Oral care during head and neck radiotherapy (modified from Refs. [68–70]).
\r\n\tThere are a variety of approaches to reversing biodiversity loss, ranging from economic, to ecological and ethical. The utilitarian approach to conservation, bolstered by the concept of ecosystem services, can be utilized to improve the conservation case by supplementing the burgeoning biodiversity rhetoric. To address this issue, a pluralistic approach to biodiversity is required for conservation and sustainability.
",isbn:"978-1-80356-339-8",printIsbn:"978-1-80356-338-1",pdfIsbn:"978-1-80356-340-4",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,hash:"ab014f8ed1669757335225786833e9a9",bookSignature:"Dr. Gopal Shukla, Dr. Jahangeer Bhat and Dr. Sumit Chakravarty",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11460.jpg",keywords:"Ecosystem Services, Intrinsic Value, Global Trends in Biodiversity Loss, Convention on Biological Diversity, Utilitarian Value, Biodiversity Conservation, Perception, In Situ and Ex Situ Conservation, Nature Conservation, Sustainable Development Goals, Drivers of Degradation, Prioritizing Biodiversity",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"February 17th 2022",dateEndSecondStepPublish:"April 22nd 2022",dateEndThirdStepPublish:"June 21st 2022",dateEndFourthStepPublish:"September 9th 2022",dateEndFifthStepPublish:"November 8th 2022",remainingDaysToSecondStep:"a month",secondStepPassed:!0,currentStepOfPublishingProcess:3,editedByType:null,kuFlag:!1,biosketch:"Dr. Gopal Shukla, prior to becoming an assistant professor, has worked under NAIP (National Agricultural Innovation Project), NICRA ( National Innovations on Climate Resilient Agriculture), and SERB (Science and Engineering Research Board) projects. 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Most often, radiotherapy (RT) is delivered after surgery, alone or in combination with chemotherapy to assure better locoregional control. Indication for postoperative radio‐/chemoradiotherapy includes: T3 or T4 tumor, close (<5 mm) or positive surgical margin, positive cervical lymph nodes with or without extracapsular spread, lymphovascular and/or perineural invasion. RT can be delivered as a primary treatment in cases of unresectable disease, compromised patient\'s health, unfavorable cosmetic, or functional outcome of anticipated surgery and recurrent disease with multiple previous surgeries [1].
\nHead and neck cancer patients usually receive the total dose of 60–70 Gy divided into 2 Gy daily fractions (5 days a week) over 6–7 weeks. Along with therapeutic action on tumor cells, ionizing radiation causes damage to surrounding healthy tissues located in the radiation field. Radiation induced damage to surrounding healthy tissues is responsible for complications that arise during and after radiotherapy. There are several reasons why these complications are very frequent in the oral cavity:
\nfast turnover rate of oral mucosal cells
rich and complex oral microflora
mucosal microtrauma during mastication [2]
Most orofacial complications are dose‐dependent and side effects occur when doses greater than 45 Gy are delivered. Apart from the total dose, intensity of oral side effects depends on the fraction size and scheduling, field size/affected tissue volume, and concomitant use of chemotherapy. In order to minimize the irradiation damage to surrounding tissue, novel techniques such as 3D (three‐dimensional) conformal radiotherapy and intensity‐modulated radiotherapy (IMRT) are introduced. These techniques allow more precise design of radiation field enabling delivery of high doses to the target tissue while reducing doses to surrounding structures [3].
\nRadiation‐related oral side effects can be acute or chronic. Acute side effects begin during the RT and last several weeks after the therapy cessation. Acute side effects include
\noral mucositis
taste disorder
xerostomia
Chronic oral side effects begin several weeks, months, or even years after the RT. Chronic side effects are as follows:
\ntrismus
radiation‐induced dental caries
osteoradionecrosis [4]
Patients undergoing RT demand a multidisciplinary approach in order to reduce the intensity of radiation‐induced oral side effects and understand the role of dentist and themselves in their prevention and therapy.
\nOral mucositis (OM) is the most common complication of head and neck irradiation affecting 80–90% of the patients. Oral mucositis is defined as reactive inflammation of oral mucosa due to radiation‐induced damage of cellular DNA and subsequent cellular death of basal keratinocytes. Mucositis manifests as ulcerative inflammation of the oral mucosa (Figure 1) which can cause severe pain, deteriorated oral function, increased drug consumption, and can lead to temporary treatment interruption with consequent reduction in therapeutic effect [4].
\nOral mucositis.
Pathogenesis of oral mucositis can be divided into five stages: initiation, upregulation/activation, signal amplification, ulceration, and healing. First step, initiation is characterized by radiation‐induced DNA damage and generation of reactive oxygen species (ROS). In the next step, ROS activate nuclear factor‐κB (NF‐κB) transcription factor, which further upregulates genes responsible for the synthesis of pro‐inflammatory cytokines like interleukin 6 (IL‐6) and tumor necrosis factor alpha (TNF‐α). As the RT continues, generated pro‐inflammatory cytokines further amplify inflammatory mucosal damage by providing positive feedback on NF‐κB activation. In the next stage, patients develop ulcerations which are colonized by oral microorganisms that further promote epithelial damage. Last stage characterized by healing of the ulcers occurs when radiation‐induced DNA damage stops [5].
\nFirst clinical sign of oral mucositis is whitish appearance of oral mucosa which begins at the end of the first week of irradiation. In the third week, patients usually develop ulcerations covered with fibrinous pseudomembranes that are prone to secondary infection. Mucositis persists throughout the radiotherapy with a peak at the end of irradiation and lasts for 2–4 weeks after treatment cessation. Intensity of mucositis is strongly dependent on the total dose, fraction size, field size, number and frequency of fraction delivery, and type of ionizing irradiation [4, 5].
\nEven though there are numerous scales for the assessment/classification of mucositis available, most commonly used scoring system is the one established by the World Health Organization [6–9]. The scoring system is very simple to apply and based on patient\'s ability to eat solid food. According to WHO, oral mucositis can be divided into four stages as follows [9]:
\nstage 0 = no pain
stage 1 = erythema and mild edema
stage 2 = erythema and ulcers, patient is able to eat solid food
stage 3 = erythema and ulcers, patient is unable to eat solid food
stage 4 = peroral alimentation is not possible
There is still no effective agent that could prevent the development of oral mucositis in patients undergoing head and neck irradiation [10]. The treatment of oral mucositis therefore remains symptomatic, aimed at relieving pain, preventing infection of oral lesions, and maintaining normal functioning of oral cavity.
\nXerostomia is one of the most frequent and debilitating side effects of head and neck RT. It develops acutely (early in the course of irradiation), but frequently remains chronic (permanent) complication (Figure 2). Lack of saliva affects the health of the entire oral cavity and favors the occurrence of other oral complications, which impair patient\'s quality of life, such as development of dental caries, oral infections, dysgeusia, dysphagia, oral discomfort, and pain [11]. Major salivary glands produce 70–80% of the total salivary flow. Parotid gland predominantly produces stimulated, watery saliva, and its serous acinar cells are more radiosensitive than mucous cells of submandibular and sublingual glands [12]. It seems that the extent of parotid irradiation is a major contributing factor for the development of xerostomia, as well as a total dose of received irradiation [3]. Xerostomia often remains permanent if radiation dose is greater than 40 Gy. Head and neck tumors are usually treated with a total dose greater than 60 Gy, during 6 weeks, which can lead to decrease in salivary production by 80% [2]. Together with quantitative effect on salivary flow, RT also changes the composition of saliva. Concentration of different ions and proteins in saliva rises, while the bicarbonate concentration decreases, causing a low salivary pH and a low buffering capacity [13, 14]. Quantitative and qualitative changes in saliva seriously impair patient\'s quality of life. Sparing salivary glands during irradiation, if possible, can reduce the long‐term reduction in salivary flow [11].
\nXerostomia.
During the RT, majority of patients experience complete or partial taste loss. According to a recent literature review, taste disorder affects 66.5% of patients undergoing RT alone and 76% of patients undergoing combined chemoradiotherapy [15].
\nTaste disorder is a result of two factors: (i) a direct radiation effect on the taste buds and (ii) changes in salivary flow and composition. Taste buds are very sensitive to irradiation and demonstrate signs of degeneration and atrophy at doses of 10 Gy [4]. Decreased salivary flow disrupts transport of flavor molecules to taste buds while changed ionic composition of saliva further impairs taste perception. Most patients report their taste disorder as mild. Impact of taste disorder on the quality of life is difficult to assess because patients often report taste disorder along with other, more severe side effects of head and neck irradiation like xerostomia, sticky saliva, and difficulty swallowing [15].
\nIn majority of cases, taste gradually returns to normal or near‐normal levels within 1 year after RT. Because of this transitory aspect, there is usually no need for treatment. However, in around 15% of patients, taste disorder can last longer. There have been cases of patients whose taste disorder lasted 5–7 years after RT. To date, no universally recommended preventive or management strategies are available [15].
\nThe primary cause of radiation‐induced dental caries is change in quality and quantity of saliva, due to radiation‐induced salivary gland damage. After RT, salivary viscosity is increased and its buffering capacity and pH are reduced. Salivary pH becomes cariogenic, decreasing from 7.0 to 5.0 and making minerals of enamel and dentin dissolve easily [16]. A defensive role of saliva is impaired, which leads to changes in oral flora of these patients. Within 3 months of completing RT, oral flora becomes more acidogenic and cariogenic because of increased concentration of
Radiation caries.
Osteoradionecrosis (ORN) is the most serious complication of head and neck RT, which affects the bone in irradiated area. RT alters collagen synthesis and induces inflammation and obliteration of the blood vessels that provide blood supply to the bone. Irradiated bone becomes hypovascularized and hypoxic, with impaired healing capacity [20]. The process is irreversible and progressive, and the risk of osteonecrosis is lifelong. The most commonly used definition of ORN implies exposed bone without healing for 3 months, without recurrence of the tumor [2], although there is no universally accepted definition in the literature. Due to the disagreement about the definition, there are no accurate data about the prevalence and incidence of ORN in the jaws. The reported relative frequency of ORN is between 0 and 7.1%, but patients with tumors localized in the oral cavity have higher relative frequency of ORN, up to 13.6% [21]. Results from one literature review report a weighed ORN prevalence of 7.4% for conventional radiotherapy, 5.1% for IMRT, 6.8% for chemoradiotherapy, and 5.3% for brachytherapy [22]. The literature shows that two‐thirds of ORN in the orofacial region appear after a traumatic event, such as tooth extractions, ill‐fitting dentures, biopsies, or periodontal dental procedures, while one‐third can appear spontaneously. The most frequently affected bone in the head and neck region is the mandible [21, 22].
\nRisk factors for the development of ORN include therapeutic dose and mode of irradiation or combined chemotherapy and radiotherapy. Doses greater than 60 Gy, use of brachytherapy, or combined chemo‐ and radiotherapy increases the risk of development of ORN, while hyperfractioned RT or moderately accelerated fractioned RT, even in greater doses, decrease the risk of its occurrence [23]. Other risk factors include poor oral hygiene, malnutrition, chronic trauma from ill‐fitting dentures, or acute trauma from surgical procedures in the jaw, especially in posterior mandible [24].
\nORN manifests as an area of exposed bone in the oral cavity (Figure 4). Symptoms of ORN include pain, dysgeusia, dysesthesia, halitosis, or food impaction in the area of exposed bone, although in early stages it can be asymptomatic. Untreated, it can lead to fistulas and pathological fractures of the bone (Figure 5) [20–24]. Still, there is no universally accepted classification system for ORN, which makes comparison of different studies difficult [25].
\nOsteoradionecrosis.
Osteoradionecrosis progressing to pathological fracture of the mandible (
Trismus can occur if temporomandibular joint and masticatory muscles are located in irradiated area during head and neck cancer therapy. Irradiation causes spasm and fibrosis of masticatory muscles, which limits mouth opening [26, 27]. Trismus is often defined as reduced mouth opening with interincisal space less than 35 mm, but there is no universally accepted definition in the literature which is the reason for a wide range of reported prevalence of trismus after head and neck RT, ranging from 5 to 38% of patients [28, 29]. Trismus is often underreported as RT side effect, although it seriously impairs quality of life, resulting with difficulties in patient\'s social life, affecting speech, food intake, and oral hygiene maintaining and even leading to depression [30]. Risk factors for the occurrence of the trismus are similar as for other late oral side effects of RT and include the total dose of radiation, fractionation regimen (mode of irradiation), treatment modality (conventional RT vs. intensity‐modulated radiotherapy (IMRT)), overall duration of RT, tumor location, and poor physical condition [26, 27, 31, 32]. Some results show that a total dose of RT greater than 55 Gy increases the incidence of trismus up to 47%, while treatment modality as conventional RT compared to IMRT decreases the mean incidence of trismus from 25.4 to 5% [27, 33]. Patients receiving RT to head and neck area should be instructed in rehabilitative exercises during and after RT to prevent the trismus development.
\nAs early as 1995, experts of the health system of the United Kingdom concluded that health policy in addition to acting on the length of survival of patients with head and neck tumors (PwHNTs) must take all measures to increase their quality of life [34].
\nOver decades, modern treatment modalities have increased the survival rate of these patients, owing to the great efforts invested. However, it is obvious that the quality of life to which PwHNTs are destined is far below the level of being comfortable and functional [35]. The function of the upper aerodigestive tract is impaired following the treatment in PwHNT, especially of structures related to the oral tissues. The function of the mouth is a very important aspect of the quality of life of cancer patients in general [36]. While significant developments occur in the field of treatment, especially in terms of procurement of modern equipment for RT, as well as in education of radiation oncologists and medical physicists, which improves the survival rate of patients, we have to ask ourselves: what about the quality of life of our PwHNT following RT?
\nOral toxicities related to RT are discussed in detail elsewhere in the text. Although oral mucositis does not last longer than a few weeks after completion of RT, its most serious consequence is interruption of RT [37]. The practice in which oncologists would temporarily interrupt radiation in case of severe form of mucositis “until the PwHNT gets his oral situation improved” might still exist. This practice reduces the cure rate by 1–2% per each day of interruption [38]. Therefore, the dentists must take all measures to help PwHNT withstand the uninterrupted treatment, no matter how uncomfortable it gets.
\nAlthough it might require a lot of effort in continuous communication with oncology surgeons and oncologists, our profession must strive to provide arguments against interruption of radiation. Dentists need to convince oncologists that good preparation of PwHNT and close monitoring during RT at 2‐week intervals can effectively prevent the need for interruption of RT, and this practice should be ever so rarer. Centers that include collaborative dentist would not normally interrupt radiation in cases of severe mucositis.
\nAs discussed elsewhere in the chapter, there are also lifelong complications of head and neck RT, which ultimately can cause pathological fractures of the jaw and, indirectly, death. It is a cascade process with connected temporal occurrences. Briefly described, it begins with the destruction of acini of the salivary glands by radiation. The teeth, as there is no saliva, cannot defend demineralization, which leads to the inevitable radiation caries. The destruction of tooth leads toward the need for extraction, which is a high‐risk procedure in the irradiated bone, because of RT‐induced hypovascularity, ultimately leading toward ORN [39]. ORN can be so extensive that it may cause pathological fracture of the mandible (Figure 5). This “domino effect” could be prevented if dental profession is included into multidisciplinary approach.
\nGood protocols for an interdisciplinary approach to PwHNT clearly emphasize that the dentist is a part of the oncology team [40]. Unfortunately, is not usually so. There are exceptions in most developed countries, but it really is not a part of standard of care, especially in developing countries such as Croatia. The causes of such inappropriate practices lay on both sides of the bridge: medical doctor (head and neck surgeon) generally is not aware of the true significance and is not easily bothered to spend his limited energy on oral complications. A dentist, on the other hand, often has “better things to do” than to deal with a handful of neglected people of low socioeconomic status, who seem hopelessly ill. It could be due to personal ignorance on the subject, and due to a fear to treat PwHNT. And so, our task is twofold: as representatives of the profession called “oral medicine” to build a bridge between our fellow dentists and fellow medical doctors, and to strive to persuade them how important it is to cooperate. In addition, we have to introduce an educational intervention among fellow dentists to foster their engagement in this important activity. What we still do not know is how to motivate fellow dentists to enthusiastically participate in the care of PwHNT. Until then, only few institutions in Croatia, such as ours, will remain one of the few places that provide this type of care.
\nDentists’ activities are directed to adherence to guidelines for oral care, which improve the quality of life in PwHNT, especially those who are treated with RT. Those include the reduction of the inevitable side effects of treatment, as well as the prevention of long‐term complications of treatment.
\nOral care needs to be based on the good practices from developed countries. The US National Comprehensive Cancer Network (“National Comprehensive Cancer Network,” NCCN) brings together 26 of the top cancer centers in the United States and publishes guidelines for good clinical practice of treating head and neck tumors [41]. According to their guidelines, it is clearly stated that patients should be referred to dental evaluation before the treatment of any head and neck cancer site: lip cancer, oral cavity, oropharynx, hypopharynx, nasopharynx, glottic, and supraglottic larynx, paranasal sinuses (pp. 11–59). With the obligatory oral and dental evaluation and treatment before cancer treatment, NCCN guidelines emphasize the necessary oral evaluation and care during and after radiotherapy, stating that dental evaluation is recommended for oral cavity and all sites exposed to significant radiotherapy (p. 83) [41]. As a mandatory postulate, the NCCN approach describes the integration of treatment, stating that it is critically important that a multidisciplinary evaluation and treatment are prospectively coordinated and integrated by all disciplines involved in the care before starting any treatment (p. 84) [41].
\nTiming of RT as the part of multimodal treatment is important. It is well established that time elapsed between surgery and RT inversely affects the prognosis [42]. There are, however, papers questioning this concept, but today it is considered the best to start RT 6 weeks following the surgery [43]. This leaves enough time for dental treatment to be completed before the RT.
\nHowever, it is not unusual that dentists sees PwHNT scheduled for RT, who comes at their first dental appointment only several days before the actual start of RT. If a dentist extracts their teeth, he would be causing further postponing of RT, which may be disastrous for the patient. Today, thanks to better planning in health care, waiting for RT is not so long anymore (at least in the institutions we work with), but the PwHNTs also come to point of oral care soon after discharge after surgery, which is early enough so that all dental procedures can be performed at a normal pace prior to the RT. This minimizes the risk of toxicities, eliminating the need for extractions after radiation. During and after RT, specific procedures are followed, as discussed elsewhere in the chapter.
\nGuidelines of the British Society for Disability and Oral Health, by Kumar et al., offer an elaborate approach to pathways of oral care in PwHNT [44]. Their basic postulate, without which we will certainly fail, is that clear pathway of care is necessary if we want to prevent or minimize oral complications. Regardless of how simple this may look, the lack of “clear pathway of care” was what caused the previous absence of this specific care. It requires strong dedication, exceptional effort, time, and preparedness for countless disappointments along the journey our profession takes in order to foster this type of oral care.
\nOne should be aware that most of PwHNTs are not easy to motivate for compliance to oral care. It is very difficult to explain PwHNT how important the preventative effect of fluoridation is, when combined with good oral hygiene. A typical PwHNT has a history of consuming large amounts of alcohol and tobacco products, and is not easily motivated to suddenly start adhering to very strict oral hygiene measures. However, the efforts lead to success in a considerable number of patients.
\nDentists should be aware of obstacles inherent in most health systems. One of them is was that primary care dentists usually are unprepared and uninterested to participate in oral care. The probable reason is the lack of specific knowledge and skills. These patients should be continuously motivated, closely followed up, and helped to obtain good adherence to our recommendations. If their primary care dentist is not collaborating with specialists, PwHNT most certainly will not comply.
\nSpecialists should write very extensive medical histories, explaining the primary care dentist what and why certain dental procedures must be done in their offices and the therapeutic rationale behind these procedures. These are written dental recommendations with an educational component. Secondary and tertiary care professionals who coordinate oral care should always clearly emphasize that they would be available for telephone or other types of consultation. Furthermore, it has been noted that the advice on oral and dental complications of head and neck RT treatment communicated by head and neck surgeon had much more impact on patients than if that same advice was communicated by the responsible dentist. It is therefore of utmost importance that head and neck surgeon possesses basic knowledge of the subject matter and that is willing to firmly insist that PwHNT complies with oral health measures. Regardless of how disappointing this might be for oral care professionals, this discovery is very important and should help guiding efforts to change oral behavior in our PwHNT. Head and neck surgeons who assume a role of “oral health advocates” can help dentists to significantly increase patients’ compliance. We have observed that if surgeons also motivate patients for good oral care, a significant increase in compliance with the recommendations will be achieved [45]. The ideal would be that the oral assessment is introduced as a legal requirement before the radiation of the head and neck. Listed experiences should be of practical help to readers who plan to start this service [46].
\nPrior to the head and neck RT, all patients without exception should be referred for oral/dental care. There are no generally accepted evidence‐based clinical guidelines for dentists how to prepare patients for RT; however, it is rational to follow effective strategies from the relevant literature [47].
\nThe main purposes of pretreatment dental evaluation are as follows:
\nto prevent or minimize acute and chronic oral side effects associated with RT
to facilitate submission of RT and radiation‐induced sequelae
(1) The task of the dentist, as a member of the oncology team preparing the patients for head and neck RT, is to perform the following procedures:
\ntreatment of oral and dental diseases
implementation of preventive procedures
education of the patients
Since treating diseased oral tissues prior to RT prevents or minimizes the development of many radiation‐induced complications, a thorough oral examination before RT is essential. The fact that some patients are edentulous does not mean that for them dental management before, during, and after radiotherapy is not or is less important.
\nIn order to reveal the presence of periapical lesions, impacted teeth, general bone conditions, and tumor rarefications, a panoramic radiograph is performed [48]. Dental caries with or without root canal infection, necrotic pulps, periodontitis, periodontal abscesses, diseases of oral mucosa are additionally assessed trough clinical dental evaluation. Oral status is evaluated and recorded: present teeth, clinical and radiographic findings (carious lesions, oral mucosa status, periodontal status, salivary gland functional assessment, interincisal opening), presence of orthodontic devices, and denture use.
\nProphylactic dental clearance includes restorative treatments, periodontal scaling, fluoride therapy, and dental extractions. The following teeth need to be extracted [49]:
\nTeeth with advanced caries lesions with questionable pulpal status or pulpal involvement
Teeth with extensive periapical lesions
Teeth with signs of severe periodontal disease (advanced bone loss and mobility or furcation involvement)
Residual root tips not fully covered with bone or showing radiolucency
Impacted or incompletely erupted teeth, particularly third molars that are not fully covered by alveolar bone or that are in contact with the oral environment
Three weeks before radiation therapy begins, all dental treatments should be completed. In the case there is less than 10 days to the beginning of the RT, teeth extractions are delayed for the “window” period after radiation (within 5–6 months after completion of RT) [50].
\nThe elimination of all potential causes of local trauma is mandatory. It is known that ORN can develop also in edentulous patients [45] and therefore the adjustment of ill‐fitting dentures is necessary. It is important to remove sharp edges and protruding teeth fillings. Orthodontic braces should be removed before the beginning of the RT.
\nBesides teeth preservation and elimination of potential trauma, it is necessary that dentist educates the patient prior to RT. The dentist should explain the expected and possible RT‐induced complications. Patients must be aware that the salivary glands may be affected by irradiation, which can result in severe decrease of salivary function [51]. Radiation‐induced xerostomia is an important chronic side effect of RT that can lead to many oral diseases and patients should be warned on the rapid occurrence of dental caries [52]. Untreated on time, it results in the extraction of teeth and the possible development of ORN. During preirradiation, dental management dentist should strongly emphasize to the patients that postirradiation caries and following oral diseases are avoidable through the regular and meticulous dental hygiene, daily fluoridation, and regular dental checkups.
\nRegrettably, in addition to poor oral health, before RT in many head and neck squamous cell carcinoma patients, even from developed countries and regardless of their dental status, poor oral hygiene is common [45]. Patients should therefore receive optimal mouth care before RT begins. During the preirradiation treatment, it is important that the dentist provides patients with instructions for oral hygiene during and after radiation therapy.
\nIt is useful to provide the patient with the Fact Sheets created by the Oral Care Study Group of the Multinational Association of Supportive Care in Cancer (MASCC) and the International Society of Oral Oncology (ISOO) [53]. These are available online, multilingual, and written in plain language and the notable parts of the Fact Sheets are provided below along with their original section numbers.
\n1.3.1. Oral care advices that dentist should give to the patient before RT include instructions about [53]
\n1.3.1.1. proper toothbrushing: “Use a soft toothbrush. Brush before bed. Gently brush tongue. Brush within 30 minutes of eating.”
\n1.3.1.2. dental floss use: “Floss at least once daily with waxed floss.”
\n1.3.1.3. rinsing: “Rinse, swish and spit rinse several times after brushing or flossing. Ensure medicated rinses are done 20 minutes apart.
\nHOW TO MAKE YOUR MOUTH RINSE 1. Mix 1 teaspoon of baking soda and 1 teaspoon of salt with 4 cups of water. 2. Put the mouthwash in a container with a lid. 3. The mouthwash should be kept at room temperature. 4. Discard at the end of each day and make a new batch.
\nHOW TO USE YOUR MOUTH RINSE Shake well before using. • Rinse and gargle with one tablespoon (15 mL) and then spit out. • Repeat 2 or 3 times at each use. • Use mouthwash every 2 hours during the day.”
\n1.3.1.4. oral moisturizing: “Moisturize nasal passages through the night with a steam vaporizer in your room. Moisturize with mouth rinse and water based lubricants often. Avoid petroleum jelly and glycerin products.”
\n1.3.1.5. lip care: “Use water‐soluble, wax‐based, or oil‐based lubricants. • Apply after cleaning, at bedtime and as needed. Do not apply petroleum Jelly.”
\n1.3.3.6. fluoridation
\n“INSTRUCTIONS FOR USE OF FLUORIDE TRAYS 1. Brush and floss before wearing trays. 2. Fill the grooves of the trays 1/3 full with gel. 3. Insert tray and spit out any excess gel. 4. Leave the tray in for 5 minutes. • Use at bedtime for longer lasting results. • Brush trays and air dry after each use. • Do not use hot water to clean trays (hot water will distort the tray). • Do not eat, drink or rinse for 30 minutes after tray use.”
\nBesides explaining how to perform fluoridation, dentist should emphasize the importance of fluoridation in preventing post‐radiation dental caries.
\n1.3.1.7. Denture care instructions
\n“• Keep your dentures out as much as possible. • Remove dentures, plates and prostheses before brushing. • Brush and rinse dentures after meals and before bed. • Soak dentures in cleansing solution for at least 8 hours. • If you are on antifungal therapy, soak in anti‐fungal solution.” [53]
\nEdentulous patient should also be instructed to remove dentures during RT. [48]
\nAs a member of oncology team, the dentist should also explain to the patients:
\n1.3.2. The necessity of avoiding the consumption of cigarettes and alcohol
\n1.3.3. The necessity of regular dental visits during and after RT.
\nDental consultation should always be in order prior to RT. During the first pre irradiation dental visit, patient should become aware that the dentist plays very important role in the management of head and neck cancer. They should realize that dental treatment before, during, and after head and neck RT is mandatory part of the more successful oncological therapy, which reduces the morbidity and mortality associated with RT.
\nOral care during head and neck RT is directed to the treatment of acute complications—oral mucositis, xerostomia and taste alterations.
\nMost pronounced symptom of oral mucositis is pain associated with dysphagia, odynophagia, and difficulty speaking. Symptoms usually begin in the third week of RT. Sometimes pain can be so intense that it can prevent oral food intake resulting in the need for parenteral nutrition, and in some cases discontinuation of RT. During this period, regular checkups at dental office every 7–10 days are recommended [54]. Up to now, a lot of treatment modalities for OM have been tested, but most of them with varying success.
\nThe treatment of OM is symptomatic, and it mainly consists of pain management and infection control. For the pain management, mouthwash containing topical anesthetic agent such as lidocaine is usually prescribed. Tetracaine, amethocaine, dyclonine, and benzocaine are also used for pain relief. The use of topical anesthetics allows patients to do regular daily activities such as eating and tooth brushing. Most of the studies, aimed at pain relief, reported less frequent interruption of RT, when topical anesthetic is used [55–57]. Administration of systemic analgesics, including opioids, is used in most patients with moderate or severe OM [58]. Except topical anesthetic, mouthwash can contain ant‐inflammatory and antimicrobial agents. A nonsteroidal anti‐inflammatory drug, benzydamine hydrochloride, is effective in reducing the intensity and duration of mucosal damage [10, 59]. Plaque control and oral hygiene is very important in controlling OM. Even though chlorhexidine (CHX) is not recommended in the prevention or management of oral mucositis, its administration may provide indirect benefits like plaque control and gingivitis prevention, as well as oral candidosis prevention [10]. In the case of oral candidosis, local antifungal drugs such as miconazole or nystatin are prescribed [54]. Cytoprotective drug amifostine and biological response modifiers (interleukin 1, interleukin 11, and transforming growth factor β) have also been introduced for management of OM, but with varying success and are not recommended [10]. From all of the above mentioned, it can be concluded that there is still no effective therapy for the prevention and treatment of OM. However, it is important to emphasize that dentist can significantly contribute to the implementation of RT in its entirety, without interrupting it.
\nThe prevalence of taste alterations in patients receiving RT is 66.5%, and approximately 15% of them continue to experience this problem after cessation of the treatment [15]. Taste disorder has a negative impact on quality of life and may cause malnutrition, weight loss, and in severe cases, significant morbidity. However, it is important to note that this problem is reversible, and in most of the patients spontaneous return of taste occurs within a year and therefore no specific treatment is necessary [15]. Additionally, up to now no efficient agent for treating or preventing RT related taste disorder exists [15]. Zinc gluconate, amifostine, and dietary counseling have been studied for that purpose. Studies that tested administration of zinc gluconate reported variable results [60, 61]. Zinc gluconate is therefore not recommended for taste disorder prevention in head and neck cancer patients, even though it was found to be beneficial in a noncancer idiopathic dysgeusia [15]. It has been shown that use of amifostine only modestly helps in reducing the severity of taste disorder, without affecting the incidence [62, 63]. Because of conflicting results of the studies which examined the use of amifostine in the prevention and/or management of taste disorder, recommendation is not to use it in head and neck cancer patients [15]. Use of dietary and educational counseling on the incidence and severity of dysgeusia in cancer patients has shown a minor impact on early‐onset taste disorder (30% vs. 40%), but with a greater effect on long‐term taste disorder (5% vs. 25%) [64].
\nIt is well known that salivary gland hypofunction and xerostomia are significant morbidities during and following head and neck RT, resulting in decrease of salivary flow rates. Treatment goals for salivary gland hypofunction are stimulation of residual salivary gland tissue, relief of oral dryness, prevention of tooth demineralization, caries, and oral infection [11]. Pilocarpine, cevimeline, bethanechol HCl, and amifostine have been tested for the prevention of salivary gland hypofunction in cancer patient undergoing RT. Due to conflicting results their use is not recommended [11]. On the other hand, recent systematic review suggested that both pilocarpine and cevimeline can reduce xerostomia symptoms and increase salivary flow compared to placebo
Intensity‐modulated radiation therapy (IMRT) can reduce the radiation dose to salivary glands, thus helping in decrease of salivary gland hypofunction and symptoms of xerostomia [66, 67]. Surgical transfer of submandibular gland to the submental space can contribute to preservation of salivary gland function and reducing xerostomia symptoms. However, this method applies only to patients with clinically negative cervical lymph nodes [11]. Despite their short‐term effect, it has been shown that use of saliva substitutes is more effective in the treatment of dry mouth than placebo. The saliva substitutes are mainly based on carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, and plyglycerylmethacrylate. Some of them contain electrolytes and fluoride for preventing teeth demineralization. Artificial saliva substitutes come in the form of gel, spray, and solution. Because its lubricating effect lasts longer, saliva substitute gel is recommended, especially during the night or other periods of severe oral dryness [11].
\nPoints to remember for the oral care during head and neck RT are presented in Table 1 [68–70].
\nOral care during head and neck radiotherapy | \n
---|
• regular checkups every 7–10 days during RT | \n
• for the pain management prescribe topical anesthetics and/or analgesics | \n
• use a soft toothbrush with a fluoride toothpaste for brushing after meals and before bed. Floss at least once a day (use xylocaine anesthetic rinse prior to brushing and flossing) | \n
• if brushing is too painful, use a clean moist gauze or foam swab soaked in baking soda mouth rinse | \n
• rinse the mouth with a baking soda and salt solution (mix 1 teaspoon of baking soda and 1 teaspoon of sat with four cups of water) several times a day. Avoid salt during mucositis | \n
• management of dry mouth (sip water frequently, use saliva substitutes, use sugar‐free candies, and gums) | \n
• keep dentures out of the mouth as much as possible; soak it in cleansing solution for at least 8 hours | \n
• exercises for the jaw muscles at least three times a day to avoid trismus | \n
• avoid spicy or acidic foods, tobacco, and alcohol | \n
After completion of RT, frequent follow‐up appointments at dental office and good oral hygiene are of utmost importance. Initially, follow‐up appointments are carried out once a month, and subsequently their dynamics is determined individually. Xerostomia and salivary gland dysfunction as acute complication of RT continues in the posttreatment period, thereby becoming chronic, which greatly increases the risk of dental caries and its sequelae. Radiation caries is extremely progressive and highly destructive type of caries, which certainly increases the risk of ORN by increasing risk for tooth extraction. Therefore, every effort should be focused on caries prevention. In order to avoid difficulties in maintaining oral hygiene and the implementation of necessary dental procedure, early signs of trismus should be recognized.
\nRadiation caries is primarily a consequence of salivary hypofunction, saliva composition changes, and increase in acidogenic bacteria number. Furthermore, direct damage on the hard dental tissues frequently occurs from RT. For caries prevention good preoperative dental treatment, frequent dental evaluation and treatment after RT, consistent home care that includes brushing after meals and before bed, daily flossing, plaque control, self‐applied fluoride products, and restricted intake of cariogenic foods are required [54].
\nIt is considered that the fluoride therapy is the best option for the prevention and treatment of radiation caries. The use of fluoride products significantly reduces caries activity in postRT patients. High concentrated fluorides (≥5000 ppm) directly applied on tooth surfaces or with custom‐made carriers should be maintained every day. Literature data have demonstrated no significant difference on caries activity related to the type of fluoride gel or fluoride delivery system [71].
\nChlorhexidine (CHX) as a bisguanide with bactericidal activity reduces plaque accumulation and helps in reducing mainly Gram‐positive and bit less Gram‐negative bacteria. It is interesting that use of CHX has shown decrease in oral
In cases where radiation caries is not possible to prevent, restoration with a proper dental material is required. Lack of salivary buffering, reduction of normal plaque pH, and formation of the hydrofluoric acid in patients with xerostomia lead to erosion of glass ionomer restorations [74]. Hence, conventional glass ionomer restorations are not recommended in patients who have been treated with RT. For the dental restoration in patients who have been treated with RT, the use of resin‐modified glass ionomer, composite resin, and amalgam restorations are recommended [71].
\nReduced mouth opening is a result of the damaging effects of RT on the masticatory muscles. It is very important to identify early signs of trismus considering the fact that early treatment can significantly affect its prevention. For the prevention as well as for the treatment of reduced mouth opening, passive and active physiotherapy from the commencement of RT can be performed. Active physiotherapy is carried out with the muscles placed around the joint, while passive motion includes use of various devices [33]. Passive physiotherapy implies the use of tongue depressors, a hand operated device “Therabite Jaw Motion Rehabilitation System,“, and forced mouth opening with finger pressure several times a day [75]. Except of the aforementioned therapeutic options, pentoxifylline and botulinum toxins have shown efficacy in reducing radiation‐induced trismus [76, 77]. However, the latter needs to be confirmed by randomized controlled studies. Whenever possible, sophisticated multiple‐field techniques should be used to reduce the dose of radiation to the mastication muscles and temporomandibular joint [2].
\nHead and neck cancer patients undergoing RT are at lifelong risk of developing ORN. Therefore, dental extractions after RT should be avoided if possible. Furthermore, every local trauma must be avoided, and endodontic therapy, instead of extractions, should be the treatment of choice. Otherwise, if there is a need for extractions in postradiation period, they should be performed during first 5–6 months after RT with minimal trauma and primary closure [25]. Obliteration of the blood vessels and hypovascularity of the bone that occurs after RT is not an overnight process and it takes 5–6 months to develop [20, 50]. This “window” period should therefore be used for necessary extractions if possible. Literature results on the incidence of ORN after tooth extraction support this as significantly lower incidence of ORN was reported when extractions were performed within 1 year postRT compared to extractions performed 2–5 years postRT (7.5% vs. 22.6%) [78]. Use of antibiotic prophylaxis for the prevention of ORN is widespread in the literature, but there is no consensus on the type and dose of application. Their administration is empirical [23]. Hyperbaric oxygen therapy (HBO) is not strongly recommended for the prevention of ORN prior dental extractions, due to unclear clinical efficacy and cost‐effectiveness. No specific and universally accepted guideline for the administration of HBO therapy exists [22]. Most of the protocols propose 20–30 dives before and 10 dives after dental extraction at 2.0–2.5 atmosphere pressure [22, 23]. Despite that, recent Cochrane systematic review concluded that HBO therapy “appears to reduce the chance of ORN following tooth extraction in an irradiated field” and that “the application of HBOT to selected participants and tissues may be justified” [79].
\nManagement of ORN includes conservative treatment, surgical debridement with the use of adjunctive antibiotics and reconstructive surgery. Conservative treatment should be the first line therapy for ORN because surgical procedure may enhance the necrotic process [23]. Treatment consists of local wound care and good oral hygiene using 0.2% chlorhexidine mouthwashes and course of systemic antibiotics in acute episodes [80, 81]. If a conservative approach does not achieve wound healing, surgical removal of necrotic bone is indicated. Indications for reconstructive surgery include advanced cases with oral and/or cutaneous fistula, radiographically visible osteolysis, and pathologic fracture [81, 82]. The use of antioxidant agent pentoxifylline and tocopherol (vitamin E) for the treatment of ORN has shown promising results but more clinical trials are needed to confirm their efficacy [82].
\nPoints to remember for the oral care after head and neck RT are presented in Table 2 [68–70].
\nOral care after head and neck radiotherapy | \n
---|
• regular checkups every 4–8 weeks for the first 6 months (afterwards based on the patient\'s needs) | \n
• avoid invasive surgical procedures including dental extractions (if necessary, the use of antibiotics and HBO therapy before and after surgery should be considered) | \n
• daily fluoride application (using a tray or brush‐on method), flossing and meticulous oral hygiene (use a soft toothbrush and 0.02% CHX mouthwash) must be performed | \n
• management of dry mouth (sip water frequently, use saliva substitutes, sugar‐free candies, and gums) | \n
• exercises for the jaw muscles at least three times a day (minimum first 6 months postRT) | \n
• a new removable denture can be made 3–6 months postRT (avoid any tissue irritation/trauma) | \n
Efforts of dental professionals will have a significant clinical and financial impact on the treatment of PwHNT. The dentist must be a member of the oncology team and must have knowledge on the specific complications of head and neck RT. Dentist should make a plan of treatment and prevention before the start of RT. Surgeons, radiation oncologists, and medical oncologists can find valuable partners in dental profession, with the aim of improving patients’ overall quality of life. Such care can greatly prevent and reduce side effects of treatment, resulting in a significant reduction in the cost of treatment, and some of those aspects facilitate implementation of radiation therapy without interruption, which increases the chances of cure.
\nChronic exposure to environmental noise is a widespread problem around the world, causing significant impacts on human health and well-being. Road traffic is the predominant source of noise in urban areas and represents the second most important health risk factor after air pollution [1]. In Europe, it is estimated that about 20% of the total population is exposed to road traffic noise levels considered harmful to health [2]. Moreover, the problem is expected to become more severe in the next decades. In the European Union, the population exposed to high road noise levels is projected to rise both inside and outside urban areas over the next years due to urban growth and increased demand for mobility [3].
In the last decades, the introduction of more stringent environmental noise legislation has resulted in a series of noise abatement measures of varied nature. These included urban planning measures (such as the designation of noise-sensitive areas, or regulations on vehicle speed limits or traffic restrictions), measures to improve the acoustic performance of vehicles, pavements and buildings, and the construction of noise barriers. Currently, noise barriers have become frequent features along many roads and railways.
The history of noise barriers precedes the appearance of the first generation of environmental regulations in the World. The first documented noise barrier installed on a road was built in 1963 [4]. In the following years, several new design criteria and new materials for barriers were rapidly introduced. And so, the first lightweight barriers with an absorptive treatment on the panel surface date back to the early 1970s [5]. By 1975, Japan had already built noise barriers along 79 km of new highways [6], and the USA had installed about 57 km of barriers at certain types of highway projects [4].
In the 1960s and 1970s, the first research studies were initiated to analyze the acoustic properties of barriers and calculate noise attenuation levels. Probably the most famous of these studies was the Maekawa empirical chart of 1968 [7], as well as the formulations developed by other authors based on Maekawa\'s original proposal [8, 9, 10, 11, 12]. It was also during this period that the first regulations for noise management and abatement were adopted in countries such as the USA (1972), Canada (1973), Germany (1974) and Japan (1974).
Since the 1980s, many countries have adopted Environmental Impact Assessment (EIA) legislation that requires the evaluation of, among others, proposed road projects that are likely to have significant environmental impacts. As part of the EIA process, the project developer is required to evaluate road traffic noise and must determine appropriate mitigation measures to minimize its effects. Constructing a noise barrier is probably the most mentioned mitigation measure in EIAs conducted around the world [13]. As an example of the extensive use of these devices, it was estimated that the global production of noise barriers reached approximately 370 million m2 in 2014 [14]. In the European Union, these devices have become the most prominent noise mitigation measure applied to major roads located outside residential areas [15]; in the USA, about 5700 km of barriers have been built to date [4].
Noise barriers have been made of many different materials and have taken many different forms over time. In the past, simple reflecting barriers made of concrete, masonry blocks, or earth berms were often used, but modern barriers tend to have absorptive treatments which minimize the level of reflected noise. In recent years, a number of innovative barriers are being developed, such as combined noise and safety barriers, low-height barriers, photovoltaic barriers, noise walls with titanium dioxide (TiO₂) coating, inox/corten steel barriers, or acoustic devices based on sonic crystals [16].
The growth in the use of noise barriers has also been coupled with a growing interest in their effectiveness as a tool to reduce noise pollution. The evaluation of this effectiveness is, however, a difficult task, given that these devices are placed outdoors under very varied conditions, with diverse barrier designs and locations, fluctuating noise sources, and changing environmental conditions. This chapter outlines the fundamentals of the acoustic performance of barriers, describes the main approaches for the evaluation of their effectiveness, as well as the main findings obtained in the studies conducted on the attenuation levels measured.
A noise barrier is a structure that obstructs the direct transmission of airborne noise produced by a source, such as road traffic, and redistributes the sound energy into several paths (Figure 1):
A reflected path, so that the noise wave reaching the exposed side of the barrier partly reflects on it. The barrier can also absorb other parts of the sound energy. Based on these acoustic properties, noise barriers are usually divided into two main groups: absorptive barriers, which are specifically designed to absorb part of the acoustic energy, and reflective barriers, from which noise is largely reflected (a special group consists of reactive barriers, which are devices that contain cavities or resonators).
A transmitted path, so that the noise reaching the exposed side of the barrier transmits through the device itself. Therefore, the transmitted energy must be as low as possible.
A diffracted path, over the top and around the ends of the barrier, so that the barrier acts as an obstacle to the noise propagation, diffracts noise waves, and then propagates to the protected side of the barrier with less energy. Noise diffraction is largely determined by the difference between the source-receiver direct path length and the extended path length due to the presence of the barrier.
The acoustic performance of a noise barrier (based on [
Noise barriers cause an area of decreased sound energy behind the barrier (also called shadow zone) which is a combination of reflection, diffraction, and transmission losses. Due to the nature of sound, diffraction does not bend all frequencies uniformly: higher frequencies are diffracted to a lesser degree; lower frequencies are, by contrast, diffracted deeper into the shadow zone behind the barrier. As a result, noise barriers are generally more effective in attenuating the higher frequencies.
The acoustic performance of a noise barrier depends on a set of intrinsic and extrinsic characteristics [18]. Intrinsic characteristics refer to the properties of individual components of the barrier, such as the type, thickness, and design of the materials used. Extrinsic characteristics consider the attenuation of the barrier once it has been installed. These characteristics are mainly determined by a set of context-specific conditions, such as:
The position of the barrier relative to the source and the receiver, and its effective height and length to block propagation paths.
The nature of the noise source in terms of traffic volume, traffic speed, types of vehicles, and road pavement.
The characteristics of the propagation medium, i.e., wind conditions, air temperature, and relative humidity.
The nature of the terrain between the road and the receiver, i.e., interfering obstacles and the acoustic impedance of the ground surface.
These contextual properties largely determine the diffraction characteristics of the barrier and the global noise attenuation that can be achieved. The noise diffracted on the top and around the ends of the barrier is the most important factor limiting its acoustic performance [18].
Determining the effectiveness of noise barriers has attracted the attention of researchers for the past 40 years, and a wide variety of both mathematical and experimental approaches have been developed. Mathematical methods have been widely used to determine the diffraction properties of the barriers. These methods can be based on the boundary element method [19, 20], the finite element method [21, 22], and the finite difference method [23].
Experimental studies have been based on diverse approaches relating to (i) the assessment of perceived annoyance reduction efficiency of noise barriers [24, 25], (ii) the effects of noise barriers on the perception of urban soundscape quality [26], (iii) the measurement of noise attenuation based on scale model experiments [27, 28], and (iv) the measurement of the acoustic properties of full-scale barriers. The latter experiments have been the most reported in the literature, and have addressed the analysis of the effectiveness of barriers based on their various acoustic characteristics:
Some research studies have addressed the intrinsic characteristics of barriers, such as sound absorption and insulation. Two types of measurement methods are commonly used to evaluate these properties: laboratory methods, using a diffuse sound field in a reverberation room, and
Other studies assessed barrier performance by measuring its “Insertion Loss”, which is defined as the difference in sound pressure level before and after the barrier is constructed.
The methods for
A substantial part of the scientific literature on the evaluation of the acoustic properties of noise barriers has been based on the
In Europe,
The measurement system consists of a fixed source (loudspeaker) reproducing a maximum length sequence (MLS) signal [30, 31] or a gunshot [29]. With these kinds of signals, the impulse response of an acoustic system can be obtained. In addition, background noise is eliminated [35]. Then a microphone is located behind the barrier to measure noise transmission or/and in front of the screen to measure noise reflection (Figure 2).
Measurement according to the “Adrienne” method (left) [
These methods are focused on the measurement at the near field (placing the microphones close to the surface to be measured) since, according to the standards, the lower power of the waves reflected, the difficulty of discerning between emitted and reflected sound, and the influence of background noise, make it really difficult to obtain meaningful results more distance [30, 31]. For this reason, some researchers prefer to extrapolate reflectivity data measured in the near field toward the effect in the far-field.
However, other researchers based on the standard EN 1793-4 [32], where receiver microphones are placed 2 m behind the barrier (see Figure 3), have situated the receiver microphones at greater distances from the screen (from 10 to 40 m) [36] considering these distances better to estimate the real IL.
Standard 1793-4 microphone location (based on [
In addition, according to Kim et al. [36], since the European test methods are based on an impulsive signal, they could be eliminating the influences of reflected sounds by ground and any other objects around the test area. So that, methods such as conventional Japanese and Kim et al. use traffic signal for their measurements.
Part of the research studies conducted to date has been based on the evaluation of the effectiveness of barriers on the calculation of Insertion Loss (IL), which is defined as the difference in the noise level before and after the installation of the barrier [37]. The IL is an extrinsic characteristic of noise barriers, depending mostly on the site geometry, meteorological conditions, ground impedance, and the relative positions of the noise source and the receiver [17]. These factors are in general not independent of each other, so the total IL cannot be calculated by the addition of partial insertion losses [17].
The international standard ISO 10847:1997 [37] establishes two methods of in situ IL measurement and calculation; direct and indirect measurement methods:
The direct method is used when the barrier has not been installed yet or can be removed. The noise level is measured before and after the installation of the barrier to determine the IL. In this method, it must be ensured that measurements before and after the installation of the barrier are performed under equivalent weather and traffic conditions.
The indirect method is used when the barrier is already installed and cannot be removed. In this case, an estimated “before” noise level is obtained by the measurement at a site that is considered equivalent to the study site.
The American standard ANSI/ASA S12.8-1998 [38] describes an additional “indirect predicted” method, which uses measurements at the site with a barrier to determine "after" noise levels, and a traffic noise prediction model to predict “before” levels at the same site without the barrier.
The ISO standard specifies general criteria for in-situ measurement of barrier IL including microphone positions, noise source conditions, and acoustic environments of the measurement sites. It also suggests generic principles for ensuring that sufficiently equivalent conditions are maintained between “before” and “after” measurements to permit reliable determination of barrier IL. The noise descriptor recommended is A-weighted equivalent sound pressure level. The materialization of the general criteria suggested by ISO has been resolved in different ways in studies based on both the direct and indirect methods.
The direct method described in the ISO 10847 standard is the approach to be used when the barrier has not been installed yet or can be removed. The method requires measurements before the barrier has been constructed to determine “before” levels and measurements at the same site after construction to determine “after” levels. According to US Federal Highway Administration (FHWA) [17, 39] this method ensures identical site geometric characteristics but also requires equivalent “before” and “after” meteorological and traffic conditions that may be difficult to reproduce. These meteorological equivalence conditions include wind, temperature, humidity, and cloud cover. In case of strong winds, “before” and “after” measurements should be avoided.
The factors to be considered in the determination of the measurement sites and procedures are briefly described below:
The ISO standard recommends the traffic itself as the sound source for the “before” and “after” measurements. Using traffic noise signal has the advantage of measuring the signal which is wanted to evaluate. However, the fluctuations in traffic may affect the accuracy of the results, so that the measurement period must be taken into consideration.
The standard recommends the use of a reference microphone, which allows for calibration of “before” and “after” measured levels and helps to consider variations in the characteristics of the noise source [17, 39].
When the reference microphone is used, it is placed in most cases according to the ISO standard, i.e., at a point on a vertical plane including the barrier, and at a height, at least, 1.5 m above the barrier edge. When the barrier is located less than 15 m from the near road lane, the microphone may be placed at 15 m from the center of the road lane, and at a height such that the line-of-sight angle between the microphone and barrier top, as measured from the center of the near road lane, is at least 10° (Figure 4) [17].
Alternative positions for reference microphones—blue circle—(based on [
Microphone location at receiver positions depends on the study objectives since the location of the microphones (distance from the barrier, height above the ground) are determinants to establish diffraction effects. In some studies, a single microphone is located at a height of 1.5 m above the ground. The most common situation is, however, to place microphones at different distances and heights [17, 39, 40, 41] for a better understanding of the performance of the shadow zone (Figure 5).
Measurement microphones in the study of Anfosso-Lédée et al. [
A range from 2 to 30 min is the usual sampling period for measurements. When weather conditions are fluctuating, longer sampling periods, such as 1 or 24 h, could be more accurate [17]. It has been suggested [40] that 2-min measurements, as specified in the standard, are too short for a stable and reliable evaluation of sound pressure levels. The optimal measurement periods are 15–30 min, as longer periods would possibly introduce atmospheric changes [40]. However, other researchers [41] established a 10 min measurement period.
The FHWA suggests avoiding measurements when wind speed exceeds 17 km/h or while raining since raindrops generate noise and tire noise increases on wet pavements. The Agency also recommends avoiding measurements when traffic flow is congested since the traffic noise level will be lowered, making it more difficult to evaluate the IL.
There is a lack of evidence on the effectiveness of barriers based on the direct method. In the study conducted by Anfosso-Lédée et al. [40], the authors suggest that it could be due to the poor applicability of the method since it took 3 years for his team to complete the measurements due to the time waited for the installation of the barrier and the difficulty to find the equivalence of traffic, weather conditions, and ground impedance.
The experiment was based on measurements at 30 m and 100 m from the barrier (or where the barrier was supposed to be installed) (Figure 5). The measurements “before” took place in 1996, and the measurements “after” (when the barrier was already installed) were implemented from June 1998 to August 1999. Results showed IL values range from 4 to 8 dB(A) at 100 and 30 m from the road.
Parnell et al. [41] constructed a new barrier 80 m long and 2.4 m high and measured, with and without the barrier, at a distance of 2.4 m in front of the barrier and 2.4 and 4.8 m behind the barrier (Figure 5). Results of the experiment showed a 6–8 dB(A) difference in measurements “before” and “after” the barrier installation.
The indirect method is, according to ISO 10847:1997, the approach to be used when the noise barrier has already been installed and cannot be removed for measurements. In this case, an estimated “before” noise level is obtained by the measurement at a site that is considered equivalent to the study site. To ensure consistency of results, the “before” and “after” measurements should be performed simultaneously.
The indirect method is the only practicable approach in the case of most new roads, where the noise barriers have been installed during road construction, and therefore it is not possible to obtain a "before" measurement under normal traffic conditions. The primary advantage of using this method is that it ensures the same environmental conditions (meteorological and traffic conditions), so this method, as highlighted by some authors [17, 42], would be preferred over the direct measurement method.
The use of the indirect method involves the identification of another measurement site that is deemed to be equivalent. For these equivalent sites, a close match is required in emission characteristics, relative positions of source, barrier and receiver, acoustic performance of ground surface, terrain profile, interfering obstacles, reflecting surfaces, and meteorological conditions. The factors to be considered in the determination of the measurement sites and procedures are briefly described below.
According to ISO 10847:1997, the “before” site must have a terrain profile, interfering obstacles, and reflecting surfaces equivalent to those of the real barrier site within a sector extending 60° on either side of the line connecting the receiver positions towards the source position, so that similar noise propagation can be achieved.
It is also necessary to ensure the equivalence of ground surface, which refers to the acoustic impedance of the ground along the source-receiver propagation path (i.e., acoustic characteristics of soil coverage, such as paved soil, vegetation on loose or packed soil, gravel, etc.) (Figure 6). The standard ISO additionally requires that the environment in the region within 30 m behind and to the side of the receiver positions shall be similar.
An example of "after" and equivalent "before" locations at one of the sites studied by the authors in Spain (aerial photograph from Iberpix, OrtoPNOA 2020 CC-BY 4.0 scne.es).
The main difficulty of the method is that an adjacent equivalent site may not always be available, especially in dense urban areas [17, 40]. As an example, a study conducted in Spain [42], which was based on an initial sample of 84 measurement sites, had to reject 54 potential locations due to various causes; the main cause was the different acoustic environment at the "before" and "after" positions due to significant differences in terrain profile and the presence of other noise sources.
Most of the indirect method-based studies use road traffic as a noise source. The ISO standard proposes that naturally occurring road noise should be used as the sound source equivalence for the “before” and “after” measurements. The use of traffic noise has the obvious advantage of representing the natural source, but also the disadvantage of describing fluctuations in traffic volume, speed, and composition that may affect the accuracy of the results.
The use of artificial noise sources is infrequent and is used only when it is not possible to use traffic noise in equivalent conditions. This artificial point source may be based on a loudspeaker that reproduces traffic noise [20] or a regulated artificial signal such as pink noise [43].
One of the key factors in the use of the indirect method is that the locations of the microphones relative to the noise source at the "before" and "after" positions should be identical, in terms of distance from the road and height above the road [39]. Some authors suggest the use of a reference microphone [17, 39], which, as mentioned before (Section 3.1.2) takes into account the effect of possible fluctuations of the noise source.
Only a few studies have considered the use of the reference microphone [39, 44], so it is understood that the rest of the studies assume that possible traffic fluctuations during the measurements are not expected to significantly affect the results.
The location of the receiver microphones varies according to the purpose of the study. The choice of these locations is sometimes determined by the possibility of finding equivalent locations at the "before" site.
In most studies, microphones are placed at regular distances from the barrier (5, 10, 15 m), or corresponding to incremental doublings of the distance (e.g., 7.5, 15, 30 m) [42, 44]. Some studies determine IL levels by placing a single microphone in the near field behind the barrier, at distances of 1–5 m [20, 43, 45, 46]. The most common height for the microphone is 1.5 m, although there are studies that consider additional heights, which are similar to or higher than the barrier height (e.g., 2, 4, 6 m). Both the distances and incremental heights of the microphone positions are intended to better understand the performance of diffraction shadow zones (Figure 7).
The experimental design of studies based on the indirect method depends on the purpose of the study. Above, a microphone distribution is intended to better understand the pattern of the shadow zone [
There is no general standard for receiver locations. The ISO standard proposes general criteria that are a very general characterization of the open space behind the barrier [47]. In recent years, the European Committee for Standardization adopted the CEN/TS 16272-7:2015 standard for railway noise barriers [48], which recommends nine locations for receiver microphones. These microphones are located at a distance of 7.5, 12.5, and 25 m away from the lines, and at a height of 3.5, 6, and 9 m above the ground. However, this standard does not appear to be in use in studies relating to the measurement of Insertion Loss at railway noise barriers [47].
The selection of the measurement period should first consider when to measure along the daily time. One of the factors to be taken into consideration concerns favorable weather conditions, in particular wind speed and direction. The preferred conditions are for daily periods when low wind or calm is expected. Some studies [42] have conducted measurements in the period after peak traffic time in order to find dense but fluid traffic conditions, where traffic fluctuations are less prominent. In most of the studies, the “before” and “after” measurements have been undertaken simultaneously to ensure the same environmental conditions (i.e., background noise, traffic, and meteorological conditions).
The duration of the measurements in studies based on the indirect method depends on the nature of the noise source. In the case of studies using an equivalent artificial noise source, the duration of measurements is usually short (such as 2 min) in accordance with the ISO standard [43]. In the case of road traffic noise, the period is usually long enough to ensure the representativeness of the spectrum of the traffic noise. In practice, measurement duration in most studies ranges from 10 to 30 min, and the most common value is 15 min. Some studies [17] have suggested using longer periods (such as 1 h, or a day) when noise variations are expected to be substantial, but these longer periods do not seem to be used in practice.
In other studies [39, 49] the procedure consists of measuring noise levels, wind speed and direction, and temperature lapse rate for a 4-h block of time in 1-min increments. Thus, the results are broken down into short periods and continuous equivalent levels and meteorological conditions are individually determined for each short period. This procedure anticipates the problem of
Occasionally [42], the choice of the measurement duration was based on traffic variations at the time of sampling. Thus, measurements were prolonged until the observed variation in the sound level meter did not vary more than a certain value (such as 0.1 dB(A)) over a certain time period (at least 1–2 min).
The results obtained in the different research studies conducted revealed moderate Insertion Loss values of the noise barriers. Attenuation values obtained in the near field, at distances from the barrier of 5–7 m, and heights above ground of 1.2–1.5 m, range between 7 and 10 dB(A) [20, 42, 44, 45, 46, 50]. Insertion Loss levels are higher at shorter distances from the barrier, such as 1 m [43]. The IL values at comparable greater distances from the barrier (20–30 m) tend to decrease to values of 3–5 dB(A) [40, 42, 44], although one study reports much higher attenuation levels of up to 10 dB(A) at intermediate distances (15 m) [51]. Attenuation levels measured at greater distances (up to 100 m) tend to decrease slightly [40].
These results seem to indicate that the barrier attenuation levels are, above a certain distance, clearly lower than expected. It is, however, generally assumed that an effective noise barrier typically reduces noise levels by about 5–10 dB(A) [16, 44]. Effectiveness usually depends on its dimensions, material type, and location relative to the source and receiver positions. In the dimensioning of the barrier, the contribution to the total sound field of the components diffracted around the top and side edges are the key elements to determine the minimum barrier height/length for which the influence of the side edges diffraction may be neglected.
The best noise reduction effect is in the frequency range of 250–4000 Hz, at which the traffic noise is dominant. The average value of Insertion Loss for the octave bands between 250 Hz and 4 kHz ranges from 4 to 9 dB(A) [42, 50]. Noise abatement reaches a maximum at 4000 Hz, and the smallest reductions are encountered for the lowest frequencies (Figure 8) [42, 50, 52].
An example of Insertion Loss levels in the range of frequencies of the octave bands at two distances (5 and 25 m) from the noise barrier [
The type of barrier material does not appear to have a significant effect on attenuation levels [42, 51]. The differences found are rather related to locational factors, such as the distance from the barrier to the source (or receiver). Thus, the Insertion Loss measured at earth berms is lower than at noise walls because the top edge of the barrier is usually further away from the source and/or receiver positions.
There is little evidence of equivalence of the results obtained with the direct and indirect methods. In the only study conducted to date evaluating the IL of the same site (the same noise barrier) using both methods [40], the results reveal that the direct and indirect methods are not equivalent. The observed differences range from −2 dB(A) to +4 dB(A). The causes of these differences were attributed in the study to variations in wind conditions (wind speed and direction) and vertical temperature gradient. The effect of microphone positions and other environmental factors on noise levels measurements also needs to be better known.
The amount of literature on the effectiveness of noise barriers has not provided sufficient evidence on the actual attenuation achieved by these devices, and there is uncertainty over the noise reduction capabilities of existing barriers. The methods described in the ISO 10847:1997 standard have drawbacks that make it difficult to obtain reliable attenuation measurements.
The direct method ensures identical propagation characteristics since the source of noise, the barrier, and the receiver are at the same positions, but the equivalence of source and meteorological conditions may not be fully satisfied. The indirect method ensures that the same local weather and traffic conditions are maintained, but the equivalence of terrain profiles, obstacles, and ground surface conditions may not be fully achieved. In addition, the usage of provisions of the ISO standard sometimes is complicated when at the site point exists a relatively high background noise level, or adverse meteorological conditions [54].
According to the ISO standard, the recommended method is the direct method, although most studies have been based on the indirect method because the barriers were installed during road construction, and therefore it was not possible to obtain equivalent "before" measurements.
The ISO standard provides generic methods for determining Insertion Loss at receiver locations. However, there are no universally acknowledged receiver positions for measurements. It is important to note that barriers are relatively ineffective at some distance from the road. The effective distance range is limited to a few tens of meters, so it is unclear that many receivers can benefit from barrier attenuation. Many of the studies conducted have calculated Insertion Loss levels at barrier near-field distances, so the noise reduction capabilities of barriers were only partially assessed. The IL levels measured at comparable greater distances from the barrier (20–30 m) were, in most cases, very moderate. This supports the argument that the barrier attenuation levels are, above a certain distance, clearly lower than expected.
Additionally, the ISO standard specifies measurements of equivalent continuous A-weighted sound pressure levels to calculate the attenuation of the barrier. However, A-weighting tends to underestimate the effects of low-frequency noise [47]. Several studies have highlighted that A-weighting does not adequately consider the perceived annoyance produced by predominantly low-frequency noise. This is the case of road traffic noise, which is characterized by the wide variability in the relative level of low-frequency noise [25, 55]. Noise barriers increase the relative level of low-frequency of noise on the shielded side of the barrier. Thus, the attenuation in A-weighted measured levels level may overestimate the estimated reduction in perceived annoyance due to the increase in the relative level of low-frequency sound [47].
In summary, the literature has described some critical points about the applicability and reliability of ISO methods. These points were dealing with (i) the reliability of results (i.e., direct IL measurements obtained at different moments, and indirect IL measurements obtained at equivalent locations), (ii) the equivalence of results of direct and indirect methods, (iii) the nature of the indicator used (A-weighted levels), and (vi) the relevance of operational factors such as weather conditions, traffic fluctuations, ground impedance, and background noise.
The effect of these factors on noise levels measurements needs to be better known. More research studies in this domain are required to bring improvements in measurement methods.
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Although there are effective drugs used to treat melanoma, some cell lines have proven resistant to chemotherapy. In this context, several research groups on natural products have investigated the anticancer effect of new natural molecules in the treatment of melanoma. Flavonoids have shown to play an important role in chemoprevention and inhibition of the proliferation, migration, and invasion of melanoma cells. In this chapter, we present a systematic review performed through a literature search over a period of 20 years, using specialized databases. Analysis of all selected manuscripts demonstrated that at least 97 flavonoids have already been investigated for the treatment of melanoma using in vitro or in vivo models. Most of the bioactive flavonoids belong to the classes of flavones (38.0%), flavonols (17.5%), or isoflavonoids (17.5%). Apigenin, diosmin, fisetin, luteolin, and quercetin were considered as the most studied flavonoids for melanoma treatment. In general, flavonoids have shown to be a promising source of molecules with great potential for the treatment of melanoma.",book:{id:"5767",slug:"natural-products-and-cancer-drug-discovery",title:"Natural Products and Cancer Drug Discovery",fullTitle:"Natural Products and Cancer Drug Discovery"},signatures:"Raimundo Gonçalves de Oliveira Júnior, Christiane Adrielly Alves\nFerraz, Mariana Gama e Silva, Érica Martins de Lavor, Larissa Araújo\nRolim, Julianeli Tolentino de Lima, Audrey Fleury, Laurent Picot,\nJullyana de Souza Siqueira Quintans, Lucindo José Quintans Júnior\nand Jackson Roberto Guedes da Silva Almeida",authors:[{id:"70159",title:"Dr.",name:"Lucindo",middleName:null,surname:"Quintans-Júnior",slug:"lucindo-quintans-junior",fullName:"Lucindo Quintans-Júnior"},{id:"72113",title:"Prof.",name:"Jackson",middleName:"Roberto Guedes Da Silva",surname:"Almeida",slug:"jackson-almeida",fullName:"Jackson Almeida"},{id:"203273",title:"Dr.",name:"Jullyana",middleName:null,surname:"de Souza Siqueira Quintans",slug:"jullyana-de-souza-siqueira-quintans",fullName:"Jullyana de Souza Siqueira Quintans"},{id:"203426",title:"Dr.",name:"Laurent",middleName:null,surname:"Picot",slug:"laurent-picot",fullName:"Laurent Picot"},{id:"204628",title:"Mr.",name:"Raimundo",middleName:null,surname:"Oliveira-Junior",slug:"raimundo-oliveira-junior",fullName:"Raimundo Oliveira-Junior"},{id:"204629",title:"MSc.",name:"Christiane",middleName:null,surname:"Ferraz",slug:"christiane-ferraz",fullName:"Christiane Ferraz"},{id:"204630",title:"MSc.",name:"Mariana",middleName:null,surname:"Silva",slug:"mariana-silva",fullName:"Mariana Silva"},{id:"204631",title:"Ms.",name:"Erica",middleName:null,surname:"Lavor",slug:"erica-lavor",fullName:"Erica Lavor"},{id:"204632",title:"Prof.",name:"Julianeli",middleName:null,surname:"Lima",slug:"julianeli-lima",fullName:"Julianeli Lima"},{id:"204633",title:"Prof.",name:"Larissa",middleName:null,surname:"Rolim",slug:"larissa-rolim",fullName:"Larissa Rolim"},{id:"204634",title:"Prof.",name:"Audrey",middleName:null,surname:"Fleury",slug:"audrey-fleury",fullName:"Audrey Fleury"}]},{id:"55925",doi:"10.5772/67797",title:"Endophytic Fungi as Alternative and Reliable Sources for Potent Anticancer Agents",slug:"endophytic-fungi-as-alternative-and-reliable-sources-for-potent-anticancer-agents",totalDownloads:1973,totalCrossrefCites:3,totalDimensionsCites:8,abstract:"In comparison with other natural sources like plants, highly diverse microorganisms are narrowly explored, especially with respect to their limitless potentials as repositories of exceptionally bioactive natural products. Of these organisms, fungi inhabiting tissues of plant in a noninvasive relationship (endophytic fungi) have proven undeniably useful and unmatchable as sources of potent bioactive molecules against several diseases such as cancer and related ailments. In general terms, endophytic fungi are highly prevalent organisms found in the tissue (intracellular or intercellular) of plants and at least for reasonable portion of their lives. It has been proven that virtually every plant, irrespective of habitat and climate, plays host to wide varieties of endophytes. Endophytic fungi produce metabolites produced by different biosynthetic pathways to that of the host plant, and this robustness equips them to synthesize unlimited structural entities and scaffolds of diverse classes. Interestingly too, the cohabitation/culture of these fungi with certain bacteria offers even stronger hopes for anticancer drug discovery. The endless need for potent drugs has necessitated the search of bioactive molecules from several sources, and endophytic fungi appear to be a recipe. This chapter is an attempt to present the current trend of research with these very promising organisms.",book:{id:"5767",slug:"natural-products-and-cancer-drug-discovery",title:"Natural Products and Cancer Drug Discovery",fullTitle:"Natural Products and Cancer Drug Discovery"},signatures:"Edwin O. Omeje, Joy E. Ahomafor, Theophilus U. Onyekaba, Philip\nO. Monioro, Ibekwe Nneka, Sunday Onyeloni, Charles Chime and\nJonathan C. Eboka",authors:[{id:"197824",title:"Dr.",name:"Edwin",middleName:"Ogechukwu",surname:"Omeje",slug:"edwin-omeje",fullName:"Edwin Omeje"},{id:"198038",title:"Dr.",name:"Nneka",middleName:null,surname:"Ibekwe",slug:"nneka-ibekwe",fullName:"Nneka Ibekwe"},{id:"198039",title:"MSc.",name:"Joy",middleName:null,surname:"Ahomafor",slug:"joy-ahomafor",fullName:"Joy Ahomafor"},{id:"198040",title:"Mr.",name:"Sunday",middleName:null,surname:"Onyeloni",slug:"sunday-onyeloni",fullName:"Sunday Onyeloni"},{id:"198041",title:"Mr.",name:"Philip",middleName:null,surname:"Monioro",slug:"philip-monioro",fullName:"Philip Monioro"},{id:"204822",title:"Dr.",name:"Charles",middleName:null,surname:"Chime",slug:"charles-chime",fullName:"Charles Chime"}]},{id:"54388",doi:"10.5772/67650",title:"Computational Studies and Biosynthesis of Natural Products with Promising Anticancer Properties",slug:"computational-studies-and-biosynthesis-of-natural-products-with-promising-anticancer-properties",totalDownloads:1933,totalCrossrefCites:5,totalDimensionsCites:6,abstract:"We present an overview of computational approaches for the prediction of metabolic pathways by which plants biosynthesise compounds, with a focus on selected very promising anticancer secondary metabolites from floral sources. We also provide an overview of databases for the retrieval of useful genomic data, discussing the strengths and limitations of selected prediction software and the main computational tools (and methods), which could be employed for the investigation of the uncharted routes towards the biosynthesis of some of the identified anticancer metabolites from plant sources, eventually using specific examples to address some knowledge gaps when using these approaches.",book:{id:"5767",slug:"natural-products-and-cancer-drug-discovery",title:"Natural Products and Cancer Drug Discovery",fullTitle:"Natural Products and Cancer Drug Discovery"},signatures:"Aurélien F.A. Moumbock, Conrad V. Simoben, Ludger Wessjohann,\nWolfgang Sippl, Stefan Günther and Fidele Ntie‐Kang",authors:[{id:"177615",title:"Prof.",name:"Ludger",middleName:null,surname:"Aloisius Wessjohann",slug:"ludger-aloisius-wessjohann",fullName:"Ludger Aloisius Wessjohann"},{id:"197160",title:"Dr.",name:"Fidele",middleName:null,surname:"Ntie-Kang",slug:"fidele-ntie-kang",fullName:"Fidele Ntie-Kang"},{id:"197406",title:"Mr.",name:"Conrad Veranso",middleName:null,surname:"Simoben",slug:"conrad-veranso-simoben",fullName:"Conrad Veranso Simoben"},{id:"197408",title:"Prof.",name:"Wolfgang",middleName:null,surname:"Sippl",slug:"wolfgang-sippl",fullName:"Wolfgang Sippl"},{id:"199056",title:"Mr.",name:"Aurelien F. A.",middleName:null,surname:"Moumbock",slug:"aurelien-f.-a.-moumbock",fullName:"Aurelien F. A. Moumbock"},{id:"199057",title:"Prof.",name:"Stefan",middleName:null,surname:"Günther",slug:"stefan-gunther",fullName:"Stefan Günther"}]},{id:"55790",doi:"10.5772/intechopen.68506",title:"Phytocompounds Targeting Cancer Angiogenesis Using the Chorioallantoic Membrane Assay",slug:"phytocompounds-targeting-cancer-angiogenesis-using-the-chorioallantoic-membrane-assay",totalDownloads:1794,totalCrossrefCites:2,totalDimensionsCites:6,abstract:"Cancer is the second cause of mortality worldwide. Angiogenesis is an important process involved in the growth of primary tumors and metastasis. New approaches for controlling the cancer progression and invasiveness can be addressed by limiting the angiogenesis process. An increasingly large number of natural compounds are evaluated as angiogenesis inhibitors. The chorioallantoic membrane (CAM) assay represents an in vivo attractive experimental model for cancer and angiogenesis studies as prescreening to the murine models. Since the discovery of tumor angiogenesis, the CAM has been intensively used in cancer research. The advantages of this in vivo technique are in terms of low time-consuming, costs, and a lower number of sacrificed animals. Currently, a great number of natural compounds are being investigated for their effectiveness in controlling tumor angiogenesis. Potential reducing of angiogenesis has been investigated by our group for pentacyclic triterpenes, in various formulations, and differences in their mechanism were registered. This chapter aims to give an overview on a number of phytocompounds investigated using in vitro, murine models and the chorioallantoic membrane assay as well as to emphasize the use of CAM assay in the study of natural compounds with potential effects in malignancies.",book:{id:"5767",slug:"natural-products-and-cancer-drug-discovery",title:"Natural Products and Cancer Drug Discovery",fullTitle:"Natural Products and Cancer Drug Discovery"},signatures:"Stefana Avram, Roxana Ghiulai, Ioana Zinuca Pavel, Marius Mioc,\nRoxana Babuta, Mirela Voicu, Dorina Coricovac, Corina Danciu,\nCristina Dehelean and Codruta Soica",authors:[{id:"141027",title:"Dr.",name:"Cristina",middleName:null,surname:"Dehelean",slug:"cristina-dehelean",fullName:"Cristina Dehelean"},{id:"173283",title:"Dr.",name:"Dorina",middleName:null,surname:"Coricovac",slug:"dorina-coricovac",fullName:"Dorina Coricovac"},{id:"186372",title:"Prof.",name:"Corina",middleName:null,surname:"Danciu",slug:"corina-danciu",fullName:"Corina Danciu"},{id:"186680",title:"Dr.",name:"Roxana",middleName:null,surname:"Ghiulai",slug:"roxana-ghiulai",fullName:"Roxana Ghiulai"},{id:"197894",title:"Prof.",name:"Codruta",middleName:null,surname:"Soica",slug:"codruta-soica",fullName:"Codruta Soica"},{id:"197929",title:"Dr.",name:"Stefana",middleName:null,surname:"Avram",slug:"stefana-avram",fullName:"Stefana Avram"},{id:"202529",title:"Dr.",name:"Ioana Zinuca",middleName:null,surname:"Pavel",slug:"ioana-zinuca-pavel",fullName:"Ioana Zinuca Pavel"},{id:"205584",title:"Mr.",name:"Marius",middleName:null,surname:"Mioc",slug:"marius-mioc",fullName:"Marius Mioc"},{id:"205585",title:"Dr.",name:"Roxana",middleName:null,surname:"Racoviceanu (Babuta)",slug:"roxana-racoviceanu-(babuta)",fullName:"Roxana Racoviceanu (Babuta)"},{id:"205586",title:"Ms.",name:"Mirela",middleName:null,surname:"Voicu",slug:"mirela-voicu",fullName:"Mirela Voicu"}]},{id:"54745",doi:"10.5772/68131",title:"Lycopene: Multitargeted Applications in Cancer Therapy",slug:"lycopene-multitargeted-applications-in-cancer-therapy",totalDownloads:1849,totalCrossrefCites:2,totalDimensionsCites:5,abstract:"Cancer is an uncontrolled growth and division of cells, leading to significant morbidity and mortality and economic burden to the society. Natural products as anticancer molecules have drawn the attention of researchers and have resulted in the development of many successful anticancer drugs, which include camptothecins, epipodophyllotoxins, vinca alkaloids, and taxanes. Another group of compounds with anti-cancer effects include botanicals (phytochemicals) found in the diet. In recent years, a tomato carotenoid lycopene (LYC) has gained attention for its potential health benefits, especially in prevention and treatment of cancer. The studies suggest that the consumption LYC in food or by itself may reduce cancer risk. However, there are insufficient clinical trial data to support the hypothesis. LYC may play a preventive role in a variety of cancers, especially in prostate cancer. It acts by multiple mechanisms including the regulation of growth factor signalling, cell cycle arrest and/or apoptosis induction, metastasis and angiogenesis, as well as by modulating the anti-inflammatory and phase II detoxification enzymes activities. The effects can be attributed to the unique chemical structure of the carotenoid which confers it a strong antioxidant property. In this chapter, we discuss the chemopreventive and anti-cancer properties of LYC, a dietary carotenoid.”",book:{id:"5767",slug:"natural-products-and-cancer-drug-discovery",title:"Natural Products and Cancer Drug Discovery",fullTitle:"Natural Products and Cancer Drug Discovery"},signatures:"Kazim Sahin, Shakir Ali, Nurhan Sahin, Cemal Orhan and Omer\nKucuk",authors:[{id:"39589",title:"Prof.",name:"Kazim",middleName:null,surname:"Sahin",slug:"kazim-sahin",fullName:"Kazim Sahin"}]}],mostDownloadedChaptersLast30Days:[{id:"54281",title:"Towards Metabolic Engineering of Podophyllotoxin Production",slug:"towards-metabolic-engineering-of-podophyllotoxin-production",totalDownloads:1676,totalCrossrefCites:3,totalDimensionsCites:3,abstract:"The pharmaceutically important anticancer drugs etoposide and teniposide are derived from podophyllotoxin, a natural product isolated from roots of Podophyllum hexandrum growing in the wild. The overexploitation of this endangered plant has led to the search for alternative sources. Metabolic engineering aimed at constructing the pathway in another host cell is very appealing, but for that approach, an in-depth knowledge of the pathway toward podophyllotoxin is necessary. In this chapter, we give an overview of the lignan pathway leading to podophyllotoxin. Subsequently, we will discuss the engineering possibilities to produce podophyllotoxin in a heterologous host. This will require detailed knowledge on the cellular localization of the enzymes of the lignan biosynthesis pathway. Due to the high number of enzymes involved and the scarce information on compartmentalization, the heterologous production of podophyllotoxin still remains a tremendous challenge. At the moment, research is focusing on the last step(s) in the conversion of deoxypodophyllotoxin to (epi)podophyllotoxin and 4′-demethyldesoxypodophyllotoxin by plant cytochromes.",book:{id:"5767",slug:"natural-products-and-cancer-drug-discovery",title:"Natural Products and Cancer Drug Discovery",fullTitle:"Natural Products and Cancer Drug Discovery"},signatures:"Christel L. C. Seegers, Rita Setroikromo and Wim J. Quax",authors:[{id:"196901",title:"Prof.",name:"Wim",middleName:null,surname:"Quax",slug:"wim-quax",fullName:"Wim Quax"},{id:"197867",title:"MSc.",name:"Christel L.C.",middleName:null,surname:"Seegers",slug:"christel-l.c.-seegers",fullName:"Christel L.C. Seegers"},{id:"197868",title:"Ms.",name:"Rita",middleName:null,surname:"Setroikromo",slug:"rita-setroikromo",fullName:"Rita Setroikromo"}]},{id:"55831",title:"African Plants with Antiproliferative Properties",slug:"african-plants-with-antiproliferative-properties",totalDownloads:2079,totalCrossrefCites:0,totalDimensionsCites:1,abstract:"Plant-derived compounds have been an integral component in man’s quest to discover ideal anticancer agents. A number of new agents are currently in clinical development with promising selective activity against cancer cell lines and cancer-related molecular targets. This book chapter discusses 14 of such compounds isolated from African plants from 15 plant families. Also contained in this book chapter are compounds from African plants that hold prospect as potential anticancer agents as informed by their in vitro and in vivo preclinical studies. It is, therefore, worthwhile that researchers in the African continent and the world over should keep on working on identifying biomolecules with potential in cancer management.",book:{id:"5767",slug:"natural-products-and-cancer-drug-discovery",title:"Natural Products and Cancer Drug Discovery",fullTitle:"Natural Products and Cancer Drug Discovery"},signatures:"Newman Osafo, Yaw Duah Boakye, Christian Agyare, Samuel\nObeng, Judith Edem Foli and Prince Amankwaah Baffour Minkah",authors:[{id:"182058",title:"Dr.",name:"Christian",middleName:null,surname:"Agyare",slug:"christian-agyare",fullName:"Christian Agyare"},{id:"186987",title:"Dr.",name:"Yaw Duah",middleName:null,surname:"Boakye",slug:"yaw-duah-boakye",fullName:"Yaw Duah Boakye"},{id:"196452",title:"Dr.",name:"Newman",middleName:null,surname:"Osafo",slug:"newman-osafo",fullName:"Newman Osafo"},{id:"201381",title:"Ms.",name:"Judith",middleName:null,surname:"Edem Foli",slug:"judith-edem-foli",fullName:"Judith Edem Foli"},{id:"201382",title:"Mr.",name:"Prince",middleName:"Amankwah Baffour",surname:"Minkah",slug:"prince-minkah",fullName:"Prince Minkah"},{id:"204731",title:"Mr.",name:"Samuel",middleName:null,surname:"Obeng",slug:"samuel-obeng",fullName:"Samuel Obeng"}]},{id:"54388",title:"Computational Studies and Biosynthesis of Natural Products with Promising Anticancer Properties",slug:"computational-studies-and-biosynthesis-of-natural-products-with-promising-anticancer-properties",totalDownloads:1933,totalCrossrefCites:5,totalDimensionsCites:6,abstract:"We present an overview of computational approaches for the prediction of metabolic pathways by which plants biosynthesise compounds, with a focus on selected very promising anticancer secondary metabolites from floral sources. We also provide an overview of databases for the retrieval of useful genomic data, discussing the strengths and limitations of selected prediction software and the main computational tools (and methods), which could be employed for the investigation of the uncharted routes towards the biosynthesis of some of the identified anticancer metabolites from plant sources, eventually using specific examples to address some knowledge gaps when using these approaches.",book:{id:"5767",slug:"natural-products-and-cancer-drug-discovery",title:"Natural Products and Cancer Drug Discovery",fullTitle:"Natural Products and Cancer Drug Discovery"},signatures:"Aurélien F.A. Moumbock, Conrad V. Simoben, Ludger Wessjohann,\nWolfgang Sippl, Stefan Günther and Fidele Ntie‐Kang",authors:[{id:"177615",title:"Prof.",name:"Ludger",middleName:null,surname:"Aloisius Wessjohann",slug:"ludger-aloisius-wessjohann",fullName:"Ludger Aloisius Wessjohann"},{id:"197160",title:"Dr.",name:"Fidele",middleName:null,surname:"Ntie-Kang",slug:"fidele-ntie-kang",fullName:"Fidele Ntie-Kang"},{id:"197406",title:"Mr.",name:"Conrad Veranso",middleName:null,surname:"Simoben",slug:"conrad-veranso-simoben",fullName:"Conrad Veranso Simoben"},{id:"197408",title:"Prof.",name:"Wolfgang",middleName:null,surname:"Sippl",slug:"wolfgang-sippl",fullName:"Wolfgang Sippl"},{id:"199056",title:"Mr.",name:"Aurelien F. A.",middleName:null,surname:"Moumbock",slug:"aurelien-f.-a.-moumbock",fullName:"Aurelien F. A. Moumbock"},{id:"199057",title:"Prof.",name:"Stefan",middleName:null,surname:"Günther",slug:"stefan-gunther",fullName:"Stefan Günther"}]},{id:"55922",title:"Lupan-Skeleton Pentacyclic Triterpenes with Activity against Skin Cancer: Preclinical Trials Evolution",slug:"lupan-skeleton-pentacyclic-triterpenes-with-activity-against-skin-cancer-preclinical-trials-evolutio",totalDownloads:1778,totalCrossrefCites:0,totalDimensionsCites:3,abstract:"Skin cancer is an increasingly frequent pathology, with a dangerous high percentage of malignant melanoma. The use of synthetic chemotherapy raises the problem of severe adverse effects and the development of resistance to treatment. Therefore, the use of natural therapies became the focus of numerous research groups due to their high efficacy and lower systemic adverse effects. Among natural products evaluated as therapeutical agents against skin cancer, betulinic acid was emphasized as a highly selective anti-melanoma agent and is currently undergoing phase II clinical trials as topical application. Several other pentacyclic triterpenes exhibit antiproliferative activities. This chapter aims to present the latest main discoveries in the class of pentacyclic triterenes with antitumor effect and the evolution of their preclinical trials. Furthermore, it includes reports on plant sources containing pentacyclic triterpenes, as well as the main possibilities of their water solubilization and cancer cell targeting. A review on recent data regarding mechanisms of action at cellular and molecular levels complements information on the outstanding medicinal potential of these compounds.",book:{id:"5730",slug:"unique-aspects-of-anti-cancer-drug-development",title:"Unique Aspects of Anti-cancer Drug Development",fullTitle:"Unique Aspects of Anti-cancer Drug Development"},signatures:"Codruţa Şoica, Diana Antal, Florina Andrica, Roxana Băbuţa, Alina\nMoacă, Florina Ardelean, Roxana Ghiulai, Stefana Avram, Corina\nDanciu, Dorina Coricovac, Cristina Dehelean and Virgil Păunescu",authors:[{id:"141027",title:"Dr.",name:"Cristina",middleName:null,surname:"Dehelean",slug:"cristina-dehelean",fullName:"Cristina Dehelean"},{id:"173283",title:"Dr.",name:"Dorina",middleName:null,surname:"Coricovac",slug:"dorina-coricovac",fullName:"Dorina Coricovac"},{id:"186372",title:"Prof.",name:"Corina",middleName:null,surname:"Danciu",slug:"corina-danciu",fullName:"Corina Danciu"},{id:"186678",title:"Dr.",name:"Codruta",middleName:null,surname:"Soica",slug:"codruta-soica",fullName:"Codruta Soica"},{id:"186679",title:"Dr.",name:"Diana",middleName:null,surname:"Antal",slug:"diana-antal",fullName:"Diana Antal"},{id:"186680",title:"Dr.",name:"Roxana",middleName:null,surname:"Ghiulai",slug:"roxana-ghiulai",fullName:"Roxana Ghiulai"},{id:"202526",title:"Dr.",name:"Stefana",middleName:null,surname:"Avram",slug:"stefana-avram",fullName:"Stefana Avram"},{id:"205282",title:"Dr.",name:"Florina",middleName:null,surname:"Ardelean",slug:"florina-ardelean",fullName:"Florina Ardelean"},{id:"205679",title:"Dr.",name:"Florina",middleName:null,surname:"Andrica",slug:"florina-andrica",fullName:"Florina Andrica"},{id:"205680",title:"Dr.",name:"Roxana",middleName:null,surname:"Racoviceanu (Babuta)",slug:"roxana-racoviceanu-(babuta)",fullName:"Roxana Racoviceanu (Babuta)"},{id:"205681",title:"Dr.",name:"Alina",middleName:null,surname:"Moaca",slug:"alina-moaca",fullName:"Alina Moaca"}]},{id:"55925",title:"Endophytic Fungi as Alternative and Reliable Sources for Potent Anticancer Agents",slug:"endophytic-fungi-as-alternative-and-reliable-sources-for-potent-anticancer-agents",totalDownloads:1973,totalCrossrefCites:3,totalDimensionsCites:8,abstract:"In comparison with other natural sources like plants, highly diverse microorganisms are narrowly explored, especially with respect to their limitless potentials as repositories of exceptionally bioactive natural products. Of these organisms, fungi inhabiting tissues of plant in a noninvasive relationship (endophytic fungi) have proven undeniably useful and unmatchable as sources of potent bioactive molecules against several diseases such as cancer and related ailments. In general terms, endophytic fungi are highly prevalent organisms found in the tissue (intracellular or intercellular) of plants and at least for reasonable portion of their lives. It has been proven that virtually every plant, irrespective of habitat and climate, plays host to wide varieties of endophytes. Endophytic fungi produce metabolites produced by different biosynthetic pathways to that of the host plant, and this robustness equips them to synthesize unlimited structural entities and scaffolds of diverse classes. Interestingly too, the cohabitation/culture of these fungi with certain bacteria offers even stronger hopes for anticancer drug discovery. The endless need for potent drugs has necessitated the search of bioactive molecules from several sources, and endophytic fungi appear to be a recipe. This chapter is an attempt to present the current trend of research with these very promising organisms.",book:{id:"5767",slug:"natural-products-and-cancer-drug-discovery",title:"Natural Products and Cancer Drug Discovery",fullTitle:"Natural Products and Cancer Drug Discovery"},signatures:"Edwin O. Omeje, Joy E. Ahomafor, Theophilus U. Onyekaba, Philip\nO. Monioro, Ibekwe Nneka, Sunday Onyeloni, Charles Chime and\nJonathan C. Eboka",authors:[{id:"197824",title:"Dr.",name:"Edwin",middleName:"Ogechukwu",surname:"Omeje",slug:"edwin-omeje",fullName:"Edwin Omeje"},{id:"198038",title:"Dr.",name:"Nneka",middleName:null,surname:"Ibekwe",slug:"nneka-ibekwe",fullName:"Nneka Ibekwe"},{id:"198039",title:"MSc.",name:"Joy",middleName:null,surname:"Ahomafor",slug:"joy-ahomafor",fullName:"Joy Ahomafor"},{id:"198040",title:"Mr.",name:"Sunday",middleName:null,surname:"Onyeloni",slug:"sunday-onyeloni",fullName:"Sunday Onyeloni"},{id:"198041",title:"Mr.",name:"Philip",middleName:null,surname:"Monioro",slug:"philip-monioro",fullName:"Philip Monioro"},{id:"204822",title:"Dr.",name:"Charles",middleName:null,surname:"Chime",slug:"charles-chime",fullName:"Charles Chime"}]}],onlineFirstChaptersFilter:{topicId:"1076",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:0,limit:8,total:null},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:87,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:98,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:27,numberOfPublishedChapters:287,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:9,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:11,numberOfPublishedChapters:139,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:8,numberOfPublishedChapters:129,numberOfOpenTopics:0,numberOfUpcomingTopics:2,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!1},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:107,numberOfOpenTopics:3,numberOfUpcomingTopics:1,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:10,numberOfPublishedChapters:103,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:12,numberOfOpenTopics:2,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:0,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!1},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:0,numberOfPublishedChapters:10,numberOfOpenTopics:4,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{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"}}}},{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"}}}}]},series:{item:{id:"10",title:"Physiology",doi:"10.5772/intechopen.72796",issn:"2631-8261",scope:"Modern physiology requires a comprehensive understanding of the integration of tissues and organs throughout the mammalian body, including the cooperation between structure and function at the cellular and molecular levels governed by gene and protein expression. While a daunting task, learning is facilitated by identifying common and effective signaling pathways mediated by a variety of factors employed by nature to preserve and sustain homeostatic life. \r\nAs a leading example, the cellular interaction between intracellular concentration of Ca+2 increases, and changes in plasma membrane potential is integral for coordinating blood flow, governing the exocytosis of neurotransmitters, and modulating gene expression and cell effector secretory functions. Furthermore, in this manner, understanding the systemic interaction between the cardiovascular and nervous systems has become more important than ever as human populations' life prolongation, aging and mechanisms of cellular oxidative signaling are utilised for sustaining life. \r\nAltogether, physiological research enables our identification of distinct and precise points of transition from health to the development of multimorbidity throughout the inevitable aging disorders (e.g., diabetes, hypertension, chronic kidney disease, heart failure, peptic ulcer, inflammatory bowel disease, age-related macular degeneration, cancer). With consideration of all organ systems (e.g., brain, heart, lung, gut, skeletal and smooth muscle, liver, pancreas, kidney, eye) and the interactions thereof, this Physiology Series will address the goals of resolving (1) Aging physiology and chronic disease progression (2) Examination of key cellular pathways as they relate to calcium, oxidative stress, and electrical signaling, and (3) how changes in plasma membrane produced by lipid peroxidation products can affect aging physiology, covering new research in the area of cell, human, plant and animal physiology.",coverUrl:"https://cdn.intechopen.com/series/covers/10.jpg",latestPublicationDate:"May 14th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:11,editor:{id:"35854",title:"Prof.",name:"Tomasz",middleName:null,surname:"Brzozowski",slug:"tomasz-brzozowski",fullName:"Tomasz Brzozowski",profilePictureURL:"https://mts.intechopen.com/storage/users/35854/images/system/35854.jpg",biography:"Prof. Dr. Thomas Brzozowski works as a professor of Human Physiology and is currently Chairman at the Department of Physiology and is V-Dean of the Medical Faculty at Jagiellonian University Medical College, Cracow, Poland. His primary area of interest is physiology and pathophysiology of the gastrointestinal (GI) tract, with the major focus on the mechanism of GI mucosal defense, protection, and ulcer healing. He was a postdoctoral NIH fellow at the University of California and the Gastroenterology VA Medical Center, Irvine, Long Beach, CA, USA, and at the Gastroenterology Clinics Erlangen-Nuremberg and Munster in Germany. He has published 290 original articles in some of the most prestigious scientific journals and seven book chapters on the pathophysiology of the GI tract, gastroprotection, ulcer healing, drug therapy of peptic ulcers, hormonal regulation of the gut, and inflammatory bowel disease.",institutionString:null,institution:{name:"Jagiellonian University",institutionURL:null,country:{name:"Poland"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:4,paginationItems:[{id:"10",title:"Animal Physiology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/10.jpg",isOpenForSubmission:!0,annualVolume:11406,editor:{id:"202192",title:"Dr.",name:"Catrin",middleName:null,surname:"Rutland",slug:"catrin-rutland",fullName:"Catrin Rutland",profilePictureURL:"https://mts.intechopen.com/storage/users/202192/images/system/202192.png",biography:"Catrin Rutland is an Associate Professor of Anatomy and Developmental Genetics at the University of Nottingham, UK. She obtained a BSc from the University of Derby, England, a master’s degree from Technische Universität München, Germany, and a Ph.D. from the University of Nottingham. She undertook a post-doctoral research fellowship in the School of Medicine before accepting tenure in Veterinary Medicine and Science. Dr. Rutland also obtained an MMedSci (Medical Education) and a Postgraduate Certificate in Higher Education (PGCHE). She is the author of more than sixty peer-reviewed journal articles, twelve books/book chapters, and more than 100 research abstracts in cardiovascular biology and oncology. She is a board member of the European Association of Veterinary Anatomists, Fellow of the Anatomical Society, and Senior Fellow of the Higher Education Academy. Dr. Rutland has also written popular science books for the public. https://orcid.org/0000-0002-2009-4898. www.nottingham.ac.uk/vet/people/catrin.rutland",institutionString:null,institution:{name:"University of Nottingham",institutionURL:null,country:{name:"United Kingdom"}}},editorTwo:null,editorThree:null},{id:"11",title:"Cell Physiology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/11.jpg",isOpenForSubmission:!0,annualVolume:11407,editor:{id:"133493",title:"Prof.",name:"Angel",middleName:null,surname:"Catala",slug:"angel-catala",fullName:"Angel Catala",profilePictureURL:"https://mts.intechopen.com/storage/users/133493/images/3091_n.jpg",biography:"Prof. Dr. Angel Catalá \r\nShort Biography Angel Catalá was born in Rodeo (San Juan, Argentina). He studied \r\nchemistry at the Universidad Nacional de La Plata, Argentina, where received aPh.D. degree in chemistry (Biological Branch) in 1965. 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