neurocomputing, Swarm, and Evolutionary Computation and IEEE ITS Magazine.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"275829",title:"Dr.",name:"Esther",middleName:null,surname:"Villar-Rodriguez",slug:"esther-villar-rodriguez",fullName:"Esther Villar-Rodriguez",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/275829/images/system/275829.jpg",biography:"Dr. Esther Villar obtained a Ph.D. in Information and Communication Technologies from the University of Alcalá, Spain, in 2015. She obtained a degree in Computer Science from the University of Deusto, Spain, in 2010, and an MSc in Computer Languages and Systems from the National University of Distance Education, Spain, in 2012. Her areas of interest and knowledge include natural language processing (NLP), detection of impersonation in social networks, semantic web, and machine learning. Dr. Esther Villar made several contributions at conferences and publishing in various journals in those fields. Currently, she is working within the OPTIMA (Optimization Modeling & Analytics) business of TECNALIA’s ICT Division as a data scientist in projects related to the prediction and optimization of management and industrial processes (resource planning, energy efficiency, etc).",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"49813",title:"Dr.",name:"Javier",middleName:null,surname:"Del Ser",slug:"javier-del-ser",fullName:"Javier Del Ser",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/49813/images/system/49813.png",biography:"Prof. Dr. Javier Del Ser received his first PhD in Telecommunication Engineering (Cum Laude) from the University of Navarra, Spain, in 2006, and a second PhD in Computational Intelligence (Summa Cum Laude) from the University of Alcala, Spain, in 2013. He is currently a principal researcher in data analytics and optimisation at TECNALIA (Spain), a visiting fellow at the Basque Center for Applied Mathematics (BCAM) and a part-time lecturer at the University of the Basque Country (UPV/EHU). His research interests gravitate on the use of descriptive, prescriptive and predictive algorithms for data mining and optimization in a diverse range of application fields such as Energy, Transport, Telecommunications, Health and Industry, among others. In these fields he has published more than 240 articles, co-supervised 8 Ph.D. theses, edited 6 books, coauthored 7 patents and participated/led more than 40 research projects. He is a Senior Member of the IEEE, and a recipient of the Biscay Talent prize for his academic career.",institutionString:"Tecnalia Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"278948",title:"Dr.",name:"Carlos Pedro",middleName:null,surname:"Gonçalves",slug:"carlos-pedro-goncalves",fullName:"Carlos Pedro Gonçalves",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRcmyQAC/Profile_Picture_1564224512145",biography:'Carlos Pedro Gonçalves (PhD) is an Associate Professor at Lusophone University of Humanities and Technologies and a researcher on Complexity Sciences, Quantum Technologies, Artificial Intelligence, Strategic Studies, Studies in Intelligence and Security, FinTech and Financial Risk Modeling. He is also a progammer with programming experience in:\n\nA) Quantum Computing using Qiskit Python module and IBM Quantum Experience Platform, with software developed on the simulation of Quantum Artificial Neural Networks and Quantum Cybersecurity;\n\nB) Artificial Intelligence and Machine learning programming in Python;\n\nC) Artificial Intelligence, Multiagent Systems Modeling and System Dynamics Modeling in Netlogo, with models developed in the areas of Chaos Theory, Econophysics, Artificial Intelligence, Classical and Quantum Complex Systems Science, with the Econophysics models having been cited worldwide and incorporated in PhD programs by different Universities.\n\nReceived an Arctic Code Vault Contributor status by GitHub, due to having developed open source software preserved in the \\"Arctic Code Vault\\" for future generations (https://archiveprogram.github.com/arctic-vault/), with the Strategy Analyzer A.I. module for decision making support (based on his PhD thesis, used in his Classes on Decision Making and in Strategic Intelligence Consulting Activities) and QNeural Python Quantum Neural Network simulator also preserved in the \\"Arctic Code Vault\\", for access to these software modules see: https://github.com/cpgoncalves. He is also a peer reviewer with outsanding review status from Elsevier journals, including Physica A, Neurocomputing and Engineering Applications of Artificial Intelligence. Science CV available at: https://www.cienciavitae.pt//pt/8E1C-A8B3-78C5 and ORCID: https://orcid.org/0000-0002-0298-3974',institutionString:"University of Lisbon",institution:{name:"Universidade Lusófona",country:{name:"Portugal"}}},{id:"310576",title:"Prof.",name:"Erick Giovani",middleName:null,surname:"Sperandio Nascimento",slug:"erick-giovani-sperandio-nascimento",fullName:"Erick Giovani Sperandio Nascimento",position:null,profilePictureURL:"https://intech-files.s3.amazonaws.com/0033Y00002pDKxDQAW/ProfilePicture%202022-06-20%2019%3A57%3A24.788",biography:"Prof. Erick Sperandio is the Lead Researcher and professor of Artificial Intelligence (AI) at SENAI CIMATEC, Bahia, Brazil, also working with Computational Modeling (CM) and HPC. He holds a PhD in Environmental Engineering in the area of Atmospheric Computational Modeling, a Master in Informatics in the field of Computational Intelligence and Graduated in Computer Science from UFES. He currently coordinates, leads and participates in R&D projects in the areas of AI, computational modeling and supercomputing applied to different areas such as Oil and Gas, Health, Advanced Manufacturing, Renewable Energies and Atmospheric Sciences, advising undergraduate, master's and doctoral students. He is the Lead Researcher at SENAI CIMATEC's Reference Center on Artificial Intelligence. In addition, he is a Certified Instructor and University Ambassador of the NVIDIA Deep Learning Institute (DLI) in the areas of Deep Learning, Computer Vision, Natural Language Processing and Recommender Systems, and Principal Investigator of the NVIDIA/CIMATEC AI Joint Lab, the first in Latin America within the NVIDIA AI Technology Center (NVAITC) worldwide program. He also works as a researcher at the Supercomputing Center for Industrial Innovation (CS2i) and at the SENAI Institute of Innovation for Automation (ISI Automação), both from SENAI CIMATEC. He is a member and vice-coordinator of the Basic Board of Scientific-Technological Advice and Evaluation, in the area of Innovation, of the Foundation for Research Support of the State of Bahia (FAPESB). He serves as Technology Transfer Coordinator and one of the Principal Investigators at the National Applied Research Center in Artificial Intelligence (CPA-IA) of SENAI CIMATEC, focusing on Industry, being one of the six CPA-IA in Brazil approved by MCTI / FAPESP / CGI.br. He also participates as one of the representatives of Brazil in the BRICS Innovation Collaboration Working Group on HPC, ICT and AI. He is the coordinator of the Work Group of the Axis 5 - Workforce and Training - of the Brazilian Strategy for Artificial Intelligence (EBIA), and member of the MCTI/EMBRAPII AI Innovation Network Training Committee. He is the coordinator, by SENAI CIMATEC, of the Artificial Intelligence Reference Network of the State of Bahia (REDE BAH.IA). He leads the working group of experts representing Brazil in the Global Partnership on Artificial Intelligence (GPAI), on the theme \"AI and the Pandemic Response\".",institutionString:null,institution:null},{id:"241400",title:"Prof.",name:"Mohammed",middleName:null,surname:"Bsiss",slug:"mohammed-bsiss",fullName:"Mohammed Bsiss",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/241400/images/8062_n.jpg",biography:null,institutionString:null,institution:null},{id:"276128",title:"Dr.",name:"Hira",middleName:null,surname:"Fatima",slug:"hira-fatima",fullName:"Hira Fatima",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/276128/images/14420_n.jpg",biography:"Dr. Hira Fatima\nAssistant Professor\nDepartment of Mathematics\nInstitute of Applied Science\nMangalayatan University, Aligarh\nMobile: no : 8532041179\nhirafatima2014@gmal.com\n\nDr. Hira Fatima has received his Ph.D. degree in pure Mathematics from Aligarh Muslim University, Aligarh India. Currently working as an Assistant Professor in the Department of Mathematics, Institute of Applied Science, Mangalayatan University, Aligarh. She taught so many courses of Mathematics of UG and PG level. Her research Area of Expertise is Functional Analysis & Sequence Spaces. She has been working on Ideal Convergence of double sequence. She has published 17 research papers in National and International Journals including Cogent Mathematics, Filomat, Journal of Intelligent and Fuzzy Systems, Advances in Difference Equations, Journal of Mathematical Analysis, Journal of Mathematical & Computer Science etc. She has also reviewed few research papers for the and international journals. She is a member of Indian Mathematical Society.",institutionString:null,institution:null},{id:"417317",title:"Mrs.",name:"Chiedza",middleName:null,surname:"Elvina Mashiri",slug:"chiedza-elvina-mashiri",fullName:"Chiedza Elvina Mashiri",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Midlands State University",country:{name:"Zimbabwe"}}},{id:"352140",title:"Dr.",name:"Edina",middleName:null,surname:"Chandiwana",slug:"edina-chandiwana",fullName:"Edina Chandiwana",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Midlands State University",country:{name:"Zimbabwe"}}},{id:"342259",title:"B.Sc.",name:"Leonard",middleName:null,surname:"Mushunje",slug:"leonard-mushunje",fullName:"Leonard Mushunje",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Midlands State University",country:{name:"Zimbabwe"}}},{id:"347042",title:"Mr.",name:"Maxwell",middleName:null,surname:"Mashasha",slug:"maxwell-mashasha",fullName:"Maxwell Mashasha",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Midlands State University",country:{name:"Zimbabwe"}}},{id:"2941",title:"Dr.",name:"Alberto J.",middleName:"Jorge",surname:"Rosales-Silva",slug:"alberto-j.-rosales-silva",fullName:"Alberto J. 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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",hasOnlineFirst:!1,hasPublishedBooks:!0,annualVolume:11420,editor:{id:"294154",title:"Prof.",name:"George",middleName:null,surname:"Papakostas",slug:"george-papakostas",fullName:"George Papakostas",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002hYaGbQAK/Profile_Picture_1624519712088",biography:"George A. Papakostas has received a diploma in Electrical and Computer Engineering in 1999 and the M.Sc. and Ph.D. degrees in Electrical and Computer Engineering in 2002 and 2007, respectively, from the Democritus University of Thrace (DUTH), Greece. Dr. Papakostas serves as a Tenured Full Professor at the Department of Computer Science, International Hellenic University, Greece. Dr. Papakostas has 10 years of experience in large-scale systems design as a senior software engineer and technical manager, and 20 years of research experience in the field of Artificial Intelligence. Currently, he is the Head of the “Visual Computing” division of HUman-MAchines INteraction Laboratory (HUMAIN-Lab) and the Director of the MPhil program “Advanced Technologies in Informatics and Computers” hosted by the Department of Computer Science, International Hellenic University. He has (co)authored more than 150 publications in indexed journals, international conferences and book chapters, 1 book (in Greek), 3 edited books, and 5 journal special issues. His publications have more than 2100 citations with h-index 27 (GoogleScholar). His research interests include computer/machine vision, machine learning, pattern recognition, computational intelligence. \nDr. Papakostas served as a reviewer in numerous journals, as a program\ncommittee member in international conferences and he is a member of the IAENG, MIR Labs, EUCogIII, INSTICC and the Technical Chamber of Greece (TEE).",institutionString:null,institution:{name:"International Hellenic University",institutionURL:null,country:{name:"Greece"}}},editorTwo:null,editorThree:null,series:{id:"14",title:"Artificial Intelligence",doi:"10.5772/intechopen.79920",issn:"2633-1403"},editorialBoard:[{id:"1177",title:"Prof.",name:"António",middleName:"J. 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